WO2021025018A1 - Pharmaceutical composition for therapy and/or prophylaxis of colorectal cancer - Google Patents

Pharmaceutical composition for therapy and/or prophylaxis of colorectal cancer Download PDF

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Publication number
WO2021025018A1
WO2021025018A1 PCT/JP2020/029832 JP2020029832W WO2021025018A1 WO 2021025018 A1 WO2021025018 A1 WO 2021025018A1 JP 2020029832 W JP2020029832 W JP 2020029832W WO 2021025018 A1 WO2021025018 A1 WO 2021025018A1
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Prior art keywords
cancer
nfkbiz
item
composition according
legnes
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PCT/JP2020/029832
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French (fr)
Japanese (ja)
Inventor
誠司 小川
伸之 垣内
大石　潤
良作 稲垣
上田　豊
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国立大学法人京都大学
大日本住友製薬株式会社
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Publication of WO2021025018A1 publication Critical patent/WO2021025018A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present disclosure relates to a pharmaceutical composition for treating and / or preventing cancer, which comprises an NFKBIZ inhibitor and / or a Regnes 1 enhancer. It is also intended to provide a screening method for selecting substances or factors that treat and / or prevent cancer.
  • Non-Patent Document 1 Chronic inflammation is a condition in which the activities of inflammatory substances, cells, etc. do not converge even though the tissue abnormalities have been resolved, making it more susceptible to various diseases and becoming a serious risk factor for carcinogenesis.
  • Non-Patent Document 2 Chronic inflammation is characterized by an excessive immune response, repeated tissue damage and tissue repair. Among the cells that make up tissue repair, the presence of cells with gene mutations related to carcinogenesis has been reported, and repeated tissue damage and tissue repair with aging further increases the risk of carcinogenesis. It is known to increase (Non-Patent Document 2).
  • IBD Inflammatory bowel disease
  • Ulcerative colitis is a major inflammatory bowel disease, and is characterized by a pathological condition in which chronic inflammation occurs in a wide range of intestinal tracts, resulting in damage to the intestinal mucosa and intractable ulcers.
  • enterative colitis enterative colitis-related carcinogenesis in ulcerative colitis; epithelial associated carcinoma (CAC)
  • CAC epithelial associated carcinoma
  • the present disclosure relates to a pharmaceutical composition for treating and / or preventing cancer, which comprises an NFKBIZ inhibitor and / or a Regnes 1 enhancer. It is also intended to provide a screening method for selecting substances that treat and / or prevent cancer.
  • the present inventors have found that the NFKBIZ inhibitor and / or the Regnes 1 enhancer show a special growth inhibitory effect on cancer.
  • the present inventors have identified that the large intestine mucosal cells of patients with ulcerative colitis have a specific gene mutation, and the gene mutation is "characteristic of inflammatory bowel disease.” It was found that it is deeply involved in "repeated tissue damage and tissue regeneration related to pathological conditions" and "development and proliferation of inflammatory carcinogenesis”. Among these gene mutations, the NFKBIZ deficient mutation suppresses the production of inflammatory cytokines in tissues in a mouse enteritis model, alleviates enteritis associated with tissue destruction and regeneration, and causes carcinogenesis and cancer cells in the inflammatory mucosa. It was found to suppress proliferation.
  • NFKBIZ is an epoch-making drug discovery for the treatment and / or prevention of colorectal cancer. I found it to be a target.
  • the present disclosure includes:
  • a pharmaceutical composition for treating and / or preventing cancer which comprises an NFKBIZ inhibitor.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, stomach cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant mela
  • Item 7 The pharmaceutical composition according to Item 6, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 12 The pharmaceutical composition according to any one of Items 1 to 11, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence. ..
  • Item 16 The pharmaceutical composition according to Item 14, wherein the inhibitor is an anti-NFKBIZ antibody.
  • Item 17 The pharmaceutical composition according to Item 14, wherein the inhibitor is a low molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • a pharmaceutical composition for treating and / or preventing cancer which comprises a Legnes 1 enhancer.
  • Item 20 The pharmaceutical composition according to Item 19, wherein the cancer is a cancer associated with chronic inflammation.
  • Item 21 The pharmaceutical composition according to Item 20, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item 22 The pharmaceutical composition according to Item 21, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant mel
  • Item 25 The pharmaceutical composition according to Item 24, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 28 The pharmaceutical composition according to any one of Items 19 to 27, wherein the enhancer inhibits a legnes monodegrading enzyme.
  • Item 29 The pharmaceutical composition according to Item 28, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • Item 30 The pharmaceutical composition according to Item 29, wherein the enhancer has an E3 ligase inhibitory activity.
  • Item 31 The pharmaceutical composition according to any one of Items 19 to 30, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • Item 32 The pharmaceutical composition according to Item 31, wherein the enhancer is a nucleic acid.
  • Item 33 The pharmaceutical composition according to Item 26, wherein the enhancer is an antibody.
  • Item 34 The pharmaceutical composition according to Item 26, wherein the enhancer is a low molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • a pharmaceutical composition for treating and / or preventing cancer which comprises an E3 ligase inhibitor.
  • Item 37 The pharmaceutical composition according to Item 36, wherein the cancer is a cancer associated with chronic inflammation.
  • Item 38 The pharmaceutical composition according to Item 37, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item 39 The pharmaceutical composition according to Item 38, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant mel
  • Item 41 The pharmaceutical composition according to Item 40, wherein the cancer is colorectal cancer.
  • Item 42 The pharmaceutical composition according to Item 41, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 43 The pharmaceutical composition according to any one of Items 36 to 42, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  • Item 44 The pharmaceutical composition according to any one of Items 36 to 43, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • Item 45 The pharmaceutical composition according to Item 44, wherein the inhibitor is a nucleic acid.
  • Item 46 The pharmaceutical composition according to Item 44, wherein the inhibitor is an anti-E3 ligase antibody.
  • Item 47 The pharmaceutical composition according to Item 44, wherein the inhibitor is a low molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • NFKBIZ inhibitor for use in the treatment and / or prevention of cancer.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, stomach cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant mel
  • NFKBIZ inhibitor for use according to any one of Items A1 to A13, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant lymphoma, plasma
  • Item A25 Legnes 1 for use according to item A24, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer. Enhancer.
  • legnes 1 enhancer for use according to item A28, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • legnes 1 enhancer for use according to item A29, wherein the enhancer has an E3 ligase inhibitory activity.
  • the legnace 1 enhancer for use according to any one of items A19 to A31, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • legnes 1 enhancer for use according to item A31, wherein the enhancer is a nucleic acid.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • E3 ligase inhibitor for use in the treatment and / or prevention of cancer.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer.
  • Esophageal cancer thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis Item A36 to include at least one selected from the group consisting of germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma.
  • E3 ligase inhibitor for use according to any one of A39.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, stomach cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant mel
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B17, which is benzoic acid (GS143).
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, stomach cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant mel
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B34, which is benzoic acid (GS143).
  • a method for treating and / or preventing cancer in a subject which comprises a step of administering an effective amount of an E3 ligase inhibitor to the subject.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B47, which is benzoic acid (GS143).
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • Il -the use according to item C17, which is benzoic acid (GS143).
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • Il -the use according to item C34, which is benzoic acid (GS143).
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer.
  • Esophageal cancer thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis Item C36 to include at least one selected from the group consisting of germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. Use according to any one of C39.
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • Il -the use according to item C47, which is benzoic acid (GS143).
  • a subject in which the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ is increased is (1) A step of measuring the expression and / or activity of the NFKBIZ gene in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ. 49.
  • Item 51 The composition according to item 49 or 50, wherein the cancer is a cancer associated with chronic inflammation.
  • Item 52 The composition according to Item 51, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item 53 The composition according to Item 52, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant lymphoma
  • Item 56 The composition according to Item 55, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 58 The composition according to any one of Items 49 to 57, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
  • Item 59 The composition according to any one of Items 49 to 58, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
  • Item 61 The composition according to any one of Items 49 to 60, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence.
  • Item 62 The composition according to any one of Items 49 to 61, wherein the inhibitor has an E3 ligase inhibitory activity.
  • Item 65 The composition according to Item 63, wherein the inhibitor is an anti-NFKBIZ antibody.
  • Item 66 The composition according to Item 63, wherein the inhibitor is a low molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • NFKBIZ inhibitor for use in the treatment and / or prevention of cancer, wherein the NFKBIZ inhibitor is used in subjects with increased expression of NFKBIZ and / or increased activity of NFKBIZ.
  • An NFKBIZ inhibitor characterized in that it is administered.
  • a subject in which the expression of NFKBIZ is increased and / or the activity of NFKBIZ is increased is (1) A step of measuring the expression and / or activity of the NFKBIZ gene in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ.
  • NFKBIZ inhibitor for use according to item A49 characterized in that it is determined in a step comprising determining that is elevated.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • NFKBIZ inhibitor for use according to any one of items A49 to A57, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
  • NFKBIZ inhibitor for use according to any one of items A49 to A58, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
  • NFKBIZ inhibitor for use according to any one of Items A49 to A62, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • a method for treating and / or preventing cancer in a subject which comprises the step of administering to the subject an effective amount of NFKBIZ inhibitor, in which the subject has increased expression of NFKBIZ and / or.
  • a method of being a subject with elevated NFKBIZ activity comprises the step of administering to the subject an effective amount of NFKBIZ inhibitor, in which the subject has increased expression of NFKBIZ and / or.
  • (2) A step of comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ.
  • B49 The method of item B49, further comprising a step of determining that is rising.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B66, which is benzoic acid (GS143).
  • a subject in which the expression of NFKBIZ is increased and / or the activity of NFKBIZ is increased is (1) A step of measuring the expression and / or activity of the NFKBIZ gene in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • Il -the use according to item C66, which is benzoic acid (GS143).
  • Item 68 A method for predicting the efficacy of an NFKBIZ inhibitor on a subject, which comprises measuring the gene expression of NFKBIZ and / or the activity of NFKBIZ in the cancer cells of the subject.
  • Item 6 The method according to Item 68, which is determined in a step including a step of determining that the activity of NFKBIZ is increased.
  • Item 70 The method according to item 68 or 69, wherein the cancer is a cancer associated with chronic inflammation.
  • Item 72 The method according to Item 71, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • Item 75 The method of item 74, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 7 The method according to any one of Items 68 to 75, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  • Item 78 The method according to any one of Items 68 to 77, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
  • Item 79 The method according to any one of Items 68 to 78, wherein the inhibitor inhibits the binding between NFKBIZ and p50.
  • Item 80 The method according to any one of Items 68 to 79, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence.
  • Item 8 The method according to any one of Items 68 to 79, wherein the inhibitor has an E3 ligase inhibitory activity.
  • Item 8 The method according to any one of Items 68 to 81, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • Item 8 The method according to Item 82, wherein the inhibitor is a nucleic acid.
  • Item 85 The method according to Item 82, wherein the inhibitor is a low molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • [Item 87] A method for screening an NFKBIZ inhibitor. (1) A step of measuring the gene expression and / or activity of NFKBIZ without allowing an inhibitor candidate to act on cancer cells. (2) The step of measuring the gene expression and / or activity of NFKBIZ after allowing the inhibitor candidate to act on the cancer cells, and when the results of (3) and (2) are smaller than the results of (1). In addition, a step of determining the inhibitor candidate as an NFKBIZ inhibitor, Including methods.
  • [Item 88] A method for screening a therapeutic and / or preventive agent for cancer.
  • (1) A step of measuring gene expression and / or activity of NFKBIZ without allowing a therapeutic and / or prophylactic agent candidate to act on cancer cells.
  • (2) The steps of measuring the gene expression and / or activity of NFKBIZ after allowing the therapeutic and / or prophylactic agent candidate to act on the cancer cells, and the results of (3) and (2) are the results of (1).
  • a method for screening a substance that reduces the expression level of NFKBIZ and / or a substance that suppresses the function of NFKBIZ (1) A step of measuring the gene expression and / or activity of NFKBIZ without allowing a test substance to act on cancer cells. (2) The step of measuring the gene expression and / or activity of NFKBIZ after allowing the test substance to act on the cancer cells, and when the results of (3) and (2) are smaller than the results of (1). In addition, a step of determining that the test substance is a substance that reduces the expression level of NFKBIZ and / or a substance that suppresses the function of NFKBIZ. Including methods.
  • Item 90 The method according to any one of Items 87 to 89, wherein the cancer is a cancer associated with chronic inflammation.
  • Item 9 The method according to any one of Items 87 to 90, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item 92 The method according to Item 91, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 9 The method according to any one of Items 87 to 95, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  • Item 9 The method according to any one of Items 87 to 97, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
  • Item 9 The method according to any one of Items 87 to 98, wherein the inhibitor inhibits the binding between NFKBIZ and p50.
  • Item 10 The method according to any one of Items 87 to 100, wherein the inhibitor has an E3 ligase inhibitory activity.
  • Item 10 The method according to any one of Items 87 to 101, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • Item 10 The method according to Item 102, wherein the inhibitor is a nucleic acid.
  • Item 105 The method according to Item 102, wherein the inhibitor is a low molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • Treatment and / or treatment of cancer including a Legnes 1 enhancer, characterized in that it is administered to a subject with reduced expression of Legnes 1 and / or decreased activity of Legnes 1.
  • a pharmaceutical composition for prevention is provided.
  • a subject whose expression of Legnes 1 is reduced and / or whose activity of Legnes 1 is reduced is (1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased.
  • Item 10 The composition according to Item 107, which is determined by a step including a step.
  • Item 110 The composition according to Item 109, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item 11 The composition according to Item 110, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • composition according to Item 113, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 16 The composition according to any one of Items 107 to 115, wherein the enhancer enhances the activity of Legnes 1.
  • Item 17 The composition according to any one of Items 107 to 116, wherein the enhancer inhibits a legnes monodegrading enzyme.
  • legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • Item 119 The composition according to any one of Items 107 to 118, wherein the enhancer has an E3 ligase inhibitory activity.
  • Item 120 The composition according to any one of Items 107 to 119, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • Item 12 The composition according to Item 120, wherein the enhancer is a nucleic acid.
  • Item 122 The composition according to Item 120, wherein the enhancer is an antibody.
  • Item 123 The composition according to Item 120, wherein the enhancer is a low molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • a subject whose expression of Legnes 1 is reduced and / or whose activity of Legnes 1 is reduced is (1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of legnes 1 quantified in (1) with the expression and / or activity of legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased.
  • the Legnes 1 enhancer for use according to item A107 characterized in that it is determined in a process that includes a process.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer,
  • Item A114 Legnes 1 for use according to item A113, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer. Enhancer.
  • legnes 1 enhancer for use according to any one of items A107 to 115, wherein the enhancer enhances the activity of legnes 1.
  • legnes 1 enhancer for use according to item A117, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • legnes 1 enhancer for use according to any one of items A107 to A118, wherein the enhancer has an E3 ligase inhibitory activity.
  • the legnace 1 enhancer for use according to any one of items A107 to A119, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • legnes 1 enhancer for use according to item A120, wherein the enhancer is a nucleic acid.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • a method for treating and / or preventing cancer in a subject which comprises the step of administering an effective amount of Legnes 1 enhancer to the subject, and the subject has decreased expression of Legnes 1. / Or a method in which the activity of legnes 1 is reduced.
  • [Item B108] (1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased.
  • the method of item B107 further comprising a step.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer,
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item B118 The method according to Item B117, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B123, which is benzoic acid (GS143).
  • legnes 1 enhancer in the manufacture of a drug for the treatment and / or prevention of cancer, wherein the drug has reduced expression of legnes 1 and / or activity of legnes 1.
  • Use characterized by being administered to a declining subject.
  • a subject whose expression of Legnes 1 is reduced and / or whose activity of Legnes 1 is reduced is (1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased.
  • Item 6 The use according to item C107, which is determined in a process including the process.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer,
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • Il -the use according to item C123, which is benzoic acid (GS143).
  • a method for predicting the effectiveness of a Legnes 1 enhancer on a subject which comprises measuring the expression and / or activity of Legnes 1 in the cancer cells of the subject.
  • Item 126 Measurement of the expression and / or activity of Legnes 1 in the cancer cells (1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased. Item 125. The method according to Item 125, which is determined by a step including the step.
  • Item 128 The method according to Item 127, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item 129 The method according to Item 128, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant mel
  • Item 132 The method of item 131, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • Item 137 The method according to any one of Items 125 to 136, wherein the enhancer has an E3 ligase inhibitory activity.
  • Item 138 The method according to any one of Items 125 to 137, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • Item 139 The method according to Item 138, wherein the enhancer is a nucleic acid.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • [Item 143] A method for screening a Legnes 1 enhancer. (1) A step of measuring the expression and / or activity of Legnes 1 without allowing an enhancer candidate to act on cancer cells. (2) A step of measuring the expression and / or activity of Legnes 1 after allowing the enhancer candidate to act on the cancer cells, and when the results of (3) and (2) are larger than the results of (1). In addition, a step of determining the enhancer candidate as a legnace 1 enhancer, Including methods.
  • a method for screening a therapeutic and / or preventive agent for cancer (1) A step of measuring the expression and / or activity of Legnes 1 without allowing a therapeutic and / or prophylactic agent candidate to act on cancer cells. (2) The steps of measuring the expression and / or activity of Legnes 1 after allowing the therapeutic and / or prophylactic agent candidate to act on the cancer cells, and the results of (3) and (2) are the results of (1). A step of determining the therapeutic and / or prophylactic agent candidate as a cancer therapeutic and / or prophylactic agent if it is greater than the result. Including methods.
  • (1) A step of measuring the activity of Legnes 1 without allowing a test substance to act on cancer cells.
  • (2) The step of measuring the activity of Regnes 1 after allowing the test substance to act on the cancer cells, and when the results of (3) and (2) are larger than the results of (1), the test is performed.
  • Item 147 The method according to Item 146, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item 148 The method according to Item 147, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • Item 15 The method according to Item 150, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 153 The method according to any one of Items 143 to 152, wherein the enhancer enhances the activity of Legnes 1.
  • Item 154 The method according to any one of Items 143 to 153, wherein the enhancer inhibits a legnes monodegrading enzyme.
  • legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • Item 156 The method according to any one of Items 143 to 155, wherein the enhancer has an E3 ligase inhibitory activity.
  • Item 157 The method according to any one of Items 143 to 156, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • Item 158 The method according to Item 157, wherein the enhancer is a nucleic acid.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • the E3 ligase inhibitor for use according to item D1 wherein the cancer is a cancer associated with chronic inflammation.
  • the E3 ligase inhibitor for use according to item D2 wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from
  • E3 ligase inhibitor for use according to any one of items D1 to D4.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl). )-Benzoic acid (GS143), an E3 ligase inhibitor for use according to item D12.
  • E1 The use of an E3 ligase inhibitor in the manufacture of a drug for the treatment and / or prevention of cancer, wherein the drug has increased expression of E3 ligase and / or activity of E3 ligase. Use, characterized by being administered to subjects with elevated levels.
  • Item E2 The use according to Item E1, wherein the cancer is a cancer associated with chronic inflammation.
  • Item E3 The use according to Item E2, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item E4 The use according to Item E3, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant lymphoma, plasma
  • NFKBIZ inhibitors of the present disclosure are effective in the treatment and / or prevention of cancer, particularly in the treatment and prevention of colorectal cancer. / Or effective for prevention.
  • the Regnes 1 enhancer of the present disclosure (for example, a substance that enhances the activity of Legnes 1) is effective for the treatment and / or prevention of cancer, and is particularly effective for the treatment and / or prevention of colorectal cancer.
  • a substance that reduces the expression level of NFKBIZ (for example, a substance that reduces the expression level of NFKBIZ, and / or a substance that suppresses the function of NFKBIZ) by measuring the gene expression and / or activity of NFKBIZ in cancer cells derived from a subject. ) Can be predicted for effective patients.
  • a Regnes 1 enhancer for example, a substance that enhances the activity of Legnes 1
  • a patient for whom a Regnes 1 enhancer for example, a substance that enhances the activity of Legnes 1 is effective by measuring the expression and / or activity of Legnes 1 in cancer cells derived from a subject. it can.
  • NFKBIZ inhibitors for example, substances that reduce the expression level of NFKBIZ and / or substances that suppress the function of NFKBIZ
  • NFKBIZ inhibitors that are effective in treating and / or preventing cancer can be selected. ..
  • a Legnes 1 enhancer for example, a substance that enhances the activity of Legnes 1 that is effective for the treatment and / or prevention of cancer.
  • FIG. 1 plots the number of mutations within the entire exon region in a single crypt in subjects without ulcerative colitis (non-UC subjects) and subjects with ulcerative colitis (UC subjects) against the age of the subjects. It is a figure.
  • the regression line for section 0 is drawn for samples from non-UC subjects.
  • the p-value indicates significance for the difference between non-UC and UC subjects (Bilateral Mann-Whitney U test).
  • FIG. 2 is a diagram showing the distribution of NFKBIZ, PIGR, ZC3H12A and TRAF3IP2 mutations in normal mucosa (above each domain diagram) and CAC (below each domain diagram).
  • FIG. 1 plots the number of mutations within the entire exon region in a single crypt in subjects without ulcerative colitis (non-UC subjects) and subjects with ulcerative colitis (UC subjects) against the age of the subjects. It is a figure.
  • the regression line for section 0 is drawn for samples from non-UC subjects.
  • FIG. 2 is a diagram further showing a hotspot mutation in the DSGxxS motif of the ZC3H12A gene.
  • FIG. 4 is a diagram showing mutations in the IL-17 signaling pathway observed in the normal mucosa (UC normal mucosa) of ulcerative colitis. Genes with mutations detected in UC normal mucosa are shown in gray squares.
  • FIG. 4 is a diagram showing mutations in the IL-17 signaling pathway observed in the normal mucosa (UC normal mucosa) of ulcerative colitis. Genes with mutations detected in UC normal mucosa are
  • FIG. 6 shows the knockdown efficiency (left panel) and growth curve (right panel) of NFKBIZ measured by real-time PCR for two human colon cancer cell lines (HT29, HCT116) treated with NFKBIZ and control shRNA. It is a figure.
  • FIG. 7 is a diagram showing the experimental schedule of CAC induction in Nfkbiz fl / fl VilCre (Nfkbiz cKO) and Nfkbiz fl / fl (control) mice.
  • Azoxymethane (AOM) administration was followed by 3 cycles of sodium dextran sulfate (DSS) administration (ip: intraperitoneal administration).
  • FIG. 8 is a diagram showing typical examples of AOM-DSS-induced colon tumors in control (top) and Nfkbiz cKO (bottom) mice.
  • FIG. 9 shows a box plot of the number of tumors by tumor size (diameter) (left) and a box plot of total tumor volume (right). Tumor sizes that showed a marked difference between Nfkbiz cKO and control were indicated by asterisks (bidirectional Mann-Whitney U test; p ⁇ 0.05). In addition, the significance of the difference in total tumor volume was indicated by a P value (Bidirectional Mann-Whitney U test; p ⁇ 0.05).
  • FIG. 9 shows a box plot of the number of tumors by tumor size (diameter) (left) and a box plot of total tumor volume (right). Tumor sizes that showed a marked difference between Nfkbiz cKO and control were indicated by asterisks (bidirectional Mann-Whitney U test; p ⁇ 0.05). In addition, the significance of the difference in total
  • FIG. 10 is a diagram showing that GS143, which is an E3 ligase inhibitor, suppresses the mRNA expression level of NFKBIZ in the HT29 cell line.
  • uM represents ⁇ M.
  • FIG. 11 shows that GS143, an E3 ligase inhibitor, increases the expression level of Legnes 1 in the HT29 cell line. The upper and lower rows show the results of Western blotting, respectively, and the middle row shows the expression level ratio of Legnes 1 and ⁇ -tubulin.
  • FIG. 12 is a diagram showing that GS143, which is an E3 ligase inhibitor, exhibits a concentration-dependent cell growth inhibitory effect on the HT29 cell line. uM represents ⁇ M.
  • the expression level is shown as a relative value with the expression level of the control mouse as 1.
  • NFKBIZ inhibitor includes any substance, factor, means, etc. that inhibits NFKBIZ in some way.
  • NFKBIZ inhibitors typically include substances that reduce the expression level of NFKBIZ, substances that suppress the function of NFKBIZ, etc.
  • measures may be taken to prevent NFKBIZ from functioning or not being expressed as a result. It may be a possible means (including, for example, a means for realizing genome editing) or the like.
  • NFKBIZ NF-kappa-B inhibitor zeta
  • the NFKBIZ gene belongs to the ankyrin-repeat family (ankyrin repeat family) and is known to be induced by lipopolysaccharide.
  • NFKBIZ is known to play a role in the inflammatory response to LPS by interacting with the NF-B protein via the ankyrin repeat domain (Gudrun Totzke et al. J Biol Chem. 281: 12645-12654 (2006). )).
  • the function of NFKBIZ when the function of NFKBIZ is suppressed, the development of cancer is suppressed and the growth of the developed cancer is suppressed.
  • NFKBIZ inhibitors can be used in the treatment and / or prevention of cancer.
  • One embodiment of the present disclosure may provide a composition comprising an NFKBIZ inhibitor.
  • the NFKBIZ inhibitor has been found to be effective against cancers arising from inflammatory diseases (Examples), and the NFKBIZ inhibitor is highly probable for cancers that are not accompanied by inflammation. It can be said that it is effective.
  • NFKBIZ inhibitor examples include a substance that reduces the expression level of NFKBIZ and a substance that suppresses the function of NFKBIZ, but the NFKBIZ inhibitor also includes a combination of a plurality of substances that realize inhibition of NFKBIZ.
  • the NFKBIZ inhibitor include, for example, means for genetically modifying to inhibit NFKBIZ, cells having an activity of inhibiting NFKBIZ, and the like.
  • “Reducing the expression level of NFKBIZ” means reducing the expression level of the protein related to NFKBIZ.
  • examples of the “substance that reduces the expression level of NFKBIZ” include “nucleic acid”, “antibody”, “low molecular weight compound” and “high molecular weight compound”.
  • Preferred examples of the “substance that reduces the expression level of NFKBIZ” include “nucleic acid”, “antibody”, and “low molecular weight compound”. More preferably, “nucleic acid” and “low molecular weight compound” are mentioned as “substances that reduce the expression level of NFKBIZ".
  • a “small molecule compound” is more preferable as the "substance that reduces the expression level of NFKBIZ”.
  • “Suppressing the function of NFKBIZ” means inhibiting or eliminating the function of NFKBIZ.
  • As an embodiment of inhibition or disappearance of the function of NFKBIZ for example, “inhibiting the nuclear translocation of NFKBIZ”, “inhibiting the binding between NFKBIZ and p50", and “a transcription factor consisting of a complex containing NFKBIZ” , Inhibiting interaction with a specific DNA sequence.
  • “Inhibiting the nuclear translocation of NFKBIZ” can be confirmed, for example, by using the Western Blot method using a cell lysate of cytoplasm and nuclear fraction in cells on which an inhibitor candidate is acted.
  • “Inhibiting the binding between NFKBIZ and p50” can be confirmed, for example, by immunoprecipitation with an anti-NFKBIZ antibody or an anti-p50 antibody in cells on which an inhibitor candidate is acted.
  • “Inhibiting a transcription factor consisting of a complex containing NFKBIZ from interacting with a specific DNA sequence” means, for example, amplifying an anti-NFKBIZ antibody and its specific DNA sequence in cells on which an inhibitor candidate is acted. It can be confirmed by the CHIP-PCR method using a possible primer.
  • Examples of the "substance that suppresses the function of NFKBIZ” include "nucleic acid", “antibody”, “low molecular weight compound” and "high molecular weight compound”.
  • NFKBIZ neuropeptide-binding protein
  • “substance that suppresses the function of NFKBIZ” include “nucleic acid”, “antibody”, and “low molecular weight compound”. More preferably, “substances that suppress the function of NFKBIZ” include “antibodies” and “small molecule compounds”. More preferably, a "low molecular weight compound” is mentioned as the "substance that suppresses the function of NFKBIZ".
  • reducing the expression level of NFKBIZ and “suppressing the function of NFKBIZ” may be collectively referred to as “suppressing the expression and / or function of NFKBIZ”.
  • the "Regnes 1 enhancer” includes any substance, factor, means, etc. that promotes the action of Legnes 1 in some way.
  • the legnes 1 enhancer typically includes a substance that enhances the expression of legnes 1, a substance that enhances the activity of legnes 1, and the like, and other measures that increase the function or expression of legnes 1 as a result. It may be a means that can be taken (including, for example, a means for realizing genome editing).
  • the Legnes 1 enhancer has been found to be effective against cancers arising from inflammatory diseases (Examples), and the Legnes 1 enhancer is also high against non-inflammatory cancers. It can be said that it is effective with a probability.
  • Regnase 1 (hereinafter, also referred to as Regnase-1, Regnase-1, ZC3H12A, or Zc3h12a) is a member of the CCCH zinc finger protein family having RNAse activity, and has post-transcriptional regulatory activity via degradation of target mRNA. It is an RNA-binding protein that mediates. Regnes 1 has been reported to be an RNase associated with immune disorders by directly controlling the stability of inflammatory genes (Kazufumi Matsushita et al. Nature 458: 1185-1190. (2009)). In addition, it has been reported that the dysfunction of Legnes 1 leads to the rapid onset of abnormal hematopoiesis (Hiroyasu Kidoya et al. Nature Communications 10: 1-16. (2019)).
  • legnes 1 has been reported to bind to the 3'UTR of NFKBIZ mRNA and promote its degradation (Gesine Behrens et al. Nucl Acids Res, 46: 4256 (2016)). Furthermore, it has been reported that legnes 1 can be degraded by SCF ⁇ -TrCP1- mediated ubiquitination by phosphorylation of phosphorylation sites S438 and S442 by an IKK (enzyme I ⁇ B kinase) complex (SCF ⁇ -TrCP1 mediated ubiquitination). Hidenori Iwasaki et al. Nature Immunology, 12: 1167-1175. (2011)).
  • legnes 1 enhancer examples include substances that increase the expression of legnes 1 and substances that promote the function of legnes 1, but the legnes 1 enhancer also includes a combination of a plurality of substances that realize an increase in the action of legnes 1.
  • Examples of the Legnes 1 enhancer include, for example, means for genetically modifying the expression of Legnes 1 and cells having an activity of enhancing the activity of Legnes 1.
  • enhancing the activity of legnes 1 is meant enhancing the RNase activity of legnes 1.
  • the “substance that enhances the activity of legnes 1” include “a substance that increases the expression level of legnes 1” and “a substance that inhibits legnes 1 degrading enzyme”, and preferably “a substance that inhibits legnes 1 degrading enzyme”.
  • “Substance” can be mentioned.
  • Examples of “substances that enhance the activity of legnes 1", “substances that increase the expression level of legnes 1", or “substances that inhibit legnes 1 degrading enzyme” include “nucleic acid", “antibody”, and “low molecular weight compound”. And “polymer compounds”.
  • the “substances that enhance the activity of legnes 1", the “substances that increase the expression level of legnes 1", or the “substances that inhibit the legnes 1 degrading enzyme” are preferably “nucleic acid”, “antibody”, and “low”.
  • "Molecular compound” can be mentioned. More preferably, “antibodies” and “low molecular weight compounds” are used as "substances that enhance the activity of legnes 1", “substances that increase the expression level of legnes 1", or “substances that inhibit legnes 1 degrading enzymes”. Can be mentioned. More preferably, "low molecular weight compound” is mentioned as "a substance that enhances the activity of Legnes 1", “a substance that increases the expression level of Legnes 1", or “a substance that inhibits a legnes 1 degrading enzyme”.
  • Legnes 1 degrading enzyme means an enzyme that decomposes legnes 1, and examples thereof include “legnes 1 kinase” that phosphorylates legnes 1 and “legnes 1 ubiquitinifying enzyme” that ubiquitinates legnes 1. ..
  • the NFKBIZ inhibitor and / or Legnes 1 enhancer may have E3 ligase inhibitory activity.
  • E3 ligase inhibitory activity is defined. It is understood that NFKBIZ inhibitors and / or ligase 1 enhancers with can be used for the treatment and / or prevention of cancer.
  • E3 ligase inhibition refers to ubiquitin-bound E2 ubiquitin ligase, which recognizes the substrate of the protein, assists in the transfer of ubiquitin from E2 to the substrate, or inhibits the function of E3 ubiquitin ligase that catalyzes directly. Means to do.
  • NFKBIZ inhibitor / Legnes 1 enhancer an NFKBIZ inhibitor and a Legnes 1 enhancer
  • NFKBIZ inhibitor / Legnes 1 enhancer An example of the NFKBIZ Inhibitor / Legnes 1 Enhancer is the GS143 described in the examples herein.
  • E3 ligase inhibitor includes any substance, factor, means, etc. that inhibits the action of E3 ligase in some way.
  • the E3 ligase inhibitor typically includes a substance that reduces the expression of E3 ligase, a substance that reduces the activity of E3 ligase, and the like, and other measures that reduce the function or expression of E3 ligase as a result. It may be a means that can be taken (including, for example, a means for realizing genome editing).
  • E3 ligase is also referred to as E3 ubiquitin ligase.
  • E3 ligase inhibitor examples include “nucleic acid”, “antibody”, “low molecular weight compound” and “high molecular weight compound”.
  • Preferred examples of the “E3 ligase inhibitor” include “nucleic acid”, “antibody”, and “small molecule compound”. More preferably, the “E3 ligase inhibitor” includes an “antibody” and a “small molecule compound”. More preferably, the “E3 ligase inhibitor” includes a "low molecular weight compound”.
  • a low molecular weight compound that inhibits E3 ligase is referred to as an "E3 ligase inhibitory compound".
  • E3 ligase inhibitory compound As an example of the E3 ligase inhibitor, GS143 described in the examples of the present specification can be mentioned.
  • E3 ligase inhibitors suppress the development and growth of cancer
  • E3 ligase inhibitors are used to treat cancer and to treat cancer. / Or it is understood that it can be used for prevention.
  • Nucleic acid means a molecule in which nucleotides consisting of bases, sugars and phosphates are linked by phosphodiester bonds, and contains ribonucleic acid (RNA) and deoxyribonucleic acid (DNA), and is artificially modified or substituted nucleic acid.
  • RNA ribonucleic acid
  • DNA deoxyribonucleic acid
  • nucleic acid precursors that are converted to nucleic acids in vivo Artificially modified or substituted nucleic acids include 5-substituted pyrimidines, 6-azapyrimidines, and N-2, N-6 and O-6 substituted purines (including 2-aminopropyladenine), 5-propynyl. Included include uracil and 5-propynylcytosine and the like.
  • nucleic acid As the artificially modified or substituted nucleic acid, the 2'position and the 4'position of the nucleic acid are linked (crosslinked), and the nucleic acid has two ring structures (bicyclic type). Nucleic acid (crosslinked nucleic acid (BNA)) and the like can also be used. In addition, modified nucleic acids such as peptide nucleic acids, locked nucleic acids, morpholinon nucleic acids, and thionucleic acids can be used. Examples of the "nucleic acid” include “antisense nucleic acid", “ribozyme nucleic acid” and "nucleic acid having RNAi activity”.
  • nucleic acid examples include “antisense nucleic acid” and “ribozyme nucleic acid”.
  • examples of the “nucleic acid” include “antisense nucleic acid” and “nucleic acid that causes RNAi activity”.
  • examples of the nucleic acid that causes RNAi activity include one or more combinations of siRNA, shRNA, miRNA, short or long chain RNA, or modifications thereof.
  • the "anti-NFKBIZ antibody” means an antibody that specifically recognizes NFKBIZ, and means an antibody that has a binding activity to NFKBIZ.
  • the "antibody that specifically recognizes NFKBIZ” may be either a monoclonal antibody or a polyclonal antibody.
  • Preferred examples of the "antibody that specifically recognizes NFKBIZ” include a polyclonal antibody. More preferably, a mammalian-derived monoclonal antibody is mentioned as the "antibody that specifically recognizes NFKBIZ".
  • Monoclonal and polyclonal antibodies derived from mammals are those produced in animal blood, those produced in hybridomas, and those produced in hosts transformed with an expression vector containing an antibody gene by genetic engineering techniques.
  • Optimal antibodies are screened from a vast library of 1 trillion molecules by phage display and mass-produced by CHO cells from that gene, and humans obtained directly from transgenic mice that produce human antibodies. Examples include antibodies. Monoclonal antibodies and polyclonal antibodies can be produced by methods known to those skilled in the art.
  • the "low molecular weight compound” means an "organic low molecular weight compound” or an “inorganic low molecular weight compound” having a molecular weight of less than 10,000.
  • the "low molecular weight compound” is preferably an "organic low molecular weight compound”.
  • the molecular weight of the "low molecular weight compound” is preferably 5000 or less, more preferably 3000 or less, still more preferably 2000 or less, and most preferably 1000 or less.
  • a preferred embodiment of the NFKBIZ inhibitor and / or Regnes 1 enhancer is a low molecular weight compound "E3 ligase inhibitor compound”.
  • E3 ligase inhibitory compound examples include the compounds described in International Publication 2006/129583. Specifically, as an "E3 ligase inhibitor compound", 4- (3-Benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl) -benzoic acid (GS143), ( 5-[[3-Dimethylamino) propyl] Amino] -3,10-Dimethylpyrimidino [4,5-b] Quinoline-2,4 (3H, 10H) -dione dihydrochloride (HLI373, 502137-98- 6) and [(1R, 2R, 4R, 6R, 8S, 9E, 11R) -8-hydroxy-4,9-dimethyl-14-methylidene-13-oxo-5,12-dioxatricyclo [9.
  • E3 ligase inhibitor compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-.
  • 1-yl) -benzoic acid can be mentioned.
  • GS143 has been found to be effective against cancers arising from inflammatory diseases (Examples), and GS143 is also highly probable to be effective against non-inflammatory cancers. It can be said that there is.
  • the "polymer compound” means a compound having a molecular weight of 10,000 or more.
  • Examples of the “polymer compound” include “natural polymer”, “synthetic polymer”, and “semi-synthetic polymer”.
  • Examples of the “natural polymer” include polyamine, some lipids, cellulose, amylose, starch, chitin, natural rubber, polypeptides, proteins, DNA, RNA, some lipids, lignin, asphaltene and the like.
  • Examples of the "synthetic polymer” include polymers. Examples of the “semi-synthetic polymer” include artificial cellulose and the like.
  • the “substance” in the present disclosure may exist in the form of a hydrate and / or a solvate, the hydrate and / or the solvate is also included in the disclosed compounds.
  • the substances in the present disclosure may optionally be used in their pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salt” means a salt prepared from a pharmaceutically non-toxic acid (including inorganic and organic acids).
  • Pharmaceutically acceptable salts include, for example, but not limited to acetates, alginates, anthranylates, benzenesulfonates, benzoates, camphorsulfonates, citrates, ethenesulfonates, formic acids.
  • Salt fumarate, gluconate, glutamate, glucolenate, galacturonate, glycidate, hydrobromide, hydrochloride, ISEthionate, lactate, maleate, malate, mandel Acids, methanesulfonates, mutinates, nitrates, pamoates, pantothenates, phenylacetates, propionates, phosphates, salicylates, stearate, succinates, sulfanylates, sulfates Examples include salts, tartrates, and p-toluene sulfonates.
  • Preferred examples of the pharmaceutically acceptable salt include hydrobromide salt and hydrochloride. The most preferred pharmaceutically acceptable salt is hydrochloride.
  • the present disclosure may provide treatment of cancer with the above-mentioned inhibitors and / or enhancers. Cancers, especially those associated with chronic inflammation, can be targeted. Without wishing to be bound by theory, in the examples herein, the driver genes for cancer in chronic inflammation have been identified and the inhibitors and / or enhancers described above are effective in controlling such cancers. Is understood.
  • the present disclosure may cover diseases having characteristics such as those exemplified below.
  • Chronic inflammation means a state in which the activities of inflammatory substances, cells, etc. do not converge even though the tissue abnormality has been resolved.
  • a chronic inflammatory disease for example, "inflammatory bowel disease (IBD; inflammatory bowel disease)" can be mentioned.
  • “Inflammatory bowel disease” is a general term for diseases related to chronic inflammation that causes inflammation of the gastrointestinal tract, and is a disease that causes inflammation of the intestine by causing abnormalities in the immune system and autoimmune cells attacking intestinal cells. means. Symptoms of "inflammatory bowel disease” include “diarrhea”, “bloody stool”, and “abdominal pain”. Examples of the “inflammatory bowel disease” include “ulcerative colitis (UC)” and “Crohn's disease” (CD: Crohn's disease). Preferred examples of the "inflammatory bowel disease” include “ulcerative colitis”.
  • Ulcerative colitis means a non-specific inflammatory disease of unknown cause, which mainly causes ulcers and erosions on the mucosa of the large intestine.
  • Ulcerative colitis includes “ulcerative (chronic) colitis”, “ulcerative (chronic) colitis”, “ulcerative (chronic) rectal sigmoid colitis", "inflammatory polyp", Examples include “left side colitis”, “other ulcerative colitis” and “ulcerative colitis of unknown cause”.
  • Symptoms of "ulcerative colitis” include "mucous stool”, “diarrhea”, “fever” / "weight loss”, "abdominal pain” and "anemia”.
  • ulcerative colitis Complications of "ulcerative colitis” include "erythema nodosum”, “polyarthritis”, “chilblains”, “pyoderma gangrenosum”, “perianal inflammation / anorectal abscess”, “anorectal abscess” Ulcerative colitis, addictive giant colitis, perforation, pseudopolyarthritis (polyp), gingitis, stomatitis, chilblains (feet, fingers, ears), edema , "Thirst", and “Cancer".
  • Examples of the "carcinogenesis associated with ulcerative colitis” include “enterocolitis-related cancer (CAC) in ulcerative colitis”.
  • “Crohn's disease” means an inflammatory disease of unknown cause that causes discontinuous chronic granulomatous inflammation, primarily in the entire gastrointestinal tract from the oral cavity to the anus.
  • Examples of “Crohn's disease” include “Crohn's disease of the small intestine”, “Crohn's disease of the large intestine”, “Other Crohn's disease” and “Crohn's disease of unknown details”.
  • Symptoms of "Crohn's disease” include "abdominal pain”, “diarrhea”, “fever”, “weight loss”, "anal fistula (anal fistula, anal fissure, anal ulcer, etc.)” and “vomiting".
  • Complications of "Crohn's disease” include “joint symptoms (arthralgia, arthritis)", “skin symptoms (erythema nodosum, pyoderma gangrenosum)", “Sweet disease”, and “eye symptoms (iriditis)”. , “Primary sclerosing cholangitis” and “malignant tumor (colon cancer, ileal cancer)”.
  • Cancer in this disclosure means a malignant tumor.
  • Cancer includes, for example, colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, etc.
  • the present disclosure may cover cancers that include at least one selected from the group including those described above.
  • the “cancer” is preferably “colon cancer”.
  • colonal cancer examples include “cecal cancer”, “colon cancer”, “rectal cancer”, and “anal cancer”. Preferred examples of “colorectal cancer” include “colon cancer”, “rectal cancer”, and “anal cancer”. More preferably, “colorectal cancer” includes “colon cancer” and “rectal cancer”. More preferably, “colon cancer” is mentioned. Colorectal cancers, including at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, or anal cancer, may be included in the present disclosure.
  • the "cancer” is preferably “cancer associated with chronic inflammation”.
  • “Cancer associated with chronic inflammation” refers to cancer that develops with the onset of chronic inflammation and is diagnosed as cancer associated with chronic inflammatory disease.
  • “Cancer associated with chronic inflammation” includes, for example, pancreatic cancer associated with inflammatory bowel disease, esophageal cancer associated with reflux esophagitis, liver cancer associated with alcoholic hepatitis, and non-alcoholic steatohepatitis. Examples include liver cancer associated with liver cancer, gastric cancer associated with chronic gastric inflammation, pancreatic cancer associated with chronic pancreatitis, and cholangiocarcinoma associated with primary sclerosing cholangitis.
  • the "cancer associated with chronic inflammation” preferably includes colon cancer associated with inflammatory bowel disease.
  • the "cancer associated with chronic inflammation” more preferably includes colon cancer associated with ulcerative colitis. More preferably, “cancer associated with chronic inflammation” includes "enterocolitis-related cancer in ulcerative colitis (CAC)” and "colon cancer in ulcerative colitis”.
  • CAC ulcerative colitis
  • Enterocolitis-related cancer or "inflammatory cancer” means "colon cancer associated with inflammatory bowel disease”.
  • NFKBIZ deficient mutation suppresses the production of tissue inflammatory cytokines in a mouse enteritis model and alleviates enteritis associated with tissue destruction and regeneration.
  • a composition comprising an NFKBIZ inhibitor and / or a Regnes 1 enhancer for suppressing the production of inflammatory cytokines, or use thereof, may be provided.
  • a composition comprising an NFKBIZ inhibitor and / or a Regnes 1 enhancer, or use thereof, may be provided to alleviate enteritis associated with tissue destruction and regeneration.
  • prevention is an act of administering the active ingredient of the present disclosure to a person who has not been diagnosed as developing the target disease, for example, to prevent the onset of the disease. Is the purpose.
  • treatment is an act of administering the active ingredient of the present disclosure to a person (patient) diagnosed as having a disease by a doctor, for example, reducing the disease or symptom.
  • the purpose is to prevent the growth of carcinoma or to return it to the state before the onset of the disease.
  • the purpose of administration is to prevent the exacerbation of diseases and symptoms or the growth of carcinoma, if the administration is to a patient, it is a therapeutic act.
  • the amount used varies depending on the symptoms, age, administration method, etc., but for example, in the case of intravenous injection, the lower limit per day is set for adults.
  • the effect is expected by administering 0.01 mg (preferably 0.1 mg) and, as the upper limit, 1000 mg (preferably 100 mg) in one or several divided doses according to the symptom.
  • the administration schedule include single administration, once daily administration for 3 days, or twice daily administration for 1 week. Further, each of the above-described administration methods can be repeated at intervals of about 1 day to about 60 days.
  • the inhibitors and / or enhancers of the present disclosure can be formulated and administered directly or in an appropriate dosage form by oral administration or parenteral administration.
  • Dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, haptics and the like. Formulations are made by known methods using pharmaceutically acceptable additives.
  • Additives include excipients, disintegrants, binders, fluidizers, lubricants, coatings, solubilizers, solubilizers, thickeners, dispersants, stabilizers, and sweetness, depending on the purpose. Agents, fragrances and the like can be used.
  • Specific examples of the additive include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl. Examples thereof include alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide and talc.
  • inhibitors and / or enhancers of the present disclosure can be administered by parenteral administration or oral administration, but are preferably administered by an oral method.
  • the effectiveness of the NFKBIZ inhibitor on the subject can be predicted by measuring the gene expression of NFKBIZ and / or the activity of NFKBIZ in the cancer cells of the subject.
  • subjects with increased expression of NFKBIZ and / or increased activity of NFKBIZ shall be the subject of pharmaceutical compositions or methods for treating and / or preventing cancer. Can be done.
  • the NFKBIZ inhibitor can be used in subjects with increased expression of NFKBIZ and / or increased activity of NFKBIZ.
  • the increased expression of NFKBIZ and / or the increased activity of NFKBIZ means that (1) the expression and / or activity of the NFKBIZ gene in cancer cells obtained from the subject is measured, (2). Comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and (3) ( Based on the result of 2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ is increased. It can be determined in a process that includes determining that it is.
  • Features described elsewhere herein may optionally be employed as features relating to inhibitors, subjects, cell types, measurements, and the like.
  • the effectiveness of the Legnes 1 enhancer on the subject can be predicted by measuring the expression and / or activity of Legnes 1 in the cancer cells of the subject.
  • subjects with reduced expression of Legnes 1 and / or reduced activity of Legnes 1 are subject to pharmaceutical compositions or methods for treating and / or preventing cancer. can do.
  • the Legnes 1 enhancer has been found to be effective against cancers arising from inflammatory diseases (Examples). ), It is understood that the Legnese 1 enhancer can be used for subjects with reduced expression of Legnes 1 and / or decreased activity of Legnes 1.
  • Decreased expression of legnes 1 and / or decreased activity of legnes 1 means that (1) measurement of legnes 1 expression and / or activity of cancer cells obtained from a subject, (2) ) To compare the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and (3) ( Based on the result of 2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it includes determining that the expression and / or activity of legnes 1 is decreased. It can be determined in the process.
  • Features described elsewhere herein may be incorporated as needed as features relating to enhancers, subjects, cell types, measurements and the like.
  • the inhibitors and / or enhancers of the present disclosure can be used in combination with other drugs for the purpose of enhancing their effects.
  • the inhibitors and / or enhancers of the present disclosure can be used in combination with drugs such as hormone therapies, chemotherapeutic agents, immunotherapeutic agents or cell growth factors and agents that inhibit their receptor action. ..
  • drugs that can be used in combination with the inhibitors and / or enhancers of the present disclosure are abbreviated as concomitant drugs.
  • the inhibitors and / or enhancers of the present disclosure show excellent anticancer activity even when used as a single agent, but the effect can be further enhanced by using in combination with one or several of the above-mentioned concomitant drugs (multi-drug combination). It can be further enhanced or the patient's QOL can be improved.
  • hormoneal therapeutic agent examples include phosfestol, diethylstillbestrol, chlorotrianisen, medroxyprogesterone acetate, megestrol acetate, chlormaginone acetate, ciproterone acetate, danazol, dienogest, asoprisnil, allylestradiol, and guest.
  • Linon nomegestol, tadenan, mepartricin, raloxifene, olmeroxyphene, revolmeroxyphene, anti-estrogen (eg, tamoxyphene citrate, tremiphen citrate, etc.), pills, mepitiostane, testrolactone, aminoglutetiimide, LH- RH derivatives (LH-RH agonists (eg, goselelin acetate, busererin, leuprolerin, etc.), LH-RH antagonists), raloxifene, epithiostanol, ethinylestradiol sulfonate, aromatase inhibitors (eg, fadrozol hydrochloride, ana) Strozol, retrozol, exemestane, borozol, formestane, etc.), flutamide, bicalutamide, niltamide, androgen receptor antagonists (eg, appartamide
  • chemotherapeutic agent examples include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, molecular-targeted therapeutic agents, immunomodulators, and other chemotherapeutic agents. .. A typical example is described below.
  • alkylating agent examples include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosfamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, and mel.
  • antimetabolite examples include mercaptopurine, 6-mercaptopurine riboside, thioinosin, methotrexate, pemetrexed, eocitabine, cytarabine, cytarabine octofusphate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, etc.).
  • UFT doxiflulysine, carmofur, gallositabin, emitefur, capecitabine, etc.
  • aminopterin nerzarabin
  • leukoporin calcium tabloid
  • butocin forinate calcium
  • levofolinate calcium cladribine
  • emitefur fludalabine
  • gemcitabine hydroxycarpamid , Pyritrexim, idoxyuridine, mitogazone, thiazofurin, ambamustin, bendamstin, and DDS preparations thereof.
  • anticancer antibiotic examples include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, acralubicin hydrochloride, pyrarubicin hydrochloride, and hydrochloric acid.
  • examples thereof include epirubicin, neocartinostatin, misramycin, zarkomycin, cartinophylline, mittan, sorbicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and DDS preparations thereof.
  • plant-derived anticancer agent examples include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, bindecine sulfate, teniposide, paclitaxel, docetaxel, DJ-927, vinorelbine, irinotecan, topotecan, and their DDS preparations. Can be mentioned.
  • Molecular targeted therapies include, for example, imatinib, gefitinib, erlotinib, sorafenib, dasatinib, snitinib, nirotinib, laparib, pazopanib, luxolitinib, crizotinib, bemurafenib, bandetanib, ponatib nib, vemurafenib, bandetanib, ponatib.
  • immunomodulator examples include lenalidomide and pomalidomide.
  • chemotherapeutic agents include sobzoxane.
  • BRM immunotherapeutic agent
  • pisibanil crestin, cisophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulator, granulocyte colony stimulator, erythropoietin, phosphotoxin, BCG vaccine, corinebacterium Umpalbum, levamisol, polysaccharide K, prochodazole, anti-CTLA4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, Toll-like Receptors agonist (for example, TLR7 agonist, TLR8 agonist, TLR9 agonist, etc.) Can be mentioned.
  • the cell growth factor in the drug that inhibits the action of the cell growth factor and its receptor may be any substance as long as it promotes cell growth, and is usually accepted by a peptide having a molecular weight of 20,000 or less. Factors that exert their effects at low concentrations by binding to the body. Specifically, EGF (epidermal growth factor) or a substance having substantially the same activity as it (for example, TGFalpha), insulin or a substance having substantially the same activity as it (for example, insulin, IGF (insulin-)).
  • EGF epidermal growth factor
  • TGFalpha a substance having substantially the same activity as it
  • insulin for example, insulin, IGF (insulin-)
  • FGF fibroblast growth factor
  • a substance having substantially the same assay for example, acidic FGF, basic FGF, KGK (keratinocite growth factor), FGF-10. Etc.
  • other cell growth factors for example, CSF (colory stemming factor), EPO (erythropoitin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derivted)
  • TGF-beta transforming growth factor beta
  • HGF hepatotic growth factor
  • VEGF vascular endotherial growth factor
  • hergulin angiopoetin, etc.
  • the substance of the present disclosure can be used in combination with "another therapeutic agent for inflammatory bowel disease” for the purpose of enhancing its effect and / or treating complications.
  • another therapeutic agent for inflammatory bowel disease that can be used in combination with the substance of the present disclosure.
  • “Other inflammatory bowel disease treatments” include salicylic acid, salazosulfapyridine, mesalazine, prednisolone, betamethasone, budesonide, methylprednisolone, hydrocortisone, infliximab, adalimumab, ustekinumab, sertrizumab, golimumab, tacrolimus, azathioprine. , Cyclosporine, tofacitinib, and vedrizumab.
  • the administration period of the substance of the present disclosure and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or at different times. In addition, it may be a mixture of the substance of the present disclosure and a concomitant drug.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the substance of the present disclosure and the concomitant drug can be appropriately selected depending on the administration target, administration route, target disease, symptom, combination and the like. For example, when the administration target is a human, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the compound of the present disclosure.
  • it can be used in combination with drugs (combined drugs) such as antiemetics, sleep-inducing agents, and anticonvulsants.
  • NFKBIZ inhibitors can be used in the present disclosure. Since NFKBIZ functions in the inflammatory response by interacting with the NF ⁇ -B protein via the ankyrin repeat domain, NFKBIZ inhibitors can be used to reduce the expression level of NFKBIZ and reduce the stability of NFKBIZ.
  • One embodiment of the present disclosure may provide a method of screening to screen for substances that treat and / or prevent cancer. This is based, at least in part, on the finding by the present inventors that the NFKBIZ inhibitor exhibits a particular growth inhibitory effect on cancer.
  • Methods for screening for therapeutic and / or prophylactic agents for cancer include (1) measuring gene expression and / or activity without allowing therapeutic and / or prophylactic agent candidates to act on cancer cells, (2) relevant.
  • the steps of measuring gene expression and / or activity after applying the therapeutic and / or prophylactic agent candidate to cancer cells, and the results of (3) and (2) are smaller or larger than the results of (1).
  • the treatment and / or prophylaxis may include the step of determining that the treatment and / or prophylaxis is a cancer treatment and / or prophylaxis.
  • a gene described in the present specification such as NFKBIZ or Legnes 1 can be targeted.
  • Features described elsewhere herein may optionally be employed as features relating to inhibitors, enhancers, subjects, cell types, measurements, and the like.
  • the method is characterized as a method of screening for NFKBIZ inhibitors, (1) measuring gene expression and / or activity of NFKBIZ without allowing the candidate inhibitor to act on cancer cells, (2). After the cancer cell is allowed to act on the inhibitor candidate, the step of measuring the gene expression and / or activity of NFKBIZ, and when the results of (3) and (2) are smaller than the result of (1).
  • the inhibitor candidate may include a step of determining that it is an NFKBIZ inhibitor.
  • the method is characterized as a method of screening for substances that reduce the expression level of NFKBIZ and / or suppress the function of NFKBIZ, (1) without allowing the test substance to act on the cancer cells.
  • the test substance may include a step of determining that the test substance is a substance that reduces the expression level of NFKBIZ and / or a substance that suppresses the function of NFKBIZ.
  • the method is characterized as a method of screening a legnes 1 enhancer, (1) measuring the expression and / or activity of legnes 1 without allowing the enhancer candidate to act on the cancer cells, (2).
  • the enhancer candidate may include a step of determining that it is a Legnes 1 enhancer.
  • the method is characterized as a method of screening for a substance that enhances the activity of Legnes 1, (1) measuring the activity of Legnes 1 without allowing the test substance to act on the cancer cells, (1).
  • Pathological evaluation was performed by two pathologists based on Riddell's classification (Riddell, RH et al. Human Pathology 14: 931 (1983)), and the samples were "normal (non-dysplasia)" and "low degree dysplasia". It was divided into four groups: "formation”, “severe dysplasia” and “cancer”. Specimens obtained by endoscopic biopsy were cut to a size of approximately 4 mm 2 to obtain a single crypt sample as well as a bulk crypt sample. Samples were taken from the surgical specimens using a punch biopsy (BP-25F, Kai Industries) with a diameter of 2.5 mm (4.9 mm 2 ).
  • the WES library was prepared using SureSelect Human All Exon V5 (Agilent Technologies) or xGen Exome Research Panel (IDT), and the concentrated exon fragments were prepared using HiSeq 2500 or NovaSeq 6000 (Illumina) in HiSeq 2500 or NovaSeq 6000 (Illumina). It was sequenced in the same manner (Yoshida, K. et al. Nature 478: 64 (2011)). The target sequence depth was 100x and the actual depth was 133x. The average depth of germline control from 101 individuals was 140x. Mutation detection was performed in the same manner as previously reported using Genomen2 pipeline version 2.6 (https://genomon.readedocs.io/ja/latest/) (Yokoyama, A.
  • sequence reads were aligned with the human genome reference sequence (hg19) using Burrows-Wheeler Aligner version 0.7.8 with default parameter settings. PCR duplication was excluded using biobambam version 0.0.191 (https://github.com/gt1/biobambam). Somatic mutations were detected by excluding polymorphisms and sequence errors. To this end, Genomon2 was used to first exclude low quality, unreliable reads and variants using thresholds of (i) mapping quality ⁇ 20, (ii) base quality ⁇ 15.
  • UC normal mucosa In the normal mucosa (UC normal mucosa) associated with ulcerative colitis, a gene belonging to the IL-17 signal pathway and having a protein-shortened mutation was also regarded as a driver. A total of 20 genes were considered drivers in UC normal mucosa.
  • HeLa cell line uses DMEM medium (08459-64, Nacalai Tesque) supplemented with 10% FBS (fetal bovine serum) and 100 ⁇ M 2-mercaptoethanol (21418-42, Nacalai Tesque). And maintained.
  • FBS fetal bovine serum
  • 2-mercaptoethanol 21418-42, Nacalai Tesque
  • the HT29 and HCT116 cell lines were maintained in DMEM medium supplemented with 10% FBS.
  • a cDNA having a full-length wild-type or C-terminal shortened mutation (W453 *) of the human ZC3H12A gene encoding Legnes 1 was inserted into cDNA 3.1 (+) (V79020, Thermo Fisher) together with an N-terminal Myc tag sequence.
  • the S438L mutant Regnase-1 was created using the QuikChange Lightning Site-Directed Mutagenesis Kit (210319, Agilent).
  • somatic cell mutations per unit increased more than 3 times compared to the normal mucosa of non-UC subjects, which was significantly higher (Fig. 1).
  • Analysis of gene mutations detected in the normal mucosa of UC patients revealed significant mutations in 14 genes of NFKBIZ, PIGR, ZC3H12A, TRAF3IP2, HNRNPF, ARID1A, ARID1B, KRAS, TP53, RNF43, ETV6, FBXW7, BCOR and BCORL1.
  • was positively selected and was considered to be a driver mutation ("dN / dS>1.0" and "q ⁇ 0.05").
  • mutations for most genes were considered to be loss-of-function mutations because they caused protein shortening.
  • Fig. 2 The exceptions were the ZC3H12A, HNRNPF and KRAS genes, which were considered function-acquired mutations because they formed hotspots where missense mutations were concentrated in some amino acids (Fig. 2).
  • the NFKBIZ, PIGR, ZC3H12A and TRAF3IP2 genes were mutually exclusive (Fig. 3). Since TRAF3IP2 was known to function as an adapter protein for the IL-17 signal pathway, analysis focusing on the IL-17 signal pathway revealed that the IL17RA, IL17RC, TRAF5, RELA, MAPK14 and BTRC genes were also shortened proteins.
  • the WES data (bam file) of a pair of tumors derived from patients with sporadic colorectal cancer (sCRC) and germline specimens is the The Cancer Genome Atlas (TCGA) Data Portal ( It was downloaded from https: //portal.gdc.cancer.gov/).
  • the bum file was converted to FASTQ format using biobambam, and mutation detection was performed using the same pipeline by the method applied to the fresh sample obtained in this study. For accuracy, sequence data obtained using WGA from tumors was excluded. Highly mutated tumors ( ⁇ 12 mutations / 10 6 bases) were also excluded from the analysis.
  • NFKBIZ colonic epithelial cells in which the function of NFKBIZ was deficient could not become cancerous, and even if they became cancerous, they could not proliferate, or both. This suggests that suppressing NFKBIZ has an effect of suppressing the development of cancer and an effect of suppressing the growth of the developed cancer.
  • Tumors developed were pathologically evaluated by HE staining and immunohistochemistry of ⁇ -catenin or Ki-67. For each mouse, body weight, colorectal length, and histological scores of enteritis were recorded. For histological scores of enteritis, epithelial damage and inflammatory cell infiltration were scored from 0 to 12 in five randomly selected high-power fields on the HE-stained slide (Goto, N. et al. Cancer Res 77: 3442 (2017)), the average of which was used in the analysis.
  • Maxwell manufactured by Promega
  • R Maxwell 16 LEV simplicity RNA Purification Kits
  • a real-time PCR reaction solution was prepared according to the protocol using the synthesized cDNA, human NFKBIZ or human ACTB gene-specific primer (manufactured by Origine), and iTaq Universal SYBR (R) Green Supermix (manufactured by Bio-Rad), and CFX384 (CFX384).
  • the reaction was carried out with Bio-Rad), and the reaction product was detected and quantified.
  • the value obtained by correcting the expression level of human NFKBIZ in each sample by the expression level of human ACTB was defined as the NFKBIZ expression level in each sample, and the value obtained by correcting the expression level of NFKBIZ in each sample by the expression level of NFKBIZ in the DMSO-added control sample was used. It was calculated as the relative mRNA expression level (NFKBIZ / ACTB) (FIG. 10).
  • the protein concentration was measured by BCA Protein Assay (manufactured by Thermo Fisher) and subjected to SDS-PAGE so as to be 20 ⁇ g per lane.
  • SDS-PAGE Any kD miniprotian TGX precast gel (Bio-Rad, 4569033) was used.
  • the expression of Legnes 1 was detected with an anti-Regnes 1 antibody (GTX110807, manufactured by GeneTex), and the expression of ⁇ -tubulin in the loading control was detected with an anti- ⁇ -tubulin antibody (2128S, manufactured by Cell Signaling Technology) (Fig. 11).
  • GS143 showed a strong cell growth inhibitory effect especially at a concentration of 10 ⁇ M or more. Since the concentration of 10 ⁇ M or more is the concentration at which the expression stabilization of legnes 1 and the accompanying suppression of NFKBIZ expression were observed in Examples 8 and 9, the E3 ligase inhibitor caused the expression of legnes 1. It has been found that by stabilizing and reducing the expression of NFKBIZ, it inhibits cell proliferation of colorectal cancer cell lines.
  • Example 7 Treatment example (1) Selection of patients The subject's cancer is diagnosed as being associated with chronic inflammation by colonoscopy, enema contrast examination, CT examination, MRI examination, or the like. The inflammatory state is measured by changes in the inflammatory parameters of the subject's blood and the extent and extent of inflammatory lesions in the cancerous tissue. (2) Formulation A preparation containing an NFKBIZ inhibitor and / or a Regnes 1 enhancer for treating a subject is provided. The drug is prepared as in GS143 (Example 7). (3) Treatment Considering the type of cancer of the subject, the degree of progression of the pathological condition, the suitability of GS143, the treatment history, the health condition, etc., GS143 is administered when the drug treatment is judged to be appropriate. (4) Results The therapeutic effect is evaluated by achieving the reduction or disappearance of the tumor of the subject and the alleviation of the inflammatory state by the administration of GS143.
  • Example 8 Therapeutic agent production GS143 is used as an NFKBIZ inhibitor and mixed with the following composition to prepare tablets for internal use.
  • Example 9 Examination of the role of NFKBIZ in enteritis (1) Method The following genetically modified C57BL / 6 mice were used. VilCremice (004586) and R26-LacZ mice (003309) were obtained from The Jackson Laboratory. Nfkbiz flox mice (Okuma, A. et al. Immunity 38: 450 (2013), RBRC06410) were obtained from the RIKEN BioResource Research Center. VilCre ER mice (el Marjou, F. et al. 39: 186 (2004)) were assigned by Sylvie Robine.
  • the NFKBIZ inhibitor according to the present invention is extremely useful for cancer associated with chronic inflammation.
  • the screening method of the present invention is useful for searching for an NFKBIZ inhibitor that is a candidate substance for a therapeutic or prophylactic drug for cancer.
  • SEQ ID NO: 1 shNFKBIZ 1 Target
  • SEQ ID NO: 2 shNFKBIZ 1
  • SEQ ID NO: 3 shNFKBIZ 2
  • Target SEQ ID NO: 4 shNFKBIZ 2
  • SEQ ID NO: 5 NFKBIZ Forward primer
  • SEQ ID NO: 6 NFKBIZ Reverse primer
  • SEQ ID NO: 7 18 Forward primer
  • SEQ ID NO: 8 18S rRNA Reverse primer

Abstract

The present disclosure provides a pharmaceutical composition or method for therapy and/or prophylaxis of cancer, or a screening method for screening for a substance or a factor for therapy and/or prophylaxis of cancer.　The present disclosure provides a pharmaceutical composition that is for therapy and/or prophylaxis of cancer accompanied by chronic inflammation, and that contains an NFKBIZ inhibitor. Examples of the NFKBIZ inhibitor include substances that inhibit the expression and/or function of NFKBIZ. The cancer accompanied by chronic inflammation is preferably an enterocolitis-associated cancer observed in ulcerative colitis.

Description

大腸がんを治療及び／又は予防する医薬組成物Pharmaceutical composition for treating and / or preventing colorectal cancer
　本開示は、ＮＦＫＢＩＺインヒビター及び／又はレグネース１エンハンサーを含む、がんを治療及び／又は予防するための医薬組成物に関する。また、がんを治療及び／又は予防する物質又は因子を選別するスクリーニング方法を提供することにある。 The present disclosure relates to a pharmaceutical composition for treating and / or preventing cancer, which comprises an NFKBIZ inhibitor and / or a Regnes 1 enhancer. It is also intended to provide a screening method for selecting substances or factors that treat and / or prevent cancer.
　慢性炎症とは、組織異常が解消されているのにもかかわらず炎症物質、細胞などの活動が収束しない状態をいい、多様な疾患に罹患しやすくなるとともに、発がんの重大な危険因子となっている（非特許文献１）。慢性炎症では免疫応答が過剰に生じ、組織障害と組織修復が繰り返し行われる特徴を有する。組織修復を構成する細胞の中には、発がんに関連する遺伝子変異が生じている細胞の存在が報告されており、加齢とともに組織障害と組織修復が繰り返されることで、発がんのリスクがより一層高まることが知られている（非特許文献２）。 Chronic inflammation is a condition in which the activities of inflammatory substances, cells, etc. do not converge even though the tissue abnormalities have been resolved, making it more susceptible to various diseases and becoming a serious risk factor for carcinogenesis. (Non-Patent Document 1). Chronic inflammation is characterized by an excessive immune response, repeated tissue damage and tissue repair. Among the cells that make up tissue repair, the presence of cells with gene mutations related to carcinogenesis has been reported, and repeated tissue damage and tissue repair with aging further increases the risk of carcinogenesis. It is known to increase (Non-Patent Document 2).
　炎症性腸疾患（ＩＢＤ）は、消化管に炎症をおこす慢性炎症であり、近年当該炎症性腸疾患に罹患する患者が、急激に増加する傾向にある。炎症性腸疾患の患者は腸粘膜の長期間にわたる慢性炎症のため、炎症性腸疾患を原因とする大腸がんの発生リスクが非常に高くなることが知られている。 Inflammatory bowel disease (IBD) is a chronic inflammation that causes inflammation of the gastrointestinal tract, and the number of patients suffering from the inflammatory bowel disease has been increasing rapidly in recent years. Patients with inflammatory bowel disease are known to have a very high risk of developing colorectal cancer caused by inflammatory bowel disease due to long-term chronic inflammation of the intestinal mucosa.
　潰瘍性大腸炎（ＵＣ）は、主要な炎症性腸疾患であり、慢性化した炎症が広範囲な腸管で生じることにより腸管粘膜が損傷し、難治性の潰瘍が生じる病態を特徴とする。潰瘍性大腸炎に伴う発がん（潰瘍性大腸炎における腸炎関連性発がん；ｃｏｌｉｔｉｓ　ａｓｓｏｃｉａｔｅｄ　ｃａｒｃｉｎｏｍａ（ＣＡＣ））の発症機序については不明な点も多いが、（１）腸管細菌叢の不全状態に起因した免疫細胞の異常やサイトカインの過剰産生により炎症が遷延し、（２）慢性的な炎症に起因する粘膜損傷と修復が繰り返され、（３）腸管上皮細胞が再構成されることでもたらされると考えられている（非特許文献３）。 Ulcerative colitis (UC) is a major inflammatory bowel disease, and is characterized by a pathological condition in which chronic inflammation occurs in a wide range of intestinal tracts, resulting in damage to the intestinal mucosa and intractable ulcers. There are many unclear points about the pathogenic mechanism of carcinogenesis associated with ulcerative colitis (enterocolitis-related carcinogenesis in ulcerative colitis; epithelial associated carcinoma (CAC)), but (1) it was caused by the insufficiency of the intestinal flora. It is thought that inflammation is prolonged due to abnormalities of immune cells and overproduction of cytokines, (2) mucosal damage and repair caused by chronic inflammation are repeated, and (3) intestinal epithelial cells are reconstituted. (Non-Patent Document 3).
　本開示は、ＮＦＫＢＩＺインヒビター及び／又はレグネース１エンハンサーを含む、がんを治療及び／又は予防するための医薬組成物に関する。また、がんを治療及び／又は予防する物質を選別するスクリーニング方法を提供することにある。 The present disclosure relates to a pharmaceutical composition for treating and / or preventing cancer, which comprises an NFKBIZ inhibitor and / or a Regnes 1 enhancer. It is also intended to provide a screening method for selecting substances that treat and / or prevent cancer.
　本発明者らは、鋭意検討した結果、ＮＦＫＢＩＺインヒビター及び／又はレグネース１エンハンサーが、がんに対して格別な増殖抑制効果を示すことを見出した。 As a result of diligent studies, the present inventors have found that the NFKBIZ inhibitor and / or the Regnes 1 enhancer show a special growth inhibitory effect on cancer.
　より具体的には、本発明者らは、潰瘍性大腸炎患者の大腸粘膜細胞が特異的な遺伝子変異を起こしていることを同定し、当該遺伝子変異が、「炎症性腸疾患の特徴的な病態に係る組織障害と組織再生の繰り返し」、及び「炎症性発がんの発生及び増殖」に深く関与していることを見出した。これら遺伝子変異の中でも、ＮＦＫＢＩＺの機能欠損変異は、マウス腸炎モデルにおいて組織の炎症性サイトカインの産生を抑制し、組織破壊と再生を伴う腸炎を緩和すること、及び炎症粘膜における発がん及びがん細胞の増殖を抑制することを見出した。さらに、本発明者らは、ＮＦＫＢＩＺの発現を抑制する化合物は、大腸がん細胞の増殖抑制効果を有することを見出し、ＮＦＫＢＩＺが、大腸がんの治療及び／又は予防の画期的な創薬ターゲットであることを見出した。 More specifically, the present inventors have identified that the large intestine mucosal cells of patients with ulcerative colitis have a specific gene mutation, and the gene mutation is "characteristic of inflammatory bowel disease." It was found that it is deeply involved in "repeated tissue damage and tissue regeneration related to pathological conditions" and "development and proliferation of inflammatory carcinogenesis". Among these gene mutations, the NFKBIZ deficient mutation suppresses the production of inflammatory cytokines in tissues in a mouse enteritis model, alleviates enteritis associated with tissue destruction and regeneration, and causes carcinogenesis and cancer cells in the inflammatory mucosa. It was found to suppress proliferation. Furthermore, the present inventors have found that a compound that suppresses the expression of NFKBIZ has an effect of suppressing the growth of colorectal cancer cells, and NFKBIZ is an epoch-making drug discovery for the treatment and / or prevention of colorectal cancer. I found it to be a target.
　すなわち、本開示は、以下を含む。 That is, the present disclosure includes:
［項１]　ＮＦＫＢＩＺインヒビターを含む、がんを治療及び／又は予防するための医薬組成物。 [Item 1] A pharmaceutical composition for treating and / or preventing cancer, which comprises an NFKBIZ inhibitor.
［項２]　前記がんが、慢性炎症に伴うがんである、項１に記載の医薬組成物。 [Item 2] The pharmaceutical composition according to Item 1, wherein the cancer is a cancer associated with chronic inflammation.
［項３]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項２に記載の医薬組成物。 [Item 3] The pharmaceutical composition according to Item 2, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項４]　前記炎症性腸疾患が、潰瘍性大腸炎である、項３に記載の医薬組成物。 [Item 4] The pharmaceutical composition according to Item 3, wherein the inflammatory bowel disease is ulcerative colitis.
［項５]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項１～４のいずれか一項に記載の医薬組成物。 [Item 5] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, stomach cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The pharmaceutical composition according to any one of Items 1 to 4.
［項６]　前記がんが、大腸がんである、項５に記載の医薬組成物。 [Item 6] The pharmaceutical composition according to Item 5, wherein the cancer is colorectal cancer.
［項７]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項６に記載の医薬組成物。 Item 7. The pharmaceutical composition according to Item 6, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項８]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項１～７のいずれか一項に記載の医薬組成物。 [Item 8] The pharmaceutical composition according to any one of Items 1 to 7, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項９]　前記インヒビターが、ＮＦＫＢＩＺの発現を減少させる、及び／又はＮＦＫＢＩＺの機能を抑制するものである、項１～８のいずれか一項に記載の医薬組成物。 [Item 9] The pharmaceutical composition according to any one of Items 1 to 8, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
［項１０]　前記インヒビターが、ＮＦＫＢＩＺの核内移行を阻害するものである、項１～９のいずれか一項に記載の医薬組成物。 [Item 10] The pharmaceutical composition according to any one of Items 1 to 9, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
［項１１]　前記インヒビターが、ＮＦＫＢＩＺとｐ５０との結合を阻害するものである、項１～１０のいずれか一項に記載の医薬組成物。 [Item 11] The pharmaceutical composition according to any one of Items 1 to 10, wherein the inhibitor inhibits the binding between NFKBIZ and p50.
［項１２]　前記インヒビターが、ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することを阻害するものである、項１～１１のいずれか一項に記載の医薬組成物。 Item 12. The pharmaceutical composition according to any one of Items 1 to 11, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence. ..
［項１３]　前記インヒビターが、Ｅ３リガーゼ阻害活性を有する、項１～１２のいずれか一項に記載の医薬組成物。 [Item 13] The pharmaceutical composition according to any one of Items 1 to 12, wherein the inhibitor has an E3 ligase inhibitory activity.
［項１４]　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項１～１３のいずれか一項に記載の医薬組成物。 [Item 14] The pharmaceutical composition according to any one of Items 1 to 13, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項１５]　前記インヒビターが、核酸である、項１４に記載の医薬組成物。 [Item 15] The pharmaceutical composition according to Item 14, wherein the inhibitor is a nucleic acid.
［項１６]　前記インヒビターが、抗ＮＦＫＢＩＺ抗体である、項１４に記載の医薬組成物。 Item 16. The pharmaceutical composition according to Item 14, wherein the inhibitor is an anti-NFKBIZ antibody.
［項１７]　前記インヒビターが、低分子化合物である、項１４に記載の医薬組成物。 Item 17. The pharmaceutical composition according to Item 14, wherein the inhibitor is a low molecular weight compound.
［項１８]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項１７に記載の医薬組成物。 [Item 18] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -Benzyl acid (GS143), the pharmaceutical composition according to Item 17.
［項１９]　レグネース１エンハンサーを含む、がんを治療及び／又は予防するための医薬組成物。 [Item 19] A pharmaceutical composition for treating and / or preventing cancer, which comprises a Legnes 1 enhancer.
［項２０]　前記がんが、慢性炎症に伴うがんである、項１９に記載の医薬組成物。 Item 20. The pharmaceutical composition according to Item 19, wherein the cancer is a cancer associated with chronic inflammation.
［項２１]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項２０に記載の医薬組成物。 Item 21. The pharmaceutical composition according to Item 20, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項２２]　前記炎症性腸疾患が、潰瘍性大腸炎である、項２１に記載の医薬組成物。 Item 22. The pharmaceutical composition according to Item 21, wherein the inflammatory bowel disease is ulcerative colitis.
［項２３]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項１９～２２のいずれか一項に記載の医薬組成物。 [Item 23] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The pharmaceutical composition according to any one of Items 19 to 22.
［項２４]　前記がんが、大腸がんである、項２３に記載の医薬組成物。 [Item 24] The pharmaceutical composition according to Item 23, wherein the cancer is colorectal cancer.
［項２５]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項２４に記載の医薬組成物。 Item 25. The pharmaceutical composition according to Item 24, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項２６]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項１９～２５のいずれか一項に記載の医薬組成物。 [Item 26] The pharmaceutical composition according to any one of Items 19 to 25, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項２７]　前記エンハンサーが、レグネース１の活性を増強するものである、項１９～２６のいずれか一項に記載の医薬組成物。 [Item 27] The pharmaceutical composition according to any one of Items 19 to 26, wherein the enhancer enhances the activity of Legnes 1.
［項２８]　前記エンハンサーが、レグネース１分解酵素を阻害するものである、項１９～２７のいずれか一項に記載の医薬組成物。 Item 28. The pharmaceutical composition according to any one of Items 19 to 27, wherein the enhancer inhibits a legnes monodegrading enzyme.
［項２９]　前記レグネース１分解酵素が、レグネース１リン酸化酵素、又はレグネース１ユビキチン化酵素であるものである、項２８に記載の医薬組成物。 Item 29. The pharmaceutical composition according to Item 28, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
［項３０]　前記エンハンサーが、Ｅ３リガーゼ阻害活性を有する、項２９に記載の医薬組成物。 Item 30. The pharmaceutical composition according to Item 29, wherein the enhancer has an E3 ligase inhibitory activity.
［項３１]　前記エンハンサーが、核酸、抗体、低分子化合物、又は高分子化合物である、項１９～３０のいずれか一項に記載の医薬組成物。 Item 31. The pharmaceutical composition according to any one of Items 19 to 30, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項３２]　前記エンハンサーが、核酸である、項３１に記載の医薬組成物。 Item 32. The pharmaceutical composition according to Item 31, wherein the enhancer is a nucleic acid.
［項３３]　前記エンハンサーが、抗体である、項２６に記載の医薬組成物。 Item 33. The pharmaceutical composition according to Item 26, wherein the enhancer is an antibody.
［項３４]　前記エンハンサーが、低分子化合物である、項２６に記載の医薬組成物。 Item 34. The pharmaceutical composition according to Item 26, wherein the enhancer is a low molecular weight compound.
［項３５]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項３４に記載の医薬組成物。 [Item 35] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. The pharmaceutical composition according to Item 34, which is yl) -benzoic acid (GS143).
［項３６]　Ｅ３リガーゼインヒビターを含む、がんを治療及び／又は予防するための医薬組成物。 [Item 36] A pharmaceutical composition for treating and / or preventing cancer, which comprises an E3 ligase inhibitor.
［項３７]　前記がんが、慢性炎症に伴うがんである、項３６に記載の医薬組成物。 Item 37. The pharmaceutical composition according to Item 36, wherein the cancer is a cancer associated with chronic inflammation.
［項３８]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項３７に記載の医薬組成物。 Item 38. The pharmaceutical composition according to Item 37, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項３９]　前記炎症性腸疾患が、潰瘍性大腸炎である、項３８に記載の医薬組成物。 Item 39. The pharmaceutical composition according to Item 38, wherein the inflammatory bowel disease is ulcerative colitis.
［項４０]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項３６～３９のいずれか一項に記載の医薬組成物。 [Item 40] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The pharmaceutical composition according to any one of Items 36 to 39.
［項４１]　前記がんが、大腸がんである、項４０に記載の医薬組成物。 Item 41. The pharmaceutical composition according to Item 40, wherein the cancer is colorectal cancer.
［項４２]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項４１に記載の医薬組成物。 Item 42. The pharmaceutical composition according to Item 41, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項４３]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項３６～４２のいずれか一項に記載の医薬組成物。 Item 43. The pharmaceutical composition according to any one of Items 36 to 42, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項４４]　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項３６～４３のいずれか一項に記載の医薬組成物。 Item 44. The pharmaceutical composition according to any one of Items 36 to 43, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項４５]　前記インヒビターが、核酸である、項４４に記載の医薬組成物。 Item 45. The pharmaceutical composition according to Item 44, wherein the inhibitor is a nucleic acid.
［項４６]　前記インヒビターが、抗Ｅ３リガーゼ抗体である、項４４に記載の医薬組成物。 Item 46. The pharmaceutical composition according to Item 44, wherein the inhibitor is an anti-E3 ligase antibody.
［項４７]　前記インヒビターが、低分子化合物である、項４４に記載の医薬組成物。 Item 47. The pharmaceutical composition according to Item 44, wherein the inhibitor is a low molecular weight compound.
［項４８]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項４７に記載の医薬組成物。 [Item 48] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. The pharmaceutical composition according to Item 47, which is yl) -benzoic acid (GS143).
［項Ａ１]　がんの治療及び／又は予防における使用のためのＮＦＫＢＩＺインヒビター。 [Item A1] NFKBIZ inhibitor for use in the treatment and / or prevention of cancer.
［項Ａ２]　前記がんが、慢性炎症に伴うがんである、項Ａ１に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A2] The NFKBIZ inhibitor for use according to item A1, wherein the cancer is a cancer associated with chronic inflammation.
［項Ａ３]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ａ２に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A3] The NFKBIZ inhibitor for use according to item A2, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ａ４]　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ａ３に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A4] The NFKBIZ inhibitor for use according to item A3, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ａ５]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ａ１～Ａ４のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A5] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, stomach cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , NFKBIZ inhibitor for use according to any one of items A1 to A4.
［項Ａ６]　前記がんが、大腸がんである、項Ａ５に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A6] The NFKBIZ inhibitor for use according to item A5, wherein the cancer is colorectal cancer.
［項Ａ７]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ａ６に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A7] The NFKBIZ inhibitor for use according to item A6, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer. ..
［項Ａ８]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ａ１～Ａ７のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A8] The NFKBIZ inhibitor for use according to any one of items A1 to A7, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ａ９]　前記インヒビターが、ＮＦＫＢＩＺの発現を減少させる、及び／又はＮＦＫＢＩＺの機能を抑制するものである、項Ａ１～Ａ８のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A9] The NFKBIZ inhibitor for use according to any one of Items A1 to A8, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
［項Ａ１０]　前記インヒビターが、ＮＦＫＢＩＺの核内移行を阻害するものである、項Ａ１～Ａ９のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A10] The NFKBIZ inhibitor for use according to any one of Items A1 to A9, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
［項Ａ１１]　前記インヒビターが、ＮＦＫＢＩＺとｐ５０との結合を阻害するものである、項Ａ１～Ａ１０のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A11] The NFKBIZ inhibitor for use according to any one of Items A1 to A10, wherein the inhibitor inhibits the binding of NFKBIZ to p50.
［項Ａ１２]　前記インヒビターが、ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することを阻害するものである、項Ａ１～Ａ１１のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A12] For the use according to any one of Items A1 to A11, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence. NFKBIZ inhibitor.
［項Ａ１３]　前記インヒビターが、Ｅ３リガーゼ阻害活性を有する、項Ａ１～１２のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A13] The NFKBIZ inhibitor for use according to any one of Items A1 to 12, wherein the inhibitor has an E3 ligase inhibitory activity.
［項Ａ１４]　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ａ１～Ａ１３のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A14] The NFKBIZ inhibitor for use according to any one of Items A1 to A13, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ａ１５]　前記インヒビターが、核酸である、項Ａ１４に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A15] The NFKBIZ inhibitor for use according to item A14, wherein the inhibitor is a nucleic acid.
［項Ａ１６]　前記インヒビターが、抗ＮＦＫＢＩＺ抗体である、項Ａ１４に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A16] The NFKBIZ inhibitor for use according to item A14, wherein the inhibitor is an anti-NFKBIZ antibody.
［項Ａ１７]　前記インヒビターが、低分子化合物である、項Ａ１４に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A17] The NFKBIZ inhibitor for use according to Item A14, wherein the inhibitor is a low molecular weight compound.
［項Ａ１８]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ａ１７に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A18] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -benzoic acid (GS143), an NFKBIZ inhibitor for use according to item A17.
［項Ａ１９]　がんの治療及び／又は予防における使用のためのレグネース１エンハンサー。 [Item A19] Legnes 1 enhancer for use in the treatment and / or prevention of cancer.
［項Ａ２０]　前記がんが、慢性炎症に伴うがんである、項Ａ１９に記載の使用のためのレグネース１エンハンサー。 [Item A20] The Legnes 1 enhancer for use according to item A19, wherein the cancer is a cancer associated with chronic inflammation.
［項Ａ２１]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ａ２０に記載の使用のためのレグネース１エンハンサー。 [Item A21] The Legnes 1 enhancer for use according to item A20, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ａ２２]　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ａ２１に記載の使用のためのレグネース１エンハンサー。 [Item A22] The Legnes 1 enhancer for use according to item A21, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ａ２３]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ａ１９～Ａ２２のいずれか一項に記載の使用のためのレグネース１エンハンサー。 [Item A23] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , Regnes 1 Enhancer for use according to any one of Items A19-A22.
［項Ａ２４]　前記がんが、大腸がんである、項Ａ２３に記載の使用のためのレグネース１エンハンサー。 [Item A24] The Legnes 1 enhancer for use according to item A23, wherein the cancer is colorectal cancer.
［項Ａ２５]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ａ２４に記載の使用のためのレグネース１エンハンサー。 Item A25. Legnes 1 for use according to item A24, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer. Enhancer.
［項Ａ２６]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ａ１９～Ａ２５のいずれか一項に記載の使用のためのレグネース１エンハンサー。 [Item A26] The Legnes 1 enhancer for use according to any one of items A19 to A25, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ａ２７]　前記エンハンサーが、レグネース１の活性を増強するものである、項Ａ１９～Ａ２６のいずれか一項に記載の使用のためのレグネース１エンハンサー。 [Item A27] The enhancer for use according to any one of items A19 to A26, wherein the enhancer enhances the activity of legnes 1.
［項Ａ２８]　前記エンハンサーが、レグネース１分解酵素を阻害するものである、項Ａ１９～Ａ２７のいずれか一項に記載の使用のためのレグネース１エンハンサー。 [Item A28] The legnace 1 enhancer for use according to any one of items A19 to A27, wherein the enhancer inhibits a legnes monodegrading enzyme.
［項Ａ２９]　前記レグネース１分解酵素が、レグネース１リン酸化酵素、又はレグネース１ユビキチン化酵素であるものである、項Ａ２８に記載の使用のためのレグネース１エンハンサー。 [Item A29] The legnes 1 enhancer for use according to item A28, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
［項Ａ３０]　前記エンハンサーが、Ｅ３リガーゼ阻害活性を有する、項Ａ２９に記載の使用のためのレグネース１エンハンサー。 [Item A30] The legnes 1 enhancer for use according to item A29, wherein the enhancer has an E3 ligase inhibitory activity.
［項Ａ３１]　前記エンハンサーが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ａ１９～３０のいずれか一項に記載の使用のためのレグネース１エンハンサー。 [Item A31] The legnace 1 enhancer for use according to any one of items A19 to A31, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ａ３２]　前記エンハンサーが、核酸である、項Ａ３１に記載の使用のためのレグネース１エンハンサー。 [Item A32] The legnes 1 enhancer for use according to item A31, wherein the enhancer is a nucleic acid.
［項Ａ３３]　前記エンハンサーが、抗体である、項Ａ２６に記載の使用のためのレグネース１エンハンサー。 [Item A33] The legnes 1 enhancer for use according to item A26, wherein the enhancer is an antibody.
［項Ａ３４]　前記エンハンサーが、低分子化合物である、項Ａ２６に記載の使用のためのレグネース１エンハンサー。 [Item A34] The legnace 1 enhancer for use according to item A26, wherein the enhancer is a low molecular weight compound.
［項Ａ３５]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ａ３４に記載の使用のためのレグネース１エンハンサー。 [Item A35] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -Benzyl 1 enhancer for use according to item A34, which is benzoic acid (GS143).
［項Ａ３６］
がんの治療及び／又は予防における使用のためのＥ３リガーゼインヒビター。 [Item A36]
E3 ligase inhibitor for use in the treatment and / or prevention of cancer.
［項Ａ３７］
前記がんが、慢性炎症に伴うがんである、項Ａ３６に記載の使用のためのＥ３リガーゼインヒビター。 [Item A37]
The E3 ligase inhibitor for use according to item A36, wherein the cancer is a cancer associated with chronic inflammation.
［項Ａ３８］
前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ａ３７に記載の使用のためのＥ３リガーゼインヒビター。 [Item A38]
The E3 ligase inhibitor for use according to item A37, wherein the cancer associated with chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ａ３９］
前記炎症性腸疾患が、潰瘍性大腸炎である、項Ａ３８に記載の使用のためのＥ３リガーゼインヒビター。 [Item A39]
The E3 ligase inhibitor for use according to item A38, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ａ４０］
前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ａ３６～Ａ３９のいずれか一項に記載の使用のためのＥ３リガーゼインヒビター。 [Item A40]
The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer. , Esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis Item A36 to include at least one selected from the group consisting of germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. E3 ligase inhibitor for use according to any one of A39.
［項Ａ４１]　前記がんが、大腸がんである、項Ａ４０に記載の使用のためのＥ３リガーゼインヒビター。 [Item A41] The E3 ligase inhibitor for use according to item A40, wherein the cancer is colorectal cancer.
［項Ａ４２］
前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ａ４１に記載の使用のためのＥ３リガーゼインヒビター。 [Item A42]
The E3 ligase inhibitor for use according to item A41, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項Ａ４３]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ａ３６～Ａ４２のいずれか一項に記載の使用のためのＥ３リガーゼインヒビター。 [Item A43] The E3 ligase inhibitor for use according to any one of items A36 to A42, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ａ４４］　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ａ３６～Ａ４３のいずれか一項に記載の使用のためのＥ３リガーゼインヒビター。 [Item A44] The E3 ligase inhibitor for use according to any one of Items A36 to A43, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ａ４５］　前記インヒビターが、核酸である、項Ａ４４に記載の使用のためのＥ３リガーゼインヒビター。 [Item A45] The E3 ligase inhibitor for use according to item A44, wherein the inhibitor is a nucleic acid.
［項Ａ４６］　前記インヒビターが、抗Ｅ３リガーゼ抗体である、項Ａ４４に記載の使用のためのＥ３リガーゼインヒビター。 [Item A46] The E3 ligase inhibitor for use according to item A44, wherein the inhibitor is an anti-E3 ligase antibody.
［項Ａ４７］　前記インヒビターが、低分子化合物である、項Ａ４４に記載の使用のためのＥ３リガーゼインヒビター。 [Item A47] The E3 ligase inhibitor for use according to item A44, wherein the inhibitor is a low molecular weight compound.
［項Ａ４８]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ａ４７に記載の使用のためのＥ３リガーゼインヒビター。 [Item A48] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -benzoic acid (GS143), an E3 ligase inhibitor for use according to item A47.
［項Ｂ１]　被験者におけるがんを治療及び／又は予防する方法であって、有効量のＮＦＫＢＩＺインヒビターを該被験者に投与する工程を含む、方法。 [Item B1] A method for treating and / or preventing cancer in a subject, which comprises a step of administering an effective amount of NFKBIZ inhibitor to the subject.
［項Ｂ２]　前記がんが、慢性炎症に伴うがんである、項Ｂ１に記載の方法。 [Item B2] The method according to item B1, wherein the cancer is a cancer associated with chronic inflammation.
［項Ｂ３]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ｂ２に記載の方法。 [Item B3] The method according to Item B2, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ｂ４]　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ｂ３に記載の方法。 [Item B4] The method according to Item B3, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ｂ５]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ｂ１～Ｂ４のいずれか一項に記載の方法。 [Item B5] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, stomach cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The method according to any one of items B1 to B4.
［項Ｂ６]　前記がんが、大腸がんである、項Ｂ５に記載の方法。 [Item B6] The method according to item B5, wherein the cancer is colorectal cancer.
［項Ｂ７]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ｂ６に記載の方法。 [Item B7] The method according to Item B6, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項Ｂ８]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ｂ１～７のいずれか一項に記載の方法。 [Item B8] The method according to any one of Items B1 to 7, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ｂ９]　前記有効量のＮＦＫＢＩＺインヒビターの前記被験者への投与により、ＮＦＫＢＩＺの発現が減少する、及び／又はＮＦＫＢＩＺの機能が抑制される、項Ｂ１～Ｂ８のいずれか一項に記載の方法。 [Item B9] The method according to any one of Items B1 to B8, wherein administration of the effective amount of the NFKBIZ inhibitor to the subject reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
［項Ｂ１０]　前記有効量のＮＦＫＢＩＺインヒビターの前記被験者への投与により、ＮＦＫＢＩＺの核内移行が阻害される、項Ｂ１～Ｂ８のいずれか一項に記載の方法。 [Item B10] The method according to any one of Items B1 to B8, wherein administration of the effective amount of the NFKBIZ inhibitor to the subject inhibits the nuclear translocation of NFKBIZ.
［項Ｂ１１]　前記有効量のＮＦＫＢＩＺインヒビターの前記被験者への投与により、ＮＦＫＢＩＺとｐ５０との結合が阻害される、項Ｂ１～Ｂ８のいずれか一項に記載の方法。 [Item B11] The method according to any one of Items B1 to B8, wherein administration of the effective amount of the NFKBIZ inhibitor to the subject inhibits the binding between NFKBIZ and p50.
［項Ｂ１２]　前記有効量のＮＦＫＢＩＺインヒビターの前記被験者への投与により、ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することが阻害される、項Ｂ１～Ｂ８のいずれか一項に記載の方法。 [Item B12] Any of items B1 to B8, wherein administration of the effective amount of the NFKBIZ inhibitor to the subject inhibits the interaction of the transcription factor consisting of the complex containing NFKBIZ with a specific DNA sequence. The method described in paragraph 1.
［項Ｂ１３]　前記インヒビターが、Ｅ３リガーゼ阻害活性を有する、項Ｂ１～Ｂ１２のいずれか一項に記載の方法。 [Item B13] The method according to any one of Items B1 to B12, wherein the inhibitor has an E3 ligase inhibitory activity.
［項Ｂ１４]　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ｂ１～Ｂ１３のいずれか一項に記載の方法。 [Item B14] The method according to any one of Items B1 to B13, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ｂ１５]　前記インヒビターが、核酸である、項Ｂ１４に記載の方法。 [Item B15] The method according to Item B14, wherein the inhibitor is a nucleic acid.
［項Ｂ１６]　前記インヒビターが、抗ＮＦＫＢＩＺ抗体である、項Ｂ１４に記載の方法。 [Item B16] The method according to Item B14, wherein the inhibitor is an anti-NFKBIZ antibody.
［項Ｂ１７]　前記インヒビターが、低分子化合物である、項Ｂ１４に記載の方法。 [Item B17] The method according to Item B14, wherein the inhibitor is a low molecular weight compound.
［項Ｂ１８]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ｂ１７に記載の方法。 [Item B18] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B17, which is benzoic acid (GS143).
［項Ｂ１９]　被験者におけるがんを治療及び／又は予防する方法であって、有効量のレグネース１エンハンサーを該被験者に投与する工程を含む、方法。 [Item B19] A method for treating and / or preventing cancer in a subject, the method comprising administering to the subject an effective amount of Regnes 1 Enhancer.
［項Ｂ２０]　前記がんが、慢性炎症に伴うがんである、項Ｂ１９に記載の方法。 [Item B20] The method according to item B19, wherein the cancer is a cancer associated with chronic inflammation.
［項Ｂ２１]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ｂ２０に記載の方法。 [Item B21] The method according to item B20, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ｂ２２]　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ｂ２１に記載の方法。 [Item B22] The method according to Item B21, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ｂ２３]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ｂ１９～Ｂ２２のいずれか一項に記載の方法。 [Item B23] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, stomach cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The method according to any one of items B19 to B22.
［項Ｂ２４]　前記がんが、大腸がんである、項Ｂ２３に記載の方法。 [Item B24] The method according to item B23, wherein the cancer is colorectal cancer.
［項Ｂ２５]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ｂ２４に記載の方法。 [Item B25] The method according to item B24, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項Ｂ２６]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ｂ１９～Ｂ２５のいずれか一項に記載の方法。 [Item B26] The method according to any one of Items B19 to B25, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ｂ２７]　前記有効量のレグネース１エンハンサーの前記被験者への投与により、レグネース１の活性が増強される、項Ｂ１９～Ｂ２６のいずれか一項に記載の方法。 [Item B27] The method according to any one of Items B19 to B26, wherein the activity of Legnes 1 is enhanced by administration of the effective amount of the Legnes 1 enhancer to the subject.
［項Ｂ２８]　前記有効量のレグネース１エンハンサーの前記被験者への投与により、レグネース１分解酵素が阻害される、項Ｂ１９～Ｂ２７のいずれか一項に記載の方法。 [Item B28] The method according to any one of Items B19 to B27, wherein the administration of the effective amount of the Regnes 1 enhancer to the subject inhibits the Legnes 1 degrading enzyme.
［項Ｂ２９]　前記レグネース１分解酵素が、レグネース１リン酸化酵素、又はレグネース１ユビキチン化酵素である、項Ｂ２８に記載の方法。 [Item B29] The method according to Item B28, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
［項Ｂ３０]　前記エンハンサーが、Ｅ３リガーゼ阻害活性を有する、項Ｂ２９に記載の方法。 [Item B30] The method according to Item B29, wherein the enhancer has an E3 ligase inhibitory activity.
［項Ｂ３１]　前記エンハンサーが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ｂ１９～Ｂ３０のいずれか一項に記載の方法。 [Item B31] The method according to any one of Items B19 to B30, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ｂ３２]　前記エンハンサーが、核酸である、項Ｂ３１に記載の方法。 [Item B32] The method according to Item B31, wherein the enhancer is a nucleic acid.
［項Ｂ３３]　前記エンハンサーが、抗体である、項Ｂ２６に記載の方法。 [Item B33] The method according to item B26, wherein the enhancer is an antibody.
［項Ｂ３４]　前記エンハンサーが、低分子化合物である、項Ｂ２６に記載の方法。 [Item B34] The method according to Item B26, wherein the enhancer is a low molecular weight compound.
［項Ｂ３５]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ｂ３４に記載の方法。 [Item B35] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B34, which is benzoic acid (GS143).
［項Ｂ３６]　被験者におけるがんを治療及び／又は予防する方法であって、有効量のＥ３リガーゼインヒビターを該被験者に投与する工程を含む、方法。 [Item B36] A method for treating and / or preventing cancer in a subject, which comprises a step of administering an effective amount of an E3 ligase inhibitor to the subject.
［項Ｂ３７］　前記がんが、慢性炎症に伴うがんである、項Ｂ３６に記載の方法。 [Item B37] The method according to item B36, wherein the cancer is a cancer associated with chronic inflammation.
［項Ｂ３８］　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ｂ３７に記載の方法。 [Item B38] The method according to item B37, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ｂ３９］　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ｂ３８に記載の方法。 [Item B39] The method according to item B38, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ｂ４０］　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ｂ３６～Ｂ３９のいずれか一項に記載の方法。 [Item B40] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The method according to any one of items B36 to B39.
［項Ｂ４１］　前記がんが、大腸がんである、項Ｂ４０に記載の方法。 [Item B41] The method according to item B40, wherein the cancer is colorectal cancer.
［項Ｂ４２］　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ｂ４１に記載の方法。 [Item B42] The method according to item B41, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項Ｂ４３］　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ｂ３６～Ｂ４２のいずれか一項に記載の方法。 [Item B43] The method according to any one of Items B36 to B42, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ｂ４４］　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ｂ３６～Ｂ４３のいずれか一項に記載の方法。 [Item B44] The method according to any one of Items B36 to B43, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ｂ４５］　前記インヒビターが、核酸である、項Ｂ４４に記載の方法。 [Item B45] The method according to Item B44, wherein the inhibitor is a nucleic acid.
［項Ｂ４６］　前記インヒビターが、抗Ｅ３リガーゼ抗体である、項Ｂ４４に記載の方法。 [Item B46] The method according to Item B44, wherein the inhibitor is an anti-E3 ligase antibody.
［項Ｂ４７］　前記インヒビターが、低分子化合物である、項Ｂ４４に記載の方法。 [Item B47] The method according to Item B44, wherein the inhibitor is a low molecular weight compound.
［項Ｂ４８］　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ｂ４７に記載の方法。 [Item B48] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B47, which is benzoic acid (GS143).
［項Ｃ１]　がんを治療及び／又は予防するための医薬の製造における、ＮＦＫＢＩＺインヒビターの使用。 [Item C1] Use of NFKBIZ inhibitor in the manufacture of pharmaceuticals for treating and / or preventing cancer.
［項Ｃ２]　前記がんが、慢性炎症に伴うがんである、項Ｃ１に記載の使用。 [Item C2] The use according to item C1, wherein the cancer is a cancer associated with chronic inflammation.
［項Ｃ３]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ｃ２に記載の使用。 [Item C3] The use according to item C2, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ｃ４]　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ｃ３に記載の使用。 [Item C4] The use according to Item C3, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ｃ５]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ｃ１～Ｃ４のいずれか一項に記載の使用。 [Item C5] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The use according to any one of items C1 to C4.
［項Ｃ６]　前記がんが、大腸がんである、項Ｃ５に記載の使用。 [Item C6] The use according to item C5, wherein the cancer is colorectal cancer.
［項Ｃ７]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ｃ６に記載の使用。 [Item C7] The use according to item C6, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項Ｃ８]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ｃ１～Ｃ７のいずれか一項に記載の使用。 [Item C8] The use according to any one of items C1 to C7, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ｃ９]　前記インヒビターが、ＮＦＫＢＩＺの発現を減少させる、及び／又はＮＦＫＢＩＺの機能を抑制するものである、項Ｃ１～Ｃ８のいずれか一項に記載の使用。 [Item C9] The use according to any one of Items C1 to C8, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
［項Ｃ１０]　前記インヒビターが、ＮＦＫＢＩＺの核内移行を阻害するものである、項Ｃ１～Ｃ９のいずれか一項に記載の使用。 [Item C10] The use according to any one of Items C1 to C9, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
［項Ｃ１１]　前記インヒビターが、ＮＦＫＢＩＺとｐ５０との結合を阻害するものである、項Ｃ１～Ｃ１０のいずれか一項に記載の使用。 [Item C11] The use according to any one of Items C1 to C10, wherein the inhibitor inhibits the binding between NFKBIZ and p50.
［項Ｃ１２]　前記インヒビターが、ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することを阻害するものである、項Ｃ１～Ｃ１１のいずれか一項に記載の使用。 [Item C12] The use according to any one of Items C1 to C11, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence.
［項Ｃ１３]　前記インヒビターが、Ｅ３リガーゼ阻害活性を有する、項Ｃ１～Ｃ１２のいずれか一項に記載の使用。 [Item C13] The use according to any one of Items C1 to C12, wherein the inhibitor has an E3 ligase inhibitory activity.
［項Ｃ１４]　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ｃ１～Ｃ１３のいずれか一項に記載の使用。 [Item C14] The use according to any one of Items C1 to C13, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ｃ１５]　前記インヒビターが、核酸である、項Ｃ１４に記載の使用。 [Item C15] The use according to item C14, wherein the inhibitor is a nucleic acid.
［項Ｃ１６]　前記インヒビターが、抗ＮＦＫＢＩＺ抗体である、項Ｃ１４に記載の使用。 [Item C16] The use according to item C14, wherein the inhibitor is an anti-NFKBIZ antibody.
［項Ｃ１７]　前記インヒビターが、低分子化合物である、項Ｃ１４に記載の使用。 [Item C17] The use according to Item C14, wherein the inhibitor is a low molecular weight compound.
［項Ｃ１８]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ｃ１７に記載の使用。 [Item C18] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -the use according to item C17, which is benzoic acid (GS143).
［項Ｃ１９]　がんを治療及び／又は予防するための医薬の製造における、レグネース１エンハンサーの使用。 [Item C19] Use of the Regnes 1 Enhancer in the manufacture of drugs to treat and / or prevent cancer.
［項Ｃ２０]　前記がんが、慢性炎症に伴うがんである、項Ｃ１９に記載の使用。 [Item C20] The use according to item C19, wherein the cancer is a cancer associated with chronic inflammation.
［項Ｃ２１]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ｃ２０に記載の使用。 [Item C21] The use according to item C20, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ｃ２２]　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ｃ２１に記載の使用。 [Item C22] The use according to item C21, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ｃ２３]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ｃ１９～Ｃ２２のいずれか一項に記載の使用。 [Item C23] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The use according to any one of items C19 to C22.
［項Ｃ２４]　前記がんが、大腸がんである、項Ｃ２３に記載の使用。 [Item C24] The use according to item C23, wherein the cancer is colorectal cancer.
［項Ｃ２５]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ｃ２４に記載の使用。 [Item C25] The use according to item C24, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項Ｃ２６]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ｃ１９～Ｃ２５のいずれか一項に記載の使用。 [Item C26] The use according to any one of items C19 to C25, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ｃ２７]　前記エンハンサーが、レグネース１の活性を増強するものである、項Ｃ１９～Ｃ２６のいずれか一項に記載の使用。 [Item C27] The use according to any one of Items C19 to C26, wherein the enhancer enhances the activity of Legnes 1.
［項Ｃ２８]　前記エンハンサーが、レグネース１分解酵素を阻害するものである、項Ｃ１９～Ｃ２７のいずれか一項に記載の使用。 [Item C28] The use according to any one of items C19 to C27, wherein the enhancer inhibits a legnes monodegrading enzyme.
［項Ｃ２９]　前記レグネース１分解酵素が、レグネース１リン酸化酵素、又はレグネース１ユビキチン化酵素である、項Ｃ２８に記載の使用。 [Item C29] The use according to item C28, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
［項Ｃ３０]　前記エンハンサーが、Ｅ３リガーゼ阻害活性を有する、項Ｃ２９に記載の使用。 [Item C30] The use according to Item C29, wherein the enhancer has an E3 ligase inhibitory activity.
［項Ｃ３１]　前記エンハンサーが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ｃ１９～Ｃ３０のいずれか一項に記載の使用。 [Item C31] The use according to any one of Items C19 to C30, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ｃ３２]　前記エンハンサーが、核酸である、項Ｃ３１に記載の使用。 [Item C32] The use according to item C31, wherein the enhancer is a nucleic acid.
［項Ｃ３３]　前記エンハンサーが、抗体である、項Ｃ２６に記載の使用。 [Item C33] The use according to item C26, wherein the enhancer is an antibody.
［項Ｃ３４]　前記エンハンサーが、低分子化合物である、項Ｃ２６に記載の使用。 [Item C34] The use according to Item C26, wherein the enhancer is a low molecular weight compound.
［項Ｃ３５]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ｃ３４に記載の使用。 [Item C35] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -the use according to item C34, which is benzoic acid (GS143).
［項Ｃ３６］
がんを治療及び／又は予防するための医薬の製造における、Ｅ３リガーゼインヒビターの使用。 [Item C36]
Use of E3 ligase inhibitor in the manufacture of drugs to treat and / or prevent cancer.
［項Ｃ３７］
前記がんが、慢性炎症に伴うがんである、項Ｃ３６に記載の使用。 [Item C37]
The use according to item C36, wherein the cancer is a cancer associated with chronic inflammation.
［項Ｃ３８］
前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ｃ３７に記載の使用。 [Item C38]
The use according to item C37, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ｃ３９］
前記炎症性腸疾患が、潰瘍性大腸炎である、項Ｃ３８に記載の使用。 [Item C39]
The use according to item C38, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ｃ４０］
前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ｃ３６～Ｃ３９のいずれか一項に記載の使用。 [Item C40]
The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer. , Esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis Item C36 to include at least one selected from the group consisting of germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. Use according to any one of C39.
［項Ｃ４１]　前記がんが、大腸がんである、項Ｃ４０に記載の使用。 [Item C41] The use according to item C40, wherein the cancer is colorectal cancer.
［項Ｃ４２］　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ｃ４１に記載の使用。 [Item C42] The use according to item C41, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項Ｃ４３]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ｃ３６～Ｃ４２のいずれか一項に記載の使用。 [Item C43] The use according to any one of items C36 to C42, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ｃ４４］　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ｃ３６～Ｃ４３のいずれか一項に記載の使用。 [Item C44] The use according to any one of Items C36 to C43, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ｃ４５］　前記インヒビターが、核酸である、項Ｃ４４に記載の使用。 [Item C45] The use according to item C44, wherein the inhibitor is a nucleic acid.
［項Ｃ４６］　前記インヒビターが、抗Ｅ３リガーゼ抗体である、項Ｃ４４に記載の使用。 [Item C46] The use according to item C44, wherein the inhibitor is an anti-E3 ligase antibody.
［項Ｃ４７］　前記インヒビターが、低分子化合物である、項Ｃ４４に記載の使用。 [Item C47] The use according to Item C44, wherein the inhibitor is a low molecular weight compound.
［項Ｃ４８］　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ｃ４７に記載の使用。 [Item C48] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -the use according to item C47, which is benzoic acid (GS143).
［項４９］　ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇している被験者に投与されることを特徴とする、ＮＦＫＢＩＺインヒビターを有効成分として含む、がんを治療及び／又は予防するための医薬組成物。 [Item 49] Treatment and / or treatment of cancer containing an NFKBIZ inhibitor as an active ingredient, which is administered to a subject in which the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ is increased. A pharmaceutical composition for prevention.
［項５０]　前記ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇している被験者が、
（１）該被験者より取得したがん細胞のＮＦＫＢＩＺ遺伝子の発現及び／又は活性を測定する工程、
（２）（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又は活性を、健常者より採取した細胞中の前記ＮＦＫＢＩＺ遺伝子の発現及び／又は活性（以下、対照値という）と比較する工程、及び
（３）（２）の結果に基づき、（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又は活性が、該対照値よりも大きい場合に、ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇していると判定する工程
を含む工程で決定されることを特徴とする、項４９に記載の組成物。 [Item 50] A subject in which the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ is increased is
(1) A step of measuring the expression and / or activity of the NFKBIZ gene in cancer cells obtained from the subject.
(2) A step of comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ. 49. The composition according to Item 49, wherein the composition is determined by a step including a step of determining that is increasing.
［項５１]　前記がんが、慢性炎症に伴うがんである、項４９又は５０に記載の組成物。 Item 51. The composition according to item 49 or 50, wherein the cancer is a cancer associated with chronic inflammation.
［項５２]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項５１に記載の組成物。 Item 52. The composition according to Item 51, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項５３]　前記炎症性腸疾患が、潰瘍性大腸炎である、項５２に記載の組成物。 Item 53. The composition according to Item 52, wherein the inflammatory bowel disease is ulcerative colitis.
［項５４]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項４９～５３のいずれか一項に記載の組成物。 [Item 54] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , Item 4. The composition according to any one of Items 49 to 53.
［項５５]　前記がんが、大腸がんである、項５４に記載の組成物。 [Item 55] The composition according to Item 54, wherein the cancer is colorectal cancer.
［項５６]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項５５に記載の組成物。 Item 56. The composition according to Item 55, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項５７]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項４９～５６のいずれか一項に記載の組成物。 [Item 57] The composition according to any one of Items 49 to 56, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項５８]　前記インヒビターが、ＮＦＫＢＩＺの発現を減少させる、及び／又はＮＦＫＢＩＺの機能を抑制するものである、項４９～５７のいずれか一項に記載の組成物。 Item 58. The composition according to any one of Items 49 to 57, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
［項５９]　前記インヒビターが、ＮＦＫＢＩＺの核内移行を阻害するものである、項４９～５８のいずれか一項に記載の組成物。 Item 59. The composition according to any one of Items 49 to 58, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
［項６０]　前記インヒビターが、ＮＦＫＢＩＺとｐ５０との結合を阻害するものである、項４９～５９のいずれか一項に記載の組成物。 [Item 60] The composition according to any one of Items 49 to 59, wherein the inhibitor inhibits the binding between NFKBIZ and p50.
［項６１]　前記インヒビターが、ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することを阻害するものである、項４９～６０のいずれか一項に記載の組成物。 Item 61. The composition according to any one of Items 49 to 60, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence.
［項６２]　前記インヒビターが、Ｅ３リガーゼ阻害活性を有する、項４９～６１のいずれか一項に記載の組成物。 Item 62. The composition according to any one of Items 49 to 61, wherein the inhibitor has an E3 ligase inhibitory activity.
［項６３]　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項３９～６２のいずれか一項に記載の組成物。 [Item 63] The composition according to any one of Items 39 to 62, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項６４]　前記インヒビターが、核酸である、項６３に記載の組成物。 [Item 64] The composition according to Item 63, wherein the inhibitor is a nucleic acid.
［項６５]　前記インヒビターが、抗ＮＦＫＢＩＺ抗体である、項６３に記載の組成物。 Item 65. The composition according to Item 63, wherein the inhibitor is an anti-NFKBIZ antibody.
［項６６]　前記インヒビターが、低分子化合物である、項６３に記載の組成物。 Item 66. The composition according to Item 63, wherein the inhibitor is a low molecular weight compound.
［項６７]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項６６に記載の組成物。 [Item 67] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -Benzyl acid (GS143), item 66.
［項Ａ４９]　がんの治療及び／又は予防における使用のためのＮＦＫＢＩＺインヒビターであって、該ＮＦＫＢＩＺインヒビターは、ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇している被験者に投与されることを特徴とする、ＮＦＫＢＩＺインヒビター。 [Item A49] An NFKBIZ inhibitor for use in the treatment and / or prevention of cancer, wherein the NFKBIZ inhibitor is used in subjects with increased expression of NFKBIZ and / or increased activity of NFKBIZ. An NFKBIZ inhibitor, characterized in that it is administered.
［項Ａ５０]　前記ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇している被験者が、
（１）該被験者より取得したがん細胞のＮＦＫＢＩＺ遺伝子の発現及び／又は活性を測定する工程、
（２）（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又は活性を、健常者より採取した細胞中の前記ＮＦＫＢＩＺ遺伝子の発現及び／又は活性（以下、対照値という）と比較する工程、及び
（３）（２）の結果に基づき、（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又は活性が、該対照値よりも大きい場合に、ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇していると判定する工程
を含む工程で決定されることを特徴とする、項Ａ４９に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A50] A subject in which the expression of NFKBIZ is increased and / or the activity of NFKBIZ is increased is
(1) A step of measuring the expression and / or activity of the NFKBIZ gene in cancer cells obtained from the subject.
(2) A step of comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ. NFKBIZ inhibitor for use according to item A49, characterized in that it is determined in a step comprising determining that is elevated.
［項Ａ５１]　前記がんが、慢性炎症に伴うがんである、項Ａ４９又はＡ５０に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A51] The NFKBIZ inhibitor for use according to item A49 or A50, wherein the cancer is a cancer associated with chronic inflammation.
［項Ａ５２]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ａ５１に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A52] The NFKBIZ inhibitor for use according to item A51, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ａ５３]　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ａ５２に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A53] The NFKBIZ inhibitor for use according to item A52, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ａ５４]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ａ４９～Ａ５３のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A54] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , NFKBIZ inhibitor for use according to any one of items A49-A53.
［項Ａ５５]　前記がんが、大腸がんである、項Ａ５４に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A55] The NFKBIZ inhibitor for use according to item A54, wherein the cancer is colorectal cancer.
［項Ａ５６]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ａ５５に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A56] The NFKBIZ inhibitor for use according to item A55, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer. ..
［項Ａ５７]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ａ４９～Ａ５６のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A57] The NFKBIZ inhibitor for use according to any one of items A49 to A56, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ａ５８]　前記インヒビターが、ＮＦＫＢＩＺの発現を減少させる、及び／又はＮＦＫＢＩＺの機能を抑制するものである、項Ａ４９～Ａ５７のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A58] The NFKBIZ inhibitor for use according to any one of items A49 to A57, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
［項Ａ５９]　前記インヒビターが、ＮＦＫＢＩＺの核内移行を阻害するものである、項Ａ４９～Ａ５８のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A59] The NFKBIZ inhibitor for use according to any one of items A49 to A58, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
［項Ａ６０]　前記インヒビターが、ＮＦＫＢＩＺとｐ５０との結合を阻害するものである、項Ａ４９～Ａ５９のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A60] The NFKBIZ inhibitor for use according to any one of items A49 to A59, wherein the inhibitor inhibits the binding of NFKBIZ to p50.
［項Ａ６１]　前記インヒビターが、ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することを阻害するものである、項Ａ４９～Ａ６０のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A61] For the use according to any one of Items A49 to A60, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence. NFKBIZ inhibitor.
［項Ａ６２]　前記インヒビターが、Ｅ３リガーゼ阻害活性を有する、項Ａ４９～Ａ６１のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A62] The NFKBIZ inhibitor for use according to any one of items A49 to A61, wherein the inhibitor has an E3 ligase inhibitory activity.
［項Ａ６３]　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ａ４９～Ａ６２のいずれか一項に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A63] The NFKBIZ inhibitor for use according to any one of Items A49 to A62, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ａ６４]　前記インヒビターが、核酸である、項Ａ６３に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A64] The NFKBIZ inhibitor for use according to item A63, wherein the inhibitor is a nucleic acid.
［項Ａ６５]　前記インヒビターが、抗ＮＦＫＢＩＺ抗体である、項Ａ６３に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A65] The NFKBIZ inhibitor for use according to item A63, wherein the inhibitor is an anti-NFKBIZ antibody.
［項Ａ６６]　前記インヒビターが、低分子化合物である、項Ａ６３に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A66] The NFKBIZ inhibitor for use according to Item A63, wherein the inhibitor is a low molecular weight compound.
［項Ａ６７]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ａ６６に記載の使用のためのＮＦＫＢＩＺインヒビター。 [Item A67] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -Benzyl inhibitor for use according to item A66, which is benzoic acid (GS143).
［項Ｂ４９]　被験者においてがんを治療及び／又は予防する方法であって、該被験者に有効量のＮＦＫＢＩＺインヒビターを投与する工程を含み、該被験者はＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇している被験者である、方法。 [Item B49] A method for treating and / or preventing cancer in a subject, which comprises the step of administering to the subject an effective amount of NFKBIZ inhibitor, in which the subject has increased expression of NFKBIZ and / or. A method of being a subject with elevated NFKBIZ activity.
［項Ｂ５０]　（１）前記被験者より取得したがん細胞のＮＦＫＢＩＺ遺伝子の発現及び／又は活性を測定する工程、
（２）（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又は活性を、健常者より採取した細胞中の前記ＮＦＫＢＩＺ遺伝子の発現及び／又は活性（以下、対照値という）と比較する工程、及び
（３）（２）の結果に基づき、（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又は活性が、該対照値よりも大きい場合に、ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇していると判定する工程
をさらに含む、項Ｂ４９に記載の方法。 [Item B50] (1) A step of measuring the expression and / or activity of the NFKBIZ gene in cancer cells obtained from the subject.
(2) A step of comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ. B49. The method of item B49, further comprising a step of determining that is rising.
［項Ｂ５１]　前記がんが、慢性炎症に伴うがんである、項Ｂ４９又はＢ５０に記載の方法。 [Item B51] The method according to item B49 or B50, wherein the cancer is a cancer associated with chronic inflammation.
［項Ｂ５２]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ｂ５１に記載の方法。 [Item B52] The method according to item B51, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ｂ５３]　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ｂ５２に記載の方法。 [Item B53] The method according to Item B52, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ｂ５４]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ｂ４９～Ｂ５３のいずれか一項に記載の方法。 [Item B54] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The method according to any one of items B49 to B53.
［項Ｂ５５]　前記がんが、大腸がんである、項Ｂ５４に記載の方法。 [Item B55] The method according to item B54, wherein the cancer is colorectal cancer.
［項Ｂ５６]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ｂ５５に記載の方法。 [Item B56] The method according to item B55, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項Ｂ５７]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ｂ４９～Ｂ５６のいずれか一項に記載の方法。 [Item B57] The method according to any one of Items B49 to B56, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ｂ５８]　前記有効量のＮＦＫＢＩＺインヒビターの前記被験者への投与により、ＮＦＫＢＩＺの発現が減少し、及び／又はＮＦＫＢＩＺの機能を抑制する、項Ｂ４９～Ｂ５７のいずれか一項に記載の方法。 [Item B58] The method according to any one of Items B49 to B57, wherein administration of the effective amount of the NFKBIZ inhibitor to the subject reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
［項Ｂ５９]　前記有効量のＮＦＫＢＩＺインヒビターの前記被験者への投与により、ＮＦＫＢＩＺの核内移行が阻害される、項Ｂ４９～Ｂ５８のいずれか一項に記載の方法。 [Item B59] The method according to any one of Items B49 to B58, wherein administration of the effective amount of the NFKBIZ inhibitor to the subject inhibits the nuclear translocation of NFKBIZ.
［項Ｂ６０]　前記有効量のＮＦＫＢＩＺインヒビターの前記被験者への投与により、ＮＦＫＢＩＺとｐ５０との結合が阻害される、項Ｂ４９～Ｂ５９のいずれか一項に記載の方法。 [Item B60] The method according to any one of Items B49 to B59, wherein administration of the effective amount of the NFKBIZ inhibitor to the subject inhibits the binding between NFKBIZ and p50.
［項Ｂ６１]　前記有効量のＮＦＫＢＩＺインヒビターの前記被験者への投与により、ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することが阻害される、項Ｂ４９～６０のいずれか一項に記載の方法。 [Item B61] Any of items B49 to 60, wherein administration of the effective amount of the NFKBIZ inhibitor to the subject inhibits the interaction of the transcription factor consisting of the complex containing NFKBIZ with a specific DNA sequence. The method described in paragraph 1.
［項Ｂ６２]　前記インヒビターが、Ｅ３リガーゼ阻害活性を有する、項Ｂ４９～Ｂ６１のいずれか一項に記載の方法。 [Item B62] The method according to any one of Items B49 to B61, wherein the inhibitor has an E3 ligase inhibitory activity.
［項Ｂ６３]　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ｂ４９～Ｂ６２のいずれか一項に記載の方法。 [Item B63] The method according to any one of Items B49 to B62, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ｂ６４]　前記インヒビターが、核酸である、項Ｂ６３に記載の方法。 [Item B64] The method according to Item B63, wherein the inhibitor is a nucleic acid.
［項Ｂ６５]　前記インヒビターが、抗ＮＦＫＢＩＺ抗体である、項Ｂ６３に記載の方法。 [Item B65] The method according to Item B63, wherein the inhibitor is an anti-NFKBIZ antibody.
［項Ｂ６６]　前記インヒビターが、低分子化合物である、項Ｂ６３に記載の方法。 [Item B66] The method according to Item B63, wherein the inhibitor is a low molecular weight compound.
［項Ｂ６７]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ｂ６６に記載の方法。 [Item B67] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B66, which is benzoic acid (GS143).
［項Ｃ４９]　がんの治療及び／又は予防のための医薬の製造における、ＮＦＫＢＩＺインヒビターの使用であって、該医薬は、ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇している被験者に投与されることを特徴とする、使用。 [Item C49] The use of an NFKBIZ inhibitor in the manufacture of a drug for the treatment and / or prevention of cancer, wherein the drug has increased expression of NFKBIZ and / or increased activity of NFKBIZ. Use, characterized by being administered to a subject.
［項Ｃ５０]　前記ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇している被験者が、
（１）該被験者より取得したがん細胞のＮＦＫＢＩＺ遺伝子の発現及び／又は活性を測定する工程、
（２）（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又は活性を、健常者より採取した細胞中の前記ＮＦＫＢＩＺ遺伝子の発現及び／又は活性（以下、対照値という）と比較する工程、及び
（３）（２）の結果に基づき、（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又は活性が、該対照値よりも大きい場合に、ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇していると判定する工程
を含む工程で決定されることを特徴とする、項Ｃ４９に記載の使用。 [Item C50] A subject in which the expression of NFKBIZ is increased and / or the activity of NFKBIZ is increased is
(1) A step of measuring the expression and / or activity of the NFKBIZ gene in cancer cells obtained from the subject.
(2) A step of comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ. The use according to item C49, wherein the determination is made in a step including a step of determining that is rising.
［項Ｃ５１]　前記がんが、慢性炎症に伴うがんである、項Ｃ４９又はＣ５０に記載の使用。 [Item C51] The use according to item C49 or C50, wherein the cancer is a cancer associated with chronic inflammation.
［項Ｃ５２]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ｃ５１に記載の使用。 [Item C52] The use according to item C51, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ｃ５３]　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ｃ５２に記載の使用。 [Item C53] The use according to item C52, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ｃ５４]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ｃ４９～Ｃ５３のいずれか一項に記載の使用。 [Item C54] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The use according to any one of items C49 to C53.
［項Ｃ５５]　前記がんが、大腸がんである、項Ｃ５４に記載の使用。 [Item C55] The use according to item C54, wherein the cancer is colorectal cancer.
［項Ｃ５６]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ｃ５５に記載の使用。 [Item C56] The use according to item C55, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項Ｃ５７]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ｃ４９～Ｃ５６のいずれか一項に記載の使用。 [Item C57] The use according to any one of items C49 to C56, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ｃ５８]　前記インヒビターが、ＮＦＫＢＩＺの発現を減少させる、及び／又はＮＦＫＢＩＺの機能を抑制するものである、項Ｃ４９～Ｃ５７のいずれか一項に記載の使用。 [Item C58] The use according to any one of items C49 to C57, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
［項Ｃ５９]　前記インヒビターが、ＮＦＫＢＩＺの核内移行を阻害するものである、項Ｃ４９～Ｃ５８のいずれか一項に記載の使用。 [Item C59] The use according to any one of items C49 to C58, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
［項Ｃ６０]　前記インヒビターが、ＮＦＫＢＩＺとｐ５０との結合を阻害するものである、項Ｃ４９～Ｃ５９のいずれか一項に記載の使用。 [Item C60] The use according to any one of items C49 to C59, wherein the inhibitor inhibits the binding between NFKBIZ and p50.
［項Ｃ６１]　前記インヒビターが、ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することを阻害するものである、項Ｃ４９～Ｃ６０のいずれか一項に記載の使用。 [Item C61] The use according to any one of Items C49 to C60, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence.
［項Ｃ６２]　前記インヒビターが、Ｅ３リガーゼ阻害活性を有する、項Ｃ４９～Ｃ６１のいずれか一項に記載の使用。 [Item C62] The use according to any one of items C49 to C61, wherein the inhibitor has an E3 ligase inhibitory activity.
［項Ｃ６３]　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ｃ４９～Ｃ６２のいずれか一項に記載の使用。 [Item C63] The use according to any one of Items C49 to C62, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ｃ６４]　前記インヒビターが、核酸である、項Ｃ６３に記載の使用。 [Item C64] The use according to item C63, wherein the inhibitor is a nucleic acid.
［項Ｃ６５]　前記インヒビターが、抗ＮＦＫＢＩＺ抗体である、項Ｃ６３に記載の使用。 [Item C65] The use according to item C63, wherein the inhibitor is an anti-NFKBIZ antibody.
［項Ｃ６６]　前記インヒビターが、低分子化合物である、項Ｃ６３に記載の使用。 [Item C66] The use according to Item C63, wherein the inhibitor is a low molecular weight compound.
［項Ｃ６７]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ｃ６６に記載の使用。 [Item C67] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -the use according to item C66, which is benzoic acid (GS143).
［項６８]　被験者のがん細胞におけるＮＦＫＢＩＺの遺伝子発現及び／又はＮＦＫＢＩＺの活性を測定することを含む、ＮＦＫＢＩＺインヒビターの該被験者への有効性を予測する方法。 Item 68. A method for predicting the efficacy of an NFKBIZ inhibitor on a subject, which comprises measuring the gene expression of NFKBIZ and / or the activity of NFKBIZ in the cancer cells of the subject.
［項６９]　前記がん細胞におけるＮＦＫＢＩＺの遺伝子発現及び／又はＮＦＫＢＩＺの活性の測定が、
（１）前記被験者より取得したがん細胞のＮＦＫＢＩＺ遺伝子の発現及び／又はＮＦＫＢＩＺの活性を測定する工程、
（２）（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又はＮＦＫＢＩＺの活性を、健常者より採取した細胞中の前記ＮＦＫＢＩＺ遺伝子の発現及び／又はＮＦＫＢＩＺの活性（以下、対照値という）と比較する工程、及び
（３）（２）の結果に基づき、（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又はＮＦＫＢＩＺの活性が、該対照値よりも大きい場合に、ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇していると判定する工程
を含む工程で決定される、項６８に記載の方法。 [Item 69] Measurement of NFKBIZ gene expression and / or NFKBIZ activity in the cancer cells
(1) A step of measuring the expression of the NFKBIZ gene and / or the activity of NFKBIZ in cancer cells obtained from the subject.
(2) The expression and / or NFKBIZ activity of the NFKBIZ gene quantified in (1) is compared with the expression and / or NFKBIZ activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject. Based on the steps and the results of (3) and (2), the expression of NFKBIZ is enhanced when the expression of the NFKBIZ gene and / or the activity of NFKBIZ quantified in (1) is larger than the control value. Item 6. The method according to Item 68, which is determined in a step including a step of determining that the activity of NFKBIZ is increased.
［項７０]　前記がんが、慢性炎症に伴うがんである、項６８または６９に記載の方法。 Item 70. The method according to item 68 or 69, wherein the cancer is a cancer associated with chronic inflammation.
［項７１]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項６８～７０のいずれか一項に記載の方法。 [Item 71] The method according to any one of Items 68 to 70, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項７２]　前記炎症性腸疾患が、潰瘍性大腸炎である、項７１に記載の方法。 Item 72. The method according to Item 71, wherein the inflammatory bowel disease is ulcerative colitis.
［項７３]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項６８～７２のいずれか一項に記載の方法。 [Item 73] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The method according to any one of Items 68 to 72.
［項７４]　前記がんが、大腸がんである、項７３に記載の方法。 [Item 74] The method according to item 73, wherein the cancer is colorectal cancer.
［項７５]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項７４に記載の方法。 Item 75. The method of item 74, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項７６]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項６８～７５のいずれか一項に記載の方法。 Item 7. The method according to any one of Items 68 to 75, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項７７]　前記インヒビターが、ＮＦＫＢＩＺの発現を減少させる、及び／又はＮＦＫＢＩＺの機能を抑制するものである、項６８～７６のいずれか一項に記載の方法。 77. The method of any one of Items 68-76, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
［項７８]　前記インヒビターが、ＮＦＫＢＩＺの核内移行を阻害するものである、項６８～７７のいずれか一項に記載の方法。 Item 78. The method according to any one of Items 68 to 77, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
［項７９]　前記インヒビターが、ＮＦＫＢＩＺとｐ５０との結合を阻害するものである、項６８～７８のいずれか一項に記載の方法。 Item 79. The method according to any one of Items 68 to 78, wherein the inhibitor inhibits the binding between NFKBIZ and p50.
［項８０]　前記インヒビターが、ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することを阻害するものである、項６８～７９のいずれか一項に記載の方法。 Item 80. The method according to any one of Items 68 to 79, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence.
［項８１]　前記インヒビターが、Ｅ３リガーゼ阻害活性を有する、項６８～７９のいずれか一項に記載の方法。 Item 8. The method according to any one of Items 68 to 79, wherein the inhibitor has an E3 ligase inhibitory activity.
［項８２]　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項６８～８１のいずれか一項に記載の方法。 Item 8. The method according to any one of Items 68 to 81, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項８３]　前記インヒビターが、核酸である、項８２に記載の方法。 Item 8. The method according to Item 82, wherein the inhibitor is a nucleic acid.
［項８４]　前記インヒビターが、抗ＮＦＫＢＩＺ抗体である、項８２に記載の方法。 84. The method of item 82, wherein the inhibitor is an anti-NFKBIZ antibody.
［項８５]　前記インヒビターが、低分子化合物である、項８２に記載の方法。 Item 85. The method according to Item 82, wherein the inhibitor is a low molecular weight compound.
［項８６]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項８５に記載の方法。 [Item 86] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -benzoic acid (GS143), item 85.
［項８７]　ＮＦＫＢＩＺインヒビターをスクリーニングする方法であって、
（１）がん細胞にインヒビター候補を作用させずに、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、
（２）該がん細胞に該インヒビター候補を作用させた後に、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、及び
（３）（２）の結果が、（１）の結果よりも小さい場合に、該インヒビター候補を、ＮＦＫＢＩＺインヒビターであると判定する工程、
を含む、方法。 [Item 87] A method for screening an NFKBIZ inhibitor.
(1) A step of measuring the gene expression and / or activity of NFKBIZ without allowing an inhibitor candidate to act on cancer cells.
(2) The step of measuring the gene expression and / or activity of NFKBIZ after allowing the inhibitor candidate to act on the cancer cells, and when the results of (3) and (2) are smaller than the results of (1). In addition, a step of determining the inhibitor candidate as an NFKBIZ inhibitor,
Including methods.
［項８８]　がんの治療及び／又は予防剤をスクリーニングする方法であって、
（１）がん細胞に治療及び／又は予防剤候補を作用させずに、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、
（２）該がん細胞に該治療及び／又は予防剤候補を作用させた後に、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、及び
（３）（２）の結果が、（１）の結果よりも小さい場合に、該治療及び／又は予防剤候補を、がんの治療及び／又は予防剤であると判定する工程、
を含む、方法。 [Item 88] A method for screening a therapeutic and / or preventive agent for cancer.
(1) A step of measuring gene expression and / or activity of NFKBIZ without allowing a therapeutic and / or prophylactic agent candidate to act on cancer cells.
(2) The steps of measuring the gene expression and / or activity of NFKBIZ after allowing the therapeutic and / or prophylactic agent candidate to act on the cancer cells, and the results of (3) and (2) are the results of (1). A step of determining the therapeutic and / or prophylactic agent candidate as a cancer therapeutic and / or prophylactic agent if the result is smaller than the result.
Including methods.
［項８９]　ＮＦＫＢＩＺの発現量を減少させる物質、及び／又はＮＦＫＢＩＺの機能を抑制する物質をスクリーニングする方法であって、
（１）がん細胞に被験物質を作用させずに、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、
（２）該がん細胞に該被験物質を作用させた後に、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、及び
（３）（２）の結果が、（１）の結果よりも小さい場合に、該被験物質を、ＮＦＫＢＩＺの発現量を減少させる物質、及び／又はＮＦＫＢＩＺの機能を抑制する物質であると判定する工程、
を含む、方法。 [Item 89] A method for screening a substance that reduces the expression level of NFKBIZ and / or a substance that suppresses the function of NFKBIZ.
(1) A step of measuring the gene expression and / or activity of NFKBIZ without allowing a test substance to act on cancer cells.
(2) The step of measuring the gene expression and / or activity of NFKBIZ after allowing the test substance to act on the cancer cells, and when the results of (3) and (2) are smaller than the results of (1). In addition, a step of determining that the test substance is a substance that reduces the expression level of NFKBIZ and / or a substance that suppresses the function of NFKBIZ.
Including methods.
［項９０]　前記がんが、慢性炎症に伴うがんである、項８７～８９のいずれか一項に記載の方法。 Item 90. The method according to any one of Items 87 to 89, wherein the cancer is a cancer associated with chronic inflammation.
［項９１]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項８７～９０のいずれか一項に記載の方法。 Item 9. The method according to any one of Items 87 to 90, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項９２]　前記炎症性腸疾患が、潰瘍性大腸炎である、項９１に記載の方法。 Item 92. The method according to Item 91, wherein the inflammatory bowel disease is ulcerative colitis.
［項９３]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項８７～９１のいずれか一項に記載の方法。 [Item 93] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , Item 8. The method according to any one of Items 87 to 91.
［項９４]　前記がんが、大腸がんである、項９３に記載の方法。 [Item 94] The method according to Item 93, wherein the cancer is colorectal cancer.
［項９５]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項９４に記載の方法。 95. The method of item 94, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項９６]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項８７～９５のいずれか一項に記載の方法。 Item 9. The method according to any one of Items 87 to 95, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項９７]　前記インヒビターが、ＮＦＫＢＩＺの発現を減少させる、及び／又はＮＦＫＢＩＺの機能を抑制するものである、項８７～９６のいずれか一項に記載の方法。 [Item 97] The method according to any one of Items 87 to 96, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
［項９８]　前記インヒビターが、ＮＦＫＢＩＺの核内移行を阻害するものである、項８７～９７のいずれか一項に記載の方法。 Item 9. The method according to any one of Items 87 to 97, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
［項９９]　前記インヒビターが、ＮＦＫＢＩＺとｐ５０との結合を阻害するものである、項８７～９８のいずれか一項に記載の方法。 Item 9. The method according to any one of Items 87 to 98, wherein the inhibitor inhibits the binding between NFKBIZ and p50.
［項１００]　前記インヒビターが、ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することを阻害するものである、項８７～９９のいずれか一項に記載の方法。 [Item 100] The method according to any one of Items 87 to 99, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence.
［項１０１]　前記インヒビターが、Ｅ３リガーゼ阻害活性を有する、項８７～１００のいずれか一項に記載の方法。 Item 10. The method according to any one of Items 87 to 100, wherein the inhibitor has an E3 ligase inhibitory activity.
［項１０２]　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項８７～１０１のいずれか一項に記載の方法。 Item 10. The method according to any one of Items 87 to 101, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項１０３]　前記インヒビターが、核酸である、項１０２に記載の方法。 Item 10. The method according to Item 102, wherein the inhibitor is a nucleic acid.
［項１０４]　前記インヒビターが、抗ＮＦＫＢＩＺ抗体である、項１０２に記載の方法。 [Item 104] The method according to Item 102, wherein the inhibitor is an anti-NFKBIZ antibody.
［項１０５]　前記インヒビターが、低分子化合物である、項１０２に記載の方法。 Item 105. The method according to Item 102, wherein the inhibitor is a low molecular weight compound.
［項１０６]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項１０５に記載の方法。 [Item 106] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -Benzyl acid (GS143), item 105.
［項１０７]　レグネース１の発現が低下している、及び／又はレグネース１の活性が低下している被験者に投与されることを特徴とする、レグネース１エンハンサーを含む、がんを治療及び／又は予防するための医薬組成物。 [Item 107] Treatment and / or treatment of cancer, including a Legnes 1 enhancer, characterized in that it is administered to a subject with reduced expression of Legnes 1 and / or decreased activity of Legnes 1. A pharmaceutical composition for prevention.
［項１０８]　前記レグネース１発現が低下している、及び／又はレグネース１の活性が低下している被験者が、
（１）該被験者より取得したがん細胞のレグネース１の発現及び／又は活性を測定する工程、
（２）（１）で定量したレグネース１の発現及び／又は活性を、健常者より採取した細胞中の前記レグネース１の発現及び／又は活性（以下、対照値という）と比較する工程、及び
（３）（２）の結果に基づき、（１）で定量したレグネース１の発現及び／又は活性が、対照値よりも小さい場合に、レグネース１の発現及び／又は活性が低下していると判定する工程
を含む工程で決定されることを特徴とする、項１０７に記載の組成物。 [Item 108] A subject whose expression of Legnes 1 is reduced and / or whose activity of Legnes 1 is reduced is
(1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject.
(2) A step of comparing the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased. Item 10. The composition according to Item 107, which is determined by a step including a step.
［項１０９]　前記がんが、慢性炎症に伴うがんである、項１０７又は１０８に記載の組成物。 [Item 109] The composition according to item 107 or 108, wherein the cancer is a cancer associated with chronic inflammation.
［項１１０]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項１０９に記載の組成物。 Item 110. The composition according to Item 109, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項１１１]　前記炎症性腸疾患が、潰瘍性大腸炎である、項１１０に記載の組成物。 Item 11. The composition according to Item 110, wherein the inflammatory bowel disease is ulcerative colitis.
［項１１２]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項１０７～１１１のいずれか一項に記載の組成物。 [Item 112] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , Item 10. The composition according to any one of Items 107 to 111.
［項１１３]　前記がんが、大腸がんである、項１１２に記載の組成物。 [Item 113] The composition according to Item 112, wherein the cancer is colorectal cancer.
［項１１４]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項１１３に記載の組成物。 [Item 114] The composition according to Item 113, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項１１５]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項１０７～１１４のいずれか一項に記載の組成物。 [Item 115] The composition according to any one of Items 107 to 114, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項１１６]　前記エンハンサーが、レグネース１の活性を増強するものである、項１０７～１１５のいずれか一項に記載の組成物。 Item 16. The composition according to any one of Items 107 to 115, wherein the enhancer enhances the activity of Legnes 1.
［項１１７]　前記エンハンサーが、レグネース１分解酵素を阻害するものである、項１０７～１１６のいずれか一項に記載の組成物。 Item 17. The composition according to any one of Items 107 to 116, wherein the enhancer inhibits a legnes monodegrading enzyme.
［項１１８]　前記レグネース１分解酵素が、レグネース１リン酸化酵素、又はレグネース１ユビキチン化酵素である、項１１７に記載の組成物。 [Item 118] The composition according to Item 117, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
［項１１９]　前記エンハンサーが、Ｅ３リガーゼ阻害活性を有する、項１０７～１１８のいずれか一項に記載の組成物。 Item 119. The composition according to any one of Items 107 to 118, wherein the enhancer has an E3 ligase inhibitory activity.
［項１２０]　前記エンハンサーが、核酸、抗体、低分子化合物、又は高分子化合物である、項１０７～１１９のいずれか一項に記載の組成物。 Item 120. The composition according to any one of Items 107 to 119, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項１２１]　前記エンハンサーが、核酸である、項１２０に記載の組成物。 Item 12. The composition according to Item 120, wherein the enhancer is a nucleic acid.
［項１２２]　前記エンハンサーが、抗体である、項１２０に記載の組成物。 Item 122. The composition according to Item 120, wherein the enhancer is an antibody.
［項１２３]　前記エンハンサーが、低分子化合物である、項１２０に記載の組成物。 Item 123. The composition according to Item 120, wherein the enhancer is a low molecular weight compound.
［項１２４]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項１２３に記載の組成物。 [Item 124] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -Benzyl acid (GS143), item 123.
［項Ａ１０７]　がんの治療及び／又は予防における使用のためのレグネース１エンハンサーであって、該レグネース１エンハンサーは、レグネース１の発現が低下している、及び／又はレグネース１の活性が低下している被験者に投与されることを特徴とする、レグネース１エンハンサー。 [Item A107] A legnes 1 enhancer for use in the treatment and / or prevention of cancer, wherein the legnes 1 enhancer has decreased expression of legnes 1 and / or decreased activity of legnes 1. A legnes 1 enhancer, characterized in that it is administered to a subject.
［項Ａ１０８]　前記レグネース１発現が低下している、及び／又はレグネース１の活性が低下している被験者が、
（１）該被験者より取得したがん細胞のレグネース１の発現及び／又は活性を測定する工程、
（２）（１）で定量したレグネース１の発現及び／又は活性を、健常者より採取した細胞中の前記レグネース１の発現及び／又は活性（以下、対照値という）と比較する工程、及び
（３）（２）の結果に基づき、（１）で定量したレグネース１の発現及び／又は活性が、対照値よりも小さい場合に、レグネース１の発現及び／又は活性が低下していると判定する工程
を含む工程で決定されることを特徴とする、項Ａ１０７に記載の使用のためのレグネース１エンハンサー。 [Item A108] A subject whose expression of Legnes 1 is reduced and / or whose activity of Legnes 1 is reduced is
(1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject.
(2) A step of comparing the expression and / or activity of legnes 1 quantified in (1) with the expression and / or activity of legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased. The Legnes 1 enhancer for use according to item A107, characterized in that it is determined in a process that includes a process.
［項Ａ１０９］　前記がんが、慢性炎症に伴うがんである、項Ａ１０７又はＡ１０８に記載の使用のためのレグネース１エンハンサー。 [Item A109] The Legnes 1 enhancer for use according to item A107 or A108, wherein the cancer is a cancer associated with chronic inflammation.
［項Ａ１１０]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ａ１０９に記載の使用のためのレグネース１エンハンサー。 [Item A110] The Legnes 1 enhancer for use according to item A109, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ａ１１１]　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ａ１１０に記載の使用のためのレグネース１エンハンサー。 [Item A111] The legnes 1 enhancer for use according to item A110, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ａ１１２]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ａ１０７～Ａ１１１のいずれか一項に記載の使用のためのレグネース１エンハンサー。 [Item A112] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , A Legnes 1 Enhancer for use according to any one of Items A107 to A111.
［項Ａ１１３]　前記がんが、大腸がんである、項Ａ１１２に記載の使用のためのレグネース１エンハンサー。 [Item A113] The Legnes 1 enhancer for use according to item A112, wherein the cancer is colorectal cancer.
［項Ａ１１４]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ａ１１３に記載の使用のためのレグネース１エンハンサー。 Item A114. Legnes 1 for use according to item A113, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer. Enhancer.
［項Ａ１１５]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ａ１０７～Ａ１１４のいずれか一項に記載の使用のためのレグネース１エンハンサー。 [Item A115] The Legnes 1 enhancer for use according to any one of items A107 to A114, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ａ１１６]　前記エンハンサーが、レグネース１の活性を増強するものである、項Ａ１０７～１１５のいずれか一項に記載の使用のためのレグネース１エンハンサー。 [Item A116] The legnes 1 enhancer for use according to any one of items A107 to 115, wherein the enhancer enhances the activity of legnes 1.
［項Ａ１１７]　前記エンハンサーが、レグネース１分解酵素を阻害するものである、項Ａ１０７～Ａ１１６のいずれか一項に記載の使用のためのレグネース１エンハンサー。 [Item A117] The legnace 1 enhancer for use according to any one of items A107 to A116, wherein the enhancer inhibits a legnace degrading enzyme.
［項Ａ１１８]　前記レグネース１分解酵素が、レグネース１リン酸化酵素、又はレグネース１ユビキチン化酵素である、項Ａ１１７に記載の使用のためのレグネース１エンハンサー。 [Item A118] The legnes 1 enhancer for use according to item A117, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
［項Ａ１１９]　前記エンハンサーが、Ｅ３リガーゼ阻害活性を有する、項Ａ１０７～Ａ１１８のいずれか一項に記載の使用のためのレグネース１エンハンサー。 [Item A119] The legnes 1 enhancer for use according to any one of items A107 to A118, wherein the enhancer has an E3 ligase inhibitory activity.
［項Ａ１２０]　前記エンハンサーが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ａ１０７～Ａ１１９のいずれか一項に記載の使用のためのレグネース１エンハンサー。 [Item A120] The legnace 1 enhancer for use according to any one of items A107 to A119, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ａ１２１]　前記エンハンサーが、核酸である、項Ａ１２０に記載の使用のためのレグネース１エンハンサー。 [Item A121] The legnes 1 enhancer for use according to item A120, wherein the enhancer is a nucleic acid.
［項Ａ１２２]　前記エンハンサーが、抗体である、項Ａ１２０に記載の使用のためのレグネース１エンハンサー。 [Item A122] The legnes 1 enhancer for use according to item A120, wherein the enhancer is an antibody.
［項Ａ１２３]　前記エンハンサーが、低分子化合物である、項Ａ１２０に記載の使用のためのレグネース１エンハンサー。 [Item A123] The legnace 1 enhancer for use according to item A120, wherein the enhancer is a low molecular weight compound.
［項Ａ１２４]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ａ１２３に記載の使用のためのレグネース１エンハンサー。 [Item A124] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -benzoic acid (GS143), a legnes 1 enhancer for use according to item A123.
［項Ｂ１０７]　被験者においてがんを治療及び／又は予防する方法であって、該被験者に有効量のレグネース１エンハンサーを投与する工程を含み、該被験者はレグネース１の発現が低下している、及び／又はレグネース１の活性が低下している、方法。 [Item B107] A method for treating and / or preventing cancer in a subject, which comprises the step of administering an effective amount of Legnes 1 enhancer to the subject, and the subject has decreased expression of Legnes 1. / Or a method in which the activity of legnes 1 is reduced.
［項Ｂ１０８］
（１）前記被験者より取得したがん細胞のレグネース１の発現及び／又は活性を測定する工程、
（２）（１）で定量したレグネース１の発現及び／又は活性を、健常者より採取した細胞中の前記レグネース１の発現及び／又は活性（以下、対照値という）と比較する工程、及び
（３）（２）の結果に基づき、（１）で定量したレグネース１の発現及び／又は活性が、対照値よりも小さい場合に、レグネース１の発現及び／又は活性が低下していると判定する工程
をさらに含む、項Ｂ１０７に記載の方法。 [Item B108]
(1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject.
(2) A step of comparing the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased. Item 6. The method of item B107, further comprising a step.
［項Ｂ１０９]　前記がんが、慢性炎症に伴うがんである、項Ｂ１０７又はＢ１０８に記載の方法。 [Item B109] The method according to Item B107 or B108, wherein the cancer is a cancer associated with chronic inflammation.
［項Ｂ１１０]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ｂ１０９に記載の方法。 [Item B110] The method according to item B109, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ｂ１１１]　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ｂ１１０に記載の方法。 [Item B111] The method according to Item B110, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ｂ１１２]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ｂ１０７～Ｂ１１１のいずれか一項に記載の方法。 [Item B112] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The method according to any one of items B107 to B111.
［項Ｂ１１３]　前記がんが、大腸がんである、項Ｂ１１２に記載の方法。 [Item B113] The method according to Item B112, wherein the cancer is colorectal cancer.
［項Ｂ１１４］　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ｂ１１３に記載の方法。 [Item B114] The method according to Item B113, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項Ｂ１１５]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ｂ１０７～Ｂ１１４のいずれか一項に記載の方法。 [Item B115] The method according to any one of Items B107 to B114, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ｂ１１６]　前記有効量のレグネース１エンハンサーの前記被験者への投与により、レグネース１の活性が増強される、項Ｂ１０７～Ｂ１１５のいずれか一項に記載の方法。 [Item B116] The method according to any one of Items B107 to B115, wherein the activity of Legnes 1 is enhanced by administration of the effective amount of the Legnes 1 enhancer to the subject.
［項Ｂ１１７]　前記有効量のレグネース１エンハンサーの前記被験者への投与により、レグネース１分解酵素が阻害される、項Ｂ１０７～Ｂ１１６のいずれか一項に記載の方法。 [Item B117] The method according to any one of Items B107 to B116, wherein the administration of the effective amount of the Regnes 1 enhancer to the subject inhibits the Regnes 1 degrading enzyme.
［項Ｂ１１８]　前記レグネース１分解酵素が、レグネース１リン酸化酵素、又はレグネース１ユビキチン化酵素である、項Ｂ１１７に記載の方法。 Item B118. The method according to Item B117, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
［項Ｂ１１９]　前記エンハンサーが、Ｅ３リガーゼ阻害活性を有する、項Ｂ１０７～Ｂ１１８のいずれか一項に記載の方法。 [Item B119] The method according to any one of Items B107 to B118, wherein the enhancer has an E3 ligase inhibitory activity.
［項Ｂ１２０]　前記エンハンサーが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ｂ１０７～Ｂ１１９のいずれか一項に記載の方法。 [Item B120] The method according to any one of Items B107 to B119, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ｂ１２１]　前記エンハンサーが、核酸である、項Ｂ１２０に記載の方法。 [Item B121] The method according to Item B120, wherein the enhancer is a nucleic acid.
［項Ｂ１２２]　前記エンハンサーが、抗体である、項Ｂ１２０に記載の方法。 [Item B122] The method according to Item B120, wherein the enhancer is an antibody.
［項Ｂ１２３]　前記エンハンサーが、低分子化合物である、項Ｂ１２０に記載の方法。 [Item B123] The method according to Item B120, wherein the enhancer is a low molecular weight compound.
［項Ｂ１２４]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ｂ１２３に記載の方法。 [Item B124] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B123, which is benzoic acid (GS143).
［項Ｃ１０７］　がんの治療及び／又は予防のための医薬の製造における、レグネース１エンハンサーの使用であって、該医薬はレグネース１の発現が低下している、及び／又はレグネース１の活性が低下している被験者に投与されることを特徴とする、使用。 [Item C107] The use of a legnes 1 enhancer in the manufacture of a drug for the treatment and / or prevention of cancer, wherein the drug has reduced expression of legnes 1 and / or activity of legnes 1. Use, characterized by being administered to a declining subject.
［項Ｃ１０８］　前記レグネース１発現が低下している、及び／又はレグネース１の活性が低下している被験者が、
（１）該被験者より取得したがん細胞のレグネース１の発現及び／又は活性を測定する工程、
（２）（１）で定量したレグネース１の発現及び／又は活性を、健常者より採取した細胞中の前記レグネース１の発現及び／又は活性（以下、対照値という）と比較する工程、及び
（３）（２）の結果に基づき、（１）で定量したレグネース１の発現及び／又は活性が、対照値よりも小さい場合に、レグネース１の発現及び／又は活性が低下していると判定する工程
を含む工程で決定されることを特徴とする、項Ｃ１０７に記載の使用。 [Item C108] A subject whose expression of Legnes 1 is reduced and / or whose activity of Legnes 1 is reduced is
(1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject.
(2) A step of comparing the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased. Item 6. The use according to item C107, which is determined in a process including the process.
［項Ｃ１０９］　前記がんが、慢性炎症に伴うがんである、項Ｃ１０７又はＣ１０８に記載の使用。 [Item C109] The use according to item C107 or C108, wherein the cancer is a cancer associated with chronic inflammation.
［項Ｃ１１０］　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ｃ１０９に記載の使用。 [Item C110] The use according to item C109, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項Ｃ１１１］　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ｃ１１０に記載の使用。 [Item C111] The use according to item C110, wherein the inflammatory bowel disease is ulcerative colitis.
［項Ｃ１１２］　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ｃ１０７～Ｃ１１１のいずれか一項に記載の使用。 [Item C112] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The use according to any one of items C107 to C111.
［項Ｃ１１３］　前記がんが、大腸がんである、項Ｃ１１２に記載の使用。 [Item C113] The use according to item C112, wherein the cancer is colorectal cancer.
［項Ｃ１１４］　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ｃ１１３に記載の使用。 [Item C114] The use according to item C113, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項Ｃ１１５］　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ｃ１０７～Ｃ１１４のいずれか一項に記載の使用。 [Item C115] The use according to any one of items C107 to C114, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項Ｃ１１６］　前記エンハンサーが、レグネース１の活性を増強するものである、項Ｃ１０７～Ｃ１１５のいずれか一項に記載の使用。 [Item C116] The use according to any one of Items C107 to C115, wherein the enhancer enhances the activity of Legnes 1.
［項Ｃ１１７］　前記エンハンサーが、レグネース１分解酵素を阻害するものである、項Ｃ１０７～Ｃ１１６のいずれか一項に記載の使用。 [Item C117] The use according to any one of items C107 to C116, wherein the enhancer inhibits a legnes monodegrading enzyme.
［項Ｃ１１８］　前記レグネース１分解酵素が、レグネース１リン酸化酵素、又はレグネース１ユビキチン化酵素である、項Ｃ１１７に記載の使用。 [Item C118] The use according to Item C117, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
［項Ｃ１１９］　前記エンハンサーが、Ｅ３リガーゼ阻害活性を有する、項Ｃ１０７～Ｃ１１８のいずれか一項に記載の使用。 [Item C119] The use according to any one of Items C107 to C118, wherein the enhancer has an E3 ligase inhibitory activity.
［項Ｃ１２０］　前記エンハンサーが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ｃ１０７～Ｃ１１９のいずれか一項に記載の使用。 [Item C120] The use according to any one of Items C107 to C119, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項Ｃ１２１］　前記エンハンサーが、核酸である、項Ｃ１２０に記載の使用。 [Item C121] The use according to item C120, wherein the enhancer is a nucleic acid.
［項Ｃ１２２］　前記エンハンサーが、抗体である、項Ｃ１２０に記載の使用。 [Item C122] The use according to item C120, wherein the enhancer is an antibody.
［項Ｃ１２３］　前記エンハンサーが、低分子化合物である、項Ｃ１２０に記載の使用。 [Item C123] The use according to Item C120, wherein the enhancer is a low molecular weight compound.
［項Ｃ１２４］　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ｃ１２３に記載の使用。 [Item C124] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -the use according to item C123, which is benzoic acid (GS143).
［項１２５]　被験者のがん細胞におけるレグネース１の発現及び／又は活性を測定することを含む、レグネース１エンハンサーの該被験者への有効性を予測する方法。 [Item 125] A method for predicting the effectiveness of a Legnes 1 enhancer on a subject, which comprises measuring the expression and / or activity of Legnes 1 in the cancer cells of the subject.
［項１２６]　前記がん細胞におけるレグネース１の発現及び／又は活性の測定が、
（１）前記被験者より取得したがん細胞のレグネース１の発現及び／又は活性を測定する工程、
（２）（１）で定量したレグネース１の発現及び／又は活性を、健常者より採取した細胞中の前記レグネース１の発現及び／又は活性（以下、対照値という）と比較する工程、及び
（３）（２）の結果に基づき、（１）で定量したレグネース１の発現及び／又は活性が、対照値よりも小さい場合に、レグネース１の発現及び／又は活性が低下していると判定する工程
を含む工程で決定される、項１２５に記載の方法。 [Item 126] Measurement of the expression and / or activity of Legnes 1 in the cancer cells
(1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject.
(2) A step of comparing the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased. Item 125. The method according to Item 125, which is determined by a step including the step.
［項１２７]　前記がんが、慢性炎症に伴うがんである、項１２５又は１２６に記載の方法。 [Item 127] The method according to Item 125 or 126, wherein the cancer is a cancer associated with chronic inflammation.
［項１２８]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項１２７に記載の方法。 Item 128. The method according to Item 127, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項１２９]　前記炎症性腸疾患が、潰瘍性大腸炎である、項１２８に記載の方法。 Item 129. The method according to Item 128, wherein the inflammatory bowel disease is ulcerative colitis.
［項１３０]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項１２５～１２９のいずれか一項に記載の方法。 [Item 130] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The method according to any one of Items 125 to 129.
［項１３１]　前記がんが、大腸がんである、項１３０に記載の方法。 [Item 131] The method according to Item 130, wherein the cancer is colorectal cancer.
［項１３２]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項１３１に記載の方法。 Item 132. The method of item 131, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項１３３]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項１２５～１３２のいずれか一項に記載の方法。 [Item 133] The method according to any one of Items 125 to 132, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項１３４]　前記エンハンサーが、レグネース１の活性を増強するものである、項１２５～１３３のいずれか一項に記載の方法。 [Item 134] The method according to any one of Items 125 to 133, wherein the enhancer enhances the activity of Legnes 1.
［項１３５]　前記エンハンサーが、レグネース１分解酵素を阻害するものである、項１２５～１３４のいずれか一項に記載の方法。 [Item 135] The method according to any one of Items 125 to 134, wherein the enhancer inhibits a legnes monodegrading enzyme.
［項１３６]　前記レグネース１分解酵素が、レグネース１リン酸化酵素、又はレグネース１ユビキチン化酵素である、項１３５に記載の方法。 [Item 136] The method according to Item 135, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
［項１３７]　前記エンハンサーが、Ｅ３リガーゼ阻害活性を有する、項１２５～１３６のいずれか一項に記載の方法。 Item 137. The method according to any one of Items 125 to 136, wherein the enhancer has an E3 ligase inhibitory activity.
［項１３８]　前記エンハンサーが、核酸、抗体、低分子化合物、又は高分子化合物である、項１２５～１３７のいずれか一項に記載の方法。 Item 138. The method according to any one of Items 125 to 137, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項１３９]　前記エンハンサーが、核酸である、項１３８に記載の方法。 Item 139. The method according to Item 138, wherein the enhancer is a nucleic acid.
［項１４０]　前記エンハンサーが、抗体である、項１３８に記載の方法。 [Item 140] The method according to Item 138, wherein the enhancer is an antibody.
［項１４１]　前記エンハンサーが、低分子化合物である、項１３８に記載の方法。 [Item 141] The method according to Item 138, wherein the enhancer is a low molecular weight compound.
［項１４２]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項１４１に記載の方法。 [Item 142] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -Benzyl acid (GS143), item 141.
［項１４３]　レグネース１エンハンサーをスクリーニングする方法であって、
（１）がん細胞にエンハンサー候補を作用させずに、レグネース１の発現及び／又は活性を測定する工程、
（２）該がん細胞に該エンハンサー候補を作用させた後に、レグネース１の発現及び／又は活性を測定する工程、及び
（３）（２）の結果が、（１）の結果よりも大きい場合に、該エンハンサー候補を、レグネース１エンハンサーであると判定する工程、
を含む、方法。 [Item 143] A method for screening a Legnes 1 enhancer.
(1) A step of measuring the expression and / or activity of Legnes 1 without allowing an enhancer candidate to act on cancer cells.
(2) A step of measuring the expression and / or activity of Legnes 1 after allowing the enhancer candidate to act on the cancer cells, and when the results of (3) and (2) are larger than the results of (1). In addition, a step of determining the enhancer candidate as a legnace 1 enhancer,
Including methods.
［項１４４]　がんの治療及び／又は予防剤をスクリーニングする方法であって、
（１）がん細胞に治療及び／又は予防剤候補を作用させずに、レグネース１の発現及び／又は活性を測定する工程、
（２）該がん細胞に該治療及び／又は予防剤候補を作用させた後に、レグネース１の発現及び／又は活性を測定する工程、及び
（３）（２）の結果が、（１）の結果よりも大きい場合に、該治療及び／又は予防剤候補を、がんの治療及び／又は予防剤であると判定する工程、
を含む、方法。 [Item 144] A method for screening a therapeutic and / or preventive agent for cancer.
(1) A step of measuring the expression and / or activity of Legnes 1 without allowing a therapeutic and / or prophylactic agent candidate to act on cancer cells.
(2) The steps of measuring the expression and / or activity of Legnes 1 after allowing the therapeutic and / or prophylactic agent candidate to act on the cancer cells, and the results of (3) and (2) are the results of (1). A step of determining the therapeutic and / or prophylactic agent candidate as a cancer therapeutic and / or prophylactic agent if it is greater than the result.
Including methods.
［項１４５]　レグネース１の活性を増強する物質をスクリーニングする方法であって、
（１）がん細胞に被験物質を作用させずに、レグネース１の活性を測定する工程、
（２）該がん細胞に該被験物質を作用させた後に、レグネース１の活性を測定する工程、及び
（３）（２）の結果が、（１）の結果よりも大きい場合に、該被験物質を、レグネース１の活性を増強する物質であると判定する工程、
を含む、方法。 [Item 145] A method for screening a substance that enhances the activity of Legnes 1.
(1) A step of measuring the activity of Legnes 1 without allowing a test substance to act on cancer cells.
(2) The step of measuring the activity of Regnes 1 after allowing the test substance to act on the cancer cells, and when the results of (3) and (2) are larger than the results of (1), the test is performed. A step of determining a substance as a substance that enhances the activity of Legnes 1.
Including methods.
［項１４６]　前記がんが、慢性炎症に伴うがんである、項１４３～１４５のいずれか一項に記載の方法。 [Item 146] The method according to any one of Items 143 to 145, wherein the cancer is a cancer associated with chronic inflammation.
［項１４７]　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項１４６に記載の方法。 Item 147. The method according to Item 146, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
［項１４８]　前記炎症性腸疾患が、潰瘍性大腸炎である、項１４７に記載の方法。 Item 148. The method according to Item 147, wherein the inflammatory bowel disease is ulcerative colitis.
［項１４９]　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項１４３～１４８のいずれか一項に記載の方法。 [Item 149] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , Item 14. The method according to any one of Items 143 to 148.
［項１５０]　前記がんが、大腸がんである、項１４９に記載の方法。 [Item 150] The method according to Item 149, wherein the cancer is colorectal cancer.
［項１５１]　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項１５０に記載の方法。 Item 15. The method according to Item 150, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
［項１５２]　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項１４３～１５１のいずれか一項に記載の方法。 [Item 152] The method according to any one of Items 143 to 151, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
［項１５３]　前記エンハンサーが、レグネース１の活性を増強するものである、項１４３～１５２のいずれか一項に記載の方法。 Item 153. The method according to any one of Items 143 to 152, wherein the enhancer enhances the activity of Legnes 1.
［項１５４]　前記エンハンサーが、レグネース１分解酵素を阻害するものである、項１４３～１５３のいずれか一項に記載の方法。 Item 154. The method according to any one of Items 143 to 153, wherein the enhancer inhibits a legnes monodegrading enzyme.
［項１５５]　前記レグネース１分解酵素が、レグネース１リン酸化酵素、又はレグネース１ユビキチン化酵素である、項１５４に記載の方法。 Item 155. The method according to Item 154, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
［項１５６]　前記エンハンサーが、Ｅ３リガーゼ阻害活性を有する、項１４３～１５５のいずれか一項に記載の方法。 Item 156. The method according to any one of Items 143 to 155, wherein the enhancer has an E3 ligase inhibitory activity.
［項１５７]　前記エンハンサーが、核酸、抗体、低分子化合物、又は高分子化合物である、項１４３～１５６のいずれか一項に記載の方法。 Item 157. The method according to any one of Items 143 to 156, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
［項１５８]　前記エンハンサーが、核酸である、項１５７に記載の方法。 Item 158. The method according to Item 157, wherein the enhancer is a nucleic acid.
［項１５９]　前記エンハンサーが、抗体である、項１５７に記載の方法。 [Item 159] The method according to Item 157, wherein the enhancer is an antibody.
［項１６０]　前記エンハンサーが、低分子化合物である、項１５７に記載の方法。 [Item 160] The method according to Item 157, wherein the enhancer is a low molecular weight compound.
［項１６１]　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項１６０に記載の方法。 [Item 161] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -Benzyl acid (GS143), item 160.
［項１６２]　炎症性サイトカインの産生を抑制するための、ＮＦＫＢＩＺインヒビターを含む組成物。 [Item 162] A composition containing an NFKBIZ inhibitor for suppressing the production of inflammatory cytokines.
［項１６３]　炎症性サイトカインの産生を抑制するための、レグネース１エンハンサーを含む組成物。 [Item 163] A composition containing a Legnes 1 enhancer for suppressing the production of inflammatory cytokines.
［項１６４］　組織破壊と再生を伴う腸炎を緩和するための、ＮＦＫＢＩＺインヒビターを含む組成物。 [Item 164] A composition containing an NFKBIZ inhibitor for alleviating enteritis associated with tissue destruction and regeneration.
［項１６５］　組織破壊と再生を伴う腸炎を緩和するための、レグネース１エンハンサーを含む組成物。
［項Ｄ１］　がんの治療及び／又は予防における使用のためのＥ３リガーゼインヒビターであって、該Ｅ３リガーゼインヒビターは、Ｅ３リガーゼの発現が亢進している、及び／又はＥ３リガーゼの活性が上昇している被験者に投与されることを特徴とする、Ｅ３リガーゼインヒビター。
［項Ｄ２］　前記がんが、慢性炎症に伴うがんである、項Ｄ１に記載の使用のためのＥ３リガーゼインヒビター。
［項Ｄ３］　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ｄ２に記載の使用のためのＥ３リガーゼインヒビター。
［項Ｄ４］　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ｄ３に記載の使用のためのＥ３リガーゼインヒビター。
［項Ｄ５］　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ｄ１～Ｄ４のいずれか一項に記載の使用のためのＥ３リガーゼインヒビター。
［項Ｄ６］　前記がんが、大腸がんである、項Ｄ５に記載の使用のためのＥ３リガーゼインヒビター。
［項Ｄ７］　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ｄ６に記載の使用のためのＥ３リガーゼインヒビター。
［項Ｄ８］　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ｄ１～Ｄ７のいずれか一項に記載の使用のためのＥ３リガーゼインヒビター。
［項Ｄ９］　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ｄ１～Ｄ８のいずれか一項に記載の使用のためのＥ３リガーゼインヒビター。
［項Ｄ１０］　前記インヒビターが、核酸である、項Ｄ９に記載の使用のためのＥ３リガーゼインヒビター。
［項Ｄ１１］　前記インヒビターが、抗Ｅ３リガーゼ抗体である、項Ｄ９に記載の使用のためのＥ３リガーゼインヒビター。
［項Ｄ１２］　前記インヒビターが、低分子化合物である、項Ｄ９に記載の使用のためのＥ３リガーゼインヒビター。
［項Ｄ１３］　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオロー
 フェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ｄ１２に記載の使用のためのＥ３リガーゼインヒビター。
［項Ｅ１］　がんの治療及び／又は予防のための医薬の製造における、Ｅ３リガーゼインヒビターの使用であって、該医薬は、Ｅ３リガーゼの発現が亢進している、及び／又はＥ３リガーゼの活性が上昇している被験者に投与されることを特徴とする、使用。
［項Ｅ２］　前記がんが、慢性炎症に伴うがんである、項Ｅ１に記載の使用。
［項Ｅ３］　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、項Ｅ２に記載の使用。
［項Ｅ４］　前記炎症性腸疾患が、潰瘍性大腸炎である、項Ｅ３に記載の使用。
［項Ｅ５］　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、項Ｅ１～Ｅ４のいずれか一項に記載の使用。
［項Ｅ６］　前記がんが、大腸がんである、項Ｅ５に記載の使用。
［項Ｅ７］　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、項Ｅ６に記載の使用。
［項Ｅ８］　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、項Ｅ１～Ｅ７のいずれか一項に記載の使用。
［項Ｅ９］　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、項Ｅ１～Ｅ８のいずれか一項に記載の使用。
［項Ｅ１０］　前記インヒビターが、核酸である、項Ｅ９に記載の使用。
［項Ｅ１１］　前記インヒビターが、抗Ｅ３リガーゼ抗体である、項Ｅ９に記載の使用。
［項Ｅ１２］　前記インヒビターが、低分子化合物である、項Ｅ９に記載の使用。
［項Ｅ１３］　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、項Ｅ１２に記載の使用。 [Item 165] A composition containing a Legnes 1 enhancer for alleviating enteritis associated with tissue destruction and regeneration.
[Item D1] An E3 ligase inhibitor for use in the treatment and / or prevention of cancer, the E3 ligase inhibitor has increased expression of E3 ligase and / or increased activity of E3 ligase. An E3 ligase inhibitor, characterized in that it is administered to a subject.
[Item D2] The E3 ligase inhibitor for use according to item D1, wherein the cancer is a cancer associated with chronic inflammation.
[Item D3] The E3 ligase inhibitor for use according to item D2, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
[Item D4] The E3 ligase inhibitor for use according to item D3, wherein the inflammatory bowel disease is ulcerative colitis.
[Item D5] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , E3 ligase inhibitor for use according to any one of items D1 to D4.
[Item D6] The E3 ligase inhibitor for use according to item D5, wherein the cancer is colorectal cancer.
[Item D7] The E3 ligase for use according to item D6, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer. Inhibitor.
[Item D8] The E3 ligase inhibitor for use according to any one of items D1 to D7, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
[Item D9] The E3 ligase inhibitor for use according to any one of Items D1 to D8, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
[Item D10] The E3 ligase inhibitor for use according to item D9, wherein the inhibitor is a nucleic acid.
[Item D11] The E3 ligase inhibitor for use according to item D9, wherein the inhibitor is an anti-E3 ligase antibody.
[Item D12] The E3 ligase inhibitor for use according to item D9, wherein the inhibitor is a low molecular weight compound.
[Item D13] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl). )-Benzoic acid (GS143), an E3 ligase inhibitor for use according to item D12.
[Item E1] The use of an E3 ligase inhibitor in the manufacture of a drug for the treatment and / or prevention of cancer, wherein the drug has increased expression of E3 ligase and / or activity of E3 ligase. Use, characterized by being administered to subjects with elevated levels.
[Item E2] The use according to Item E1, wherein the cancer is a cancer associated with chronic inflammation.
[Item E3] The use according to Item E2, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
[Item E4] The use according to Item E3, wherein the inflammatory bowel disease is ulcerative colitis.
[Item E5] The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. , The use according to any one of items E1 to E4.
[Item E6] The use according to item E5, wherein the cancer is colorectal cancer.
[Item E7] The use according to Item E6, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
[Item E8] The use according to any one of Items E1 to E7, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
[Item E9] The use according to any one of Items E1 to E8, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
[Item E10] The use according to Item E9, wherein the inhibitor is a nucleic acid.
[Item E11] The use according to Item E9, wherein the inhibitor is an anti-E3 ligase antibody.
[Item E12] The use according to Item E9, wherein the inhibitor is a low molecular weight compound.
[Item E13] The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Il) -the use according to item E12, which is benzoic acid (GS143).
　本開示において、上記の一つまたは複数の特徴は、明示された組み合わせに加え、さらに組み合わせて提供され得ることが意図される。本開示のなおさらなる実施形態および利点は、必要に応じて以下の詳細な説明を読んで理解すれば、当業者に認識される。 In the present disclosure, it is intended that one or more of the above features may be provided in addition to the specified combinations. Further embodiments and advantages of the present disclosure will be appreciated by those skilled in the art upon reading and understanding the following detailed description as necessary.
　本開示のＮＦＫＢＩＺインヒビター（例えば、ＮＦＫＢＩＺの発現量を減少させる物質、及び／又はＮＦＫＢＩＺの機能を抑制する物質）は、がんの治療及び／又は予防に有効であり、特に大腸がんの治療及び／又は予防に有効である。 The NFKBIZ inhibitors of the present disclosure (eg, substances that reduce the expression level of NFKBIZ and / or substances that suppress the function of NFKBIZ) are effective in the treatment and / or prevention of cancer, particularly in the treatment and prevention of colorectal cancer. / Or effective for prevention.
　本開示のレグネース１エンハンサー（例えば、レグネース１の活性を増強する物質）は、がんの治療及び／又は予防に有効であり、特に大腸がんの治療及び／又は予防に有効である。 The Regnes 1 enhancer of the present disclosure (for example, a substance that enhances the activity of Legnes 1) is effective for the treatment and / or prevention of cancer, and is particularly effective for the treatment and / or prevention of colorectal cancer.
　本開示に基づき、被験者由来のがん細胞のＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定することにより、ＮＦＫＢＩＺインヒビター（例えば、ＮＦＫＢＩＺの発現量を減少させる物質、及び／又はＮＦＫＢＩＺの機能を抑制する物質）が有効な患者を予測することができる。 Based on the present disclosure, a substance that reduces the expression level of NFKBIZ (for example, a substance that reduces the expression level of NFKBIZ, and / or a substance that suppresses the function of NFKBIZ) by measuring the gene expression and / or activity of NFKBIZ in cancer cells derived from a subject. ) Can be predicted for effective patients.
　本開示に基づき、被験者由来のがん細胞のレグネース１の発現及び／又は活性を測定することにより、レグネース１エンハンサー（例えば、レグネース１の活性を増強する物質）が有効な患者を予測することができる。 Based on the present disclosure, it is possible to predict a patient for whom a Regnes 1 enhancer (for example, a substance that enhances the activity of Legnes 1) is effective by measuring the expression and / or activity of Legnes 1 in cancer cells derived from a subject. it can.
　また、本開示に基づき、がんの治療及び／又は予防に有効な、ＮＦＫＢＩＺインヒビター（例えば、ＮＦＫＢＩＺの発現量を減少させる物質、及び／又はＮＦＫＢＩＺの機能を抑制する物質）を選別することができる。 In addition, based on the present disclosure, NFKBIZ inhibitors (for example, substances that reduce the expression level of NFKBIZ and / or substances that suppress the function of NFKBIZ) that are effective in treating and / or preventing cancer can be selected. ..
　また、本開示に基づき、がんの治療及び／又は予防に有効な、レグネース１エンハンサー（例えば、レグネース１の活性を増強する物質）を選別することができる。 Further, based on the present disclosure, it is possible to select a Legnes 1 enhancer (for example, a substance that enhances the activity of Legnes 1) that is effective for the treatment and / or prevention of cancer.
図１は、潰瘍性大腸炎でない被験者（非ＵＣ被験者）及び潰瘍性大腸炎である被験者（ＵＣ被験者）の単一陰窩における全エキソン領域内の変異の数を被験者の年齢に対してプロットした図である。切片０の回帰直線は、非ＵＣ被験者由来のサンプルに対して描いたものである。ｐ値は非ＵＣ被験者とＵＣ被験者との間の差についての有意性を示す（両側マン－ホイットニーＵ検定）。FIG. 1 plots the number of mutations within the entire exon region in a single crypt in subjects without ulcerative colitis (non-UC subjects) and subjects with ulcerative colitis (UC subjects) against the age of the subjects. It is a figure. The regression line for section 0 is drawn for samples from non-UC subjects. The p-value indicates significance for the difference between non-UC and UC subjects (Bilateral Mann-Whitney U test). 図２は、正常粘膜（各ドメイン図の上）とＣＡＣ（各ドメイン図の下）におけるＮＦＫＢＩＺ、ＰＩＧＲ、ＺＣ３Ｈ１２Ａ及びＴＲＡＦ３ＩＰ２変異の分布を示した図である。図２は、さらにＺＣ３Ｈ１２Ａ遺伝子のＤＳＧｘｘＳモチーフ内のホットスポット変異を示した図である。FIG. 2 is a diagram showing the distribution of NFKBIZ, PIGR, ZC3H12A and TRAF3IP2 mutations in normal mucosa (above each domain diagram) and CAC (below each domain diagram). FIG. 2 is a diagram further showing a hotspot mutation in the DSGxxS motif of the ZC3H12A gene. 図３は、ドライバー変異のランドスケープをＵＣ被験者の正常粘膜で検出されたクローン（ｎ＝１８３）について描いた図である。それぞれの変異の頻度を右側に示した。FIG. 3 is a diagram depicting a landscape of driver mutations for clones (n = 183) detected in the normal mucosa of UC subjects. The frequency of each mutation is shown on the right. 図４は、潰瘍性大腸炎の正常粘膜（ＵＣ正常粘膜）で認められたＩＬ－１７シグナル経路における変異を示す図である。ＵＣ正常粘膜で検出された変異を有する遺伝子を、灰色で塗った四角で示した。FIG. 4 is a diagram showing mutations in the IL-17 signaling pathway observed in the normal mucosa (UC normal mucosa) of ulcerative colitis. Genes with mutations detected in UC normal mucosa are shown in gray squares. 図５は、ＵＣ正常粘膜（ｎ＝１８３）とＣＡＣ（ｎ＝９６）サンプルにおけるドライバー変異の頻度の比較（左）、並びに、ＵＣ正常粘膜（ｎ＝１８３）及びｓＣＲＣ（ｎ＝３５６）サンプルにおけるドライバー変異の頻度の比較（右）を示した図である。変異頻度が正常粘膜とＣＡＣあるいはｓＣＲＣとの間で有意に異なった遺伝子をアスタリスクで示した（Ｂｅｎｊａｍｉｎｉ－Ｈｏｃｈｂｅｒｇ調整を行った両側フィッシャー正確確率検定；ｑ＜０．１）。FIG. 5 compares the frequency of driver mutations in UC normal mucosa (n = 183) and CAC (n = 96) samples (left), and in UC normal mucosa (n = 183) and sCRC (n = 356) samples. It is the figure which showed the comparison (right) of the frequency of a driver mutation. Genes with significantly different mutation frequencies between normal mucosa and CAC or sCRC were indicated by asterisks (Benjamini-Hochberg-adjusted bilateral Fisher's exact test; q <0.1). 図６は、リアルタイムＰＣＲで測定したＮＦＫＢＩＺのノックダウン効率（左パネル）及び増殖曲線（右パネル）を、ＮＦＫＢＩＺ及びコントロールｓｈＲＮＡを処理した２種類のヒト大腸がん細胞株（ＨＴ２９、ＨＣＴ１１６）について示した図である。FIG. 6 shows the knockdown efficiency (left panel) and growth curve (right panel) of NFKBIZ measured by real-time PCR for two human colon cancer cell lines (HT29, HCT116) treated with NFKBIZ and control shRNA. It is a figure. 図７は、Ｎｆｋｂｉｚｆｌ／ｆｌＶｉｌＣｒｅ（Ｎｆｋｂｉｚ　ｃＫＯ）及びＮｆｋｂｉｚｆｌ／ｆｌ（コントロール）マウスにおけるＣＡＣ誘導の実験スケジュールを示した図である。アゾキシメタン（ＡＯＭ）投与に続いて３サイクルのデキストラン硫酸ナトリウム（ＤＳＳ）投与を行った（ｉ．ｐ．：腹腔内投与）。FIG. 7 is a diagram showing the experimental schedule of CAC induction in Nfkbiz fl / fl VilCre (Nfkbiz cKO) and Nfkbiz fl / fl (control) mice. Azoxymethane (AOM) administration was followed by 3 cycles of sodium dextran sulfate (DSS) administration (ip: intraperitoneal administration). 図８は、コントロール（上）及びＮｆｋｂｉｚ　ｃＫＯ（下）マウスにおけるＡＯＭ－ＤＳＳで誘導した大腸腫瘍の代表例を示した図である。FIG. 8 is a diagram showing typical examples of AOM-DSS-induced colon tumors in control (top) and Nfkbiz cKO (bottom) mice. 図９は、腫瘍サイズ（直径）ごとの腫瘍の数のボックスプロット（左）及び総腫瘍量のボックスプロット（右）を示した図である。Ｎｆｋｂｉｚ　ｃＫＯとコントロールの間で顕著な差を示した腫瘍サイズをアスタリスクで示した（両方向マン－ホイットニーＵ検定；ｐ＜０．０５）。また、総腫瘍量の差の有意性をＰ値で示した（両方向マン－ホイットニーＵ検定；ｐ＜０．０５）。FIG. 9 shows a box plot of the number of tumors by tumor size (diameter) (left) and a box plot of total tumor volume (right). Tumor sizes that showed a marked difference between Nfkbiz cKO and control were indicated by asterisks (bidirectional Mann-Whitney U test; p <0.05). In addition, the significance of the difference in total tumor volume was indicated by a P value (Bidirectional Mann-Whitney U test; p <0.05). 図１０は、Ｅ３リガーゼ阻害剤であるＧＳ１４３が、ＨＴ２９細胞株において、ＮＦＫＢＩＺのｍＲＮＡ発現量を抑制することを示した図である。ｕＭは、μＭを示す。FIG. 10 is a diagram showing that GS143, which is an E3 ligase inhibitor, suppresses the mRNA expression level of NFKBIZ in the HT29 cell line. uM represents μM. 図１１は、Ｅ３リガーゼ阻害剤であるＧＳ１４３が、ＨＴ２９細胞株において、レグネース１の発現量を増加させることを示した図である。上段と下段は、各々ウェスタンブロットの結果を示し、中段に、レグネース１とβチューブリンとの発現量比を示す。FIG. 11 shows that GS143, an E3 ligase inhibitor, increases the expression level of Legnes 1 in the HT29 cell line. The upper and lower rows show the results of Western blotting, respectively, and the middle row shows the expression level ratio of Legnes 1 and β-tubulin. 図１２は、Ｅ３リガーゼ阻害剤であるＧＳ１４３が、ＨＴ２９細胞株において、濃度依存的に細胞増殖抑制効果を示すことを示した図である。ｕＭは、μＭを示す。FIG. 12 is a diagram showing that GS143, which is an E3 ligase inhibitor, exhibits a concentration-dependent cell growth inhibitory effect on the HT29 cell line. uM represents μM. 図１３は、ＤＳＳ投与後のコントロールマウス（Ｃｏｎｔｒｏｌ，　ｎ　＝　３）およびＮｆｋｂｉｚコンディショナルノックアウトマウス（Ｎｆｋｂｉｚ　ｃＫＯ，　ｎ　＝　３）の腸粘膜における炎症性サイトカインなどの遺伝子の発現量を示す。発現量は、コントロールマウスの発現量を１とした相対値で示す。FIG. 13 shows the expression levels of genes such as inflammatory cytokines in the intestinal mucosa of control mice (Control, n = 3) and Nfkbiz conditional knockout mice (Nfkbiz cKO, n = 3) after DSS administration. The expression level is shown as a relative value with the expression level of the control mouse as 1.
　以下、本開示につき、さらに詳しく説明する。本明細書の全体にわたり、単数形の表現は、特に言及しない限り、その複数形の概念をも含むことが理解されるべきである。従って、単数形の冠詞（例えば、英語の場合は「ａ」、「ａｎ」、「ｔｈｅ」など）は、特に言及しない限り、その複数形の概念をも含むことが理解されるべきである。また、本明細書において使用される用語は、特に言及しない限り、当該分野で通常用いられる意味で用いられることが理解されるべきである。したがって、他に定義されない限り、本明細書中で使用される全ての専門用語及び科学技術用語は、本開示の属する分野の当業者によって一般的に理解されるのと同じ意味を有する。矛盾する場合、本明細書（定義を含めて）が優先する。 Hereinafter, this disclosure will be described in more detail. Throughout the specification, it should be understood that the singular representation also includes its plural concept, unless otherwise stated. Therefore, it should be understood that singular articles (eg, "a", "an", "the", etc. in English) also include the concept of their plural, unless otherwise noted. It should also be understood that the terms used herein are used in the meaning commonly used in the art unless otherwise noted. Thus, unless otherwise defined, all terminology and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. In case of conflict, this specification (including definitions) takes precedence.
　（ＮＦＫＢＩＺインヒビター／レグネース１エンハンサー） (NFKBIZ Inhibitor / Legnes 1 Enhancer)
　「ＮＦＫＢＩＺインヒビター」とは、ＮＦＫＢＩＺを何らかの形で阻害する任意の物質、因子、手段などを含む。ＮＦＫＢＩＺインヒビターには、代表的に、ＮＦＫＢＩＺの発現量を減少させる物質、ＮＦＫＢＩＺの機能を抑制する物質等が含まれ、このほか、ＮＦＫＢＩＺが結果として機能しないあるいは発現しなくなるような処置を講ずることができる手段（例えば、ゲノム編集を実現する手段などを含む）などであってもよい。 The "NFKBIZ inhibitor" includes any substance, factor, means, etc. that inhibits NFKBIZ in some way. NFKBIZ inhibitors typically include substances that reduce the expression level of NFKBIZ, substances that suppress the function of NFKBIZ, etc. In addition, measures may be taken to prevent NFKBIZ from functioning or not being expressed as a result. It may be a possible means (including, for example, a means for realizing genome editing) or the like.
　ＮＦＫＢＩＺ（ＮＦ－ｋａｐｐａ－Ｂ　ｉｎｈｉｂｉｔｏｒ　ｚｅｔａ）は、ヒトではＮＦＫＢＩＺ遺伝子によってコードされているタンパク質である。ＮＦＫＢＩＺ遺伝子は、ａｎｋｙｒｉｎ－ｒｅｐｅａｔ　ｆａｍｉｌｙ（アンキリンリピートファミリー）に属し、リポ多糖によって誘導されることが知られている。ＮＦＫＢＩＺは、アンキリンリピートドメインを介したＮＦ－Ｂタンパク質との相互作用により、ＬＰＳに対する炎症反応において役割を果たすことが知られている（Gudrun　Totzke　et　al.　J　Biol　Chem.　281:　12645-12654　(2006)）。理論に拘束されることを望むものではないが、本明細書の実施例において、ＮＦＫＢＩＺの機能が抑制された場合に、がんの発生が抑制され、また、発生したがんの増殖が抑制されることが示されており、がんの治療及び／又は予防において、ＮＦＫＢＩＺインヒビターが用いられ得ることが理解される。本開示の１つの実施形態は、ＮＦＫＢＩＺインヒビターを含む組成物を提供し得る。本開示において、ＮＦＫＢＩＺインヒビターが、炎症性疾患から発生したがんに対して有効であることが見出されており（実施例）、ＮＦＫＢＩＺインヒビターは炎症が伴わないがんに対しても高い蓋然性をもって有効であるといえる。 NFKBIZ (NF-kappa-B inhibitor zeta) is a protein encoded by the NFKBIZ gene in humans. The NFKBIZ gene belongs to the ankyrin-repeat family (ankyrin repeat family) and is known to be induced by lipopolysaccharide. NFKBIZ is known to play a role in the inflammatory response to LPS by interacting with the NF-B protein via the ankyrin repeat domain (Gudrun Totzke et al. J Biol Chem. 281: 12645-12654 (2006). )). Although not bound by theory, in the examples herein, when the function of NFKBIZ is suppressed, the development of cancer is suppressed and the growth of the developed cancer is suppressed. It has been shown that NFKBIZ inhibitors can be used in the treatment and / or prevention of cancer. One embodiment of the present disclosure may provide a composition comprising an NFKBIZ inhibitor. In the present disclosure, the NFKBIZ inhibitor has been found to be effective against cancers arising from inflammatory diseases (Examples), and the NFKBIZ inhibitor is highly probable for cancers that are not accompanied by inflammation. It can be said that it is effective.
　ＮＦＫＢＩＺインヒビターとして、ＮＦＫＢＩＺの発現量を減少させる物質、ＮＦＫＢＩＺの機能を抑制する物質が挙げられるが、ＮＦＫＢＩＺの阻害を実現する複数の物質の組み合わせなどもＮＦＫＢＩＺインヒビターに含まれる。ＮＦＫＢＩＺインヒビターの例として、例えば、ＮＦＫＢＩＺを阻害するように遺伝子改変を行う手段や、ＮＦＫＢＩＺを阻害する活性を有する細胞なども挙げられ得る。 Examples of the NFKBIZ inhibitor include a substance that reduces the expression level of NFKBIZ and a substance that suppresses the function of NFKBIZ, but the NFKBIZ inhibitor also includes a combination of a plurality of substances that realize inhibition of NFKBIZ. Examples of the NFKBIZ inhibitor include, for example, means for genetically modifying to inhibit NFKBIZ, cells having an activity of inhibiting NFKBIZ, and the like.
　「ＮＦＫＢＩＺの発現量を減少させる」とは、ＮＦＫＢＩＺに係るタンパク質の発現量を減少させることを意味する。
　「ＮＦＫＢＩＺの発現量を減少させる物質」としては、例えば「核酸」、「抗体」、「低分子化合物」及び「高分子化合物」が挙げられる。
　「ＮＦＫＢＩＺの発現量を減少させる物質」として好ましくは、「核酸」、「抗体」、及び「低分子化合物」が挙げられる。
　「ＮＦＫＢＩＺの発現量を減少させる物質」としてより好ましくは、「核酸」、及び「低分子化合物」が挙げられる。
　「ＮＦＫＢＩＺの発現量を減少させる物質」として更に好ましくは、「低分子化合物」が挙げられる。 "Reducing the expression level of NFKBIZ" means reducing the expression level of the protein related to NFKBIZ.
Examples of the "substance that reduces the expression level of NFKBIZ" include "nucleic acid", "antibody", "low molecular weight compound" and "high molecular weight compound".
Preferred examples of the "substance that reduces the expression level of NFKBIZ" include "nucleic acid", "antibody", and "low molecular weight compound".
More preferably, "nucleic acid" and "low molecular weight compound" are mentioned as "substances that reduce the expression level of NFKBIZ".
A "small molecule compound" is more preferable as the "substance that reduces the expression level of NFKBIZ".
　「ＮＦＫＢＩＺの機能を抑制する」とは、ＮＦＫＢＩＺの機能を阻害又は消失させることを意味する。ＮＦＫＢＩＺの機能の阻害又は消失の態様として、例えば、「ＮＦＫＢＩＺの核内移行を阻害すること」、「ＮＦＫＢＩＺとｐ５０との結合を阻害すること」、及び「ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することを阻害すること」が挙げられる。
　「ＮＦＫＢＩＺの核内移行を阻害すること」は、例えば、インヒビター候補を作用させた細胞において、例えば細胞質および核分画の細胞溶解液を使用したＷｅｓｔｅｒｎ　Ｂｌｏｔ法を用いて確認することができる。
　「ＮＦＫＢＩＺとｐ５０との結合を阻害すること」は、例えば、インヒビター候補を作用させた細胞において、抗ＮＦＫＢＩＺ抗体又は抗ｐ５０抗体による免疫沈降法にて確認することができる。
　「ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することを阻害すること」は、例えば、インヒビター候補を作用させた細胞において、抗ＮＦＫＢＩＺ抗体およびその特定のＤＮＡ配列を増幅しうるプライマーを使用したＣＨＩＰ－ＰＣＲ法にて確認することができる。
　「ＮＦＫＢＩＺの機能を抑制する物質」としては、例えば「核酸」、「抗体」、「低分子化合物」及び「高分子化合物」が挙げられる。
　「ＮＦＫＢＩＺの機能を抑制する物質」として好ましくは、「核酸」、「抗体」、及び「低分子化合物」が挙げられる。
　「ＮＦＫＢＩＺの機能を抑制する物質」としてより好ましくは、「抗体」、及び「低分子化合物」が挙げられる。
　「ＮＦＫＢＩＺの機能を抑制する物質」として更に好ましくは、「低分子化合物」が挙げられる。 "Suppressing the function of NFKBIZ" means inhibiting or eliminating the function of NFKBIZ. As an embodiment of inhibition or disappearance of the function of NFKBIZ, for example, "inhibiting the nuclear translocation of NFKBIZ", "inhibiting the binding between NFKBIZ and p50", and "a transcription factor consisting of a complex containing NFKBIZ" , Inhibiting interaction with a specific DNA sequence. "
"Inhibiting the nuclear translocation of NFKBIZ" can be confirmed, for example, by using the Western Blot method using a cell lysate of cytoplasm and nuclear fraction in cells on which an inhibitor candidate is acted.
"Inhibiting the binding between NFKBIZ and p50" can be confirmed, for example, by immunoprecipitation with an anti-NFKBIZ antibody or an anti-p50 antibody in cells on which an inhibitor candidate is acted.
"Inhibiting a transcription factor consisting of a complex containing NFKBIZ from interacting with a specific DNA sequence" means, for example, amplifying an anti-NFKBIZ antibody and its specific DNA sequence in cells on which an inhibitor candidate is acted. It can be confirmed by the CHIP-PCR method using a possible primer.
Examples of the "substance that suppresses the function of NFKBIZ" include "nucleic acid", "antibody", "low molecular weight compound" and "high molecular weight compound".
Preferred examples of the "substance that suppresses the function of NFKBIZ" include "nucleic acid", "antibody", and "low molecular weight compound".
More preferably, "substances that suppress the function of NFKBIZ" include "antibodies" and "small molecule compounds".
More preferably, a "low molecular weight compound" is mentioned as the "substance that suppresses the function of NFKBIZ".
　本明細書において、「ＮＦＫＢＩＺの発現量を減少させる」ことと、「ＮＦＫＢＩＺの機能を抑制する」こととを纏めて、「ＮＦＫＢＩＺの発現及び／又は機能を抑制する」と称することがある。 In the present specification, "reducing the expression level of NFKBIZ" and "suppressing the function of NFKBIZ" may be collectively referred to as "suppressing the expression and / or function of NFKBIZ".
　「レグネース１エンハンサー」とは、レグネース１の作用を何らかの形で促進する任意の物質、因子、手段などを含む。レグネース１エンハンサーには、代表的に、レグネース１の発現を亢進させる物質、レグネース１の活性を増強する物質等が含まれ、このほか、結果としてレグネース１の機能または発現を増大させるような処置を講ずることができる手段（例えば、ゲノム編集を実現する手段などを含む）などであってもよい。本開示において、レグネース１エンハンサーが、炎症性疾患から発生したがんに対して有効であることが見出されており（実施例）、レグネース１エンハンサーは炎症が伴わないがんに対しても高い蓋然性をもって有効であるといえる。 The "Regnes 1 enhancer" includes any substance, factor, means, etc. that promotes the action of Legnes 1 in some way. The legnes 1 enhancer typically includes a substance that enhances the expression of legnes 1, a substance that enhances the activity of legnes 1, and the like, and other measures that increase the function or expression of legnes 1 as a result. It may be a means that can be taken (including, for example, a means for realizing genome editing). In the present disclosure, the Legnes 1 enhancer has been found to be effective against cancers arising from inflammatory diseases (Examples), and the Legnes 1 enhancer is also high against non-inflammatory cancers. It can be said that it is effective with a probability.
　レグネース１（以下、Ｒｅｇｎａｓｅ－１、レグネース－１、ＺＣ３Ｈ１２Ａ、又はＺｃ３ｈ１２ａとも記載する。）は、ＲＮＡｓｅ活性を有するＣＣＣＨジンクフィンガータンパク質ファミリーの一種であり、標的ｍＲＮＡの分解を介して転写後の調節活性を媒介するＲＮＡ結合タンパク質である。レグネース１は、炎症性遺伝子の安定性を直接制御することにより、免疫疾患に関連するＲＮａｓｅであることが報告されている（Kazufumi　Matsushita　et　al.　Nature　458:　1185-1190.　(2009)）。また、レグネース１の機能不全が異常な造血の急速な発症をもたらすことが報告されている（Hiroyasu　Kidoya　et　al.　Nature　Communications　10:　1-16.　(2019)）。 Regnase 1 (hereinafter, also referred to as Regnase-1, Regnase-1, ZC3H12A, or Zc3h12a) is a member of the CCCH zinc finger protein family having RNAse activity, and has post-transcriptional regulatory activity via degradation of target mRNA. It is an RNA-binding protein that mediates. Regnes 1 has been reported to be an RNase associated with immune disorders by directly controlling the stability of inflammatory genes (Kazufumi Matsushita et al. Nature 458: 1185-1190. (2009)). In addition, it has been reported that the dysfunction of Legnes 1 leads to the rapid onset of abnormal hematopoiesis (Hiroyasu Kidoya et al. Nature Communications 10: 1-16. (2019)).
　レグネース１は、ＮＦＫＢＩＺ　ｍＲＮＡの３’ＵＴＲに結合し、その分解を促進することが報告されている（Gesine　Behrens　et　al.　Nucl　Acids　Res,　46:　4256　(2018)）。さらにレグネース１は、リン酸化部位であるＳ４３８及びＳ４４２がＩＫＫ（酵素ＩκＢキナーゼ）複合体によりリン酸化されることで、ＳＣＦβ－ＴｒＣＰ１を介したユビキチン化により分解されうることが報告されている（Hidenori　Iwasaki　et　al.　Nature　Immunology,　12:　1167-1175.　(2011)）。 Legnes 1 has been reported to bind to the 3'UTR of NFKBIZ mRNA and promote its degradation (Gesine Behrens et al. Nucl Acids Res, 46: 4256 (2018)). Furthermore, it has been reported that legnes 1 can be degraded by SCF β-TrCP1- mediated ubiquitination by phosphorylation of phosphorylation sites S438 and S442 by an IKK (enzyme IκB kinase) complex (SCF β-TrCP1 mediated ubiquitination). Hidenori Iwasaki et al. Nature Immunology, 12: 1167-1175. (2011)).
　レグネース１エンハンサーとして、レグネース１の発現を増加させる物質、レグネース１の機能を促進する物質が挙げられるが、レグネース１の作用の増大を実現する複数の物質の組み合わせなどもレグネース１エンハンサーに含まれる。レグネース１エンハンサーの例として、例えば、レグネース１の発現を増大させるように遺伝子改変を行う手段や、レグネース１の活性を増強する活性を有する細胞なども挙げられ得る。 Examples of the legnes 1 enhancer include substances that increase the expression of legnes 1 and substances that promote the function of legnes 1, but the legnes 1 enhancer also includes a combination of a plurality of substances that realize an increase in the action of legnes 1. Examples of the Legnes 1 enhancer include, for example, means for genetically modifying the expression of Legnes 1 and cells having an activity of enhancing the activity of Legnes 1.
　「レグネース１の活性を増強する」とは、レグネース１のＲＮａｓｅ活性を増強することを意味する。「レグネース１の活性を増強する物質」としては、「レグネース１の発現量を増加させる物質」及び「レグネース１分解酵素を阻害する物質」が挙げられ、好ましくは、「レグネース１分解酵素を阻害する物質」が挙げられる。
　「レグネース１の活性を増強する物質」、「レグネース１の発現量を増加させる物質」、又は「レグネース１分解酵素を阻害する物質」としては、例えば「核酸」、「抗体」、「低分子化合物」及び「高分子化合物」が挙げられる。
　「レグネース１の活性を増強する物質」、「レグネース１の発現量を増加させる物質」、又は「レグネース１分解酵素を阻害する物質」としては好ましくは、「核酸」、「抗体」、及び「低分子化合物」が挙げられる。
　「レグネース１の活性を増強する物質」、「レグネース１の発現量を増加させる物質」、又は「レグネース１分解酵素を阻害する物質」としてより好ましくは、「抗体」、及び「低分子化合物」が挙げられる。
　「レグネース１の活性を増強する物質」、「レグネース１の発現量を増加させる物質」、又は「レグネース１分解酵素を阻害する物質」として更に好ましくは、「低分子化合物」が挙げられる。 By "enhancing the activity of legnes 1" is meant enhancing the RNase activity of legnes 1. Examples of the "substance that enhances the activity of legnes 1" include "a substance that increases the expression level of legnes 1" and "a substance that inhibits legnes 1 degrading enzyme", and preferably "a substance that inhibits legnes 1 degrading enzyme". "Substance" can be mentioned.
Examples of "substances that enhance the activity of legnes 1", "substances that increase the expression level of legnes 1", or "substances that inhibit legnes 1 degrading enzyme" include "nucleic acid", "antibody", and "low molecular weight compound". And "polymer compounds".
The "substances that enhance the activity of legnes 1", the "substances that increase the expression level of legnes 1", or the "substances that inhibit the legnes 1 degrading enzyme" are preferably "nucleic acid", "antibody", and "low". "Molecular compound" can be mentioned.
More preferably, "antibodies" and "low molecular weight compounds" are used as "substances that enhance the activity of legnes 1", "substances that increase the expression level of legnes 1", or "substances that inhibit legnes 1 degrading enzymes". Can be mentioned.
More preferably, "low molecular weight compound" is mentioned as "a substance that enhances the activity of Legnes 1", "a substance that increases the expression level of Legnes 1", or "a substance that inhibits a legnes 1 degrading enzyme".
　「レグネース１分解酵素」とは、レグネース１を分解する酵素を意味し、レグネース１をリン酸化する「レグネース１リン酸化酵素」、及びレグネース１をユビキチン化する「レグネース１ユビキチン化酵素」が挙げられる。 "Legnes 1 degrading enzyme" means an enzyme that decomposes legnes 1, and examples thereof include "legnes 1 kinase" that phosphorylates legnes 1 and "legnes 1 ubiquitinifying enzyme" that ubiquitinates legnes 1. ..
　ＮＦＫＢＩＺインヒビター及び／又はレグネース１エンハンサーは、Ｅ３リガーゼ阻害活性を有し得る。理論に拘束されることを望まないが、本明細書の実施例において、Ｅ３リガーゼ阻害活性を有する物質によるがんの発生および成長の抑制が実証されており、本開示において、Ｅ３リガーゼ阻害活性を有するＮＦＫＢＩＺインヒビター及び／又はレグネース１エンハンサーががんの治療及び／または予防のために使用され得ることが理解される。「Ｅ３リガーゼ阻害」とは、ユビキチンが結合したＥ２ユビキチン結合酵素を呼び寄せ、タンパク質の基質を認識し、Ｅ２から基質へのユビキチンの転移を助ける、もしくは直接的に触媒するＥ３ユビキチンリガーゼの機能を阻害することを意味する。 The NFKBIZ inhibitor and / or Legnes 1 enhancer may have E3 ligase inhibitory activity. Although not bound by theory, the examples herein demonstrate that substances with E3 ligase inhibitory activity suppress the development and growth of cancer, and in the present disclosure, the E3 ligase inhibitory activity is defined. It is understood that NFKBIZ inhibitors and / or ligase 1 enhancers with can be used for the treatment and / or prevention of cancer. "E3 ligase inhibition" refers to ubiquitin-bound E2 ubiquitin ligase, which recognizes the substrate of the protein, assists in the transfer of ubiquitin from E2 to the substrate, or inhibits the function of E3 ubiquitin ligase that catalyzes directly. Means to do.
　本開示において、ＮＦＫＢＩＺインヒビターであり、かつレグネース１エンハンサーであるもの（本明細書において、「ＮＦＫＢＩＺインヒビター／レグネース１エンハンサー」と称する）を用いてもよい。ＮＦＫＢＩＺインヒビター／レグネース１エンハンサーの一例としては、本明細書の実施例において記載されているＧＳ１４３が挙げられる。 In the present disclosure, an NFKBIZ inhibitor and a Legnes 1 enhancer (referred to in the present specification as "NFKBIZ inhibitor / Legnes 1 enhancer") may be used. An example of the NFKBIZ Inhibitor / Legnes 1 Enhancer is the GS143 described in the examples herein.
　「Ｅ３リガーゼインヒビター（Ｅ３リガーゼ阻害剤）」とは、Ｅ３リガーゼの作用を何らかの形で阻害する任意の物質、因子、手段などを含む。Ｅ３リガーゼインヒビターには、代表的に、Ｅ３リガーゼの発現を低下させる物質、Ｅ３リガーゼの活性を低下させる物質等が含まれ、このほか、結果としてＥ３リガーゼの機能または発現を低下させるような処置を講ずることができる手段（例えば、ゲノム編集を実現する手段などを含む）などであってもよい。Ｅ３リガーゼは、Ｅ３ユビキチンリガーゼとも称される。
　「Ｅ３リガーゼインヒビター」としては、例えば「核酸」、「抗体」、「低分子化合物」及び「高分子化合物」が挙げられる。
　「Ｅ３リガーゼインヒビター」としては好ましくは、「核酸」、「抗体」、及び「低分子化合物」が挙げられる。
　「Ｅ３リガーゼインヒビター」としてより好ましくは、「抗体」、及び「低分子化合物」が挙げられる。
　「Ｅ３リガーゼインヒビター」として更に好ましくは、「低分子化合物」が挙げられる。ここにおいて、Ｅ３リガーゼを阻害する低分子化合物を「Ｅ３リガーゼ阻害化合物」と称す。
　Ｅ３リガーゼインヒビターの一例としては、本明細書の実施例において記載されているＧＳ１４３が挙げられる。理論に拘束されることを望まないが、本明細書の実施例において、Ｅ３リガーゼインヒビターによるがんの発生および成長の抑制が実証されており、本開示において、Ｅ３リガーゼインヒビターががんの治療及び／または予防のために使用され得ることが理解される。 The "E3 ligase inhibitor (E3 ligase inhibitor)" includes any substance, factor, means, etc. that inhibits the action of E3 ligase in some way. The E3 ligase inhibitor typically includes a substance that reduces the expression of E3 ligase, a substance that reduces the activity of E3 ligase, and the like, and other measures that reduce the function or expression of E3 ligase as a result. It may be a means that can be taken (including, for example, a means for realizing genome editing). E3 ligase is also referred to as E3 ubiquitin ligase.
Examples of the "E3 ligase inhibitor" include "nucleic acid", "antibody", "low molecular weight compound" and "high molecular weight compound".
Preferred examples of the "E3 ligase inhibitor" include "nucleic acid", "antibody", and "small molecule compound".
More preferably, the "E3 ligase inhibitor" includes an "antibody" and a "small molecule compound".
More preferably, the "E3 ligase inhibitor" includes a "low molecular weight compound". Here, a low molecular weight compound that inhibits E3 ligase is referred to as an "E3 ligase inhibitory compound".
As an example of the E3 ligase inhibitor, GS143 described in the examples of the present specification can be mentioned. Without wishing to be bound by theory, the examples herein demonstrate that E3 ligase inhibitors suppress the development and growth of cancer, and in the present disclosure, E3 ligase inhibitors are used to treat cancer and to treat cancer. / Or it is understood that it can be used for prevention.
　「核酸」とは、塩基と糖、リン酸からなるヌクレオチドがホスホジエステル結合で連なった分子を意味し、リボ核酸（ＲＮＡ）とデオキシリボ核酸（ＤＮＡ）を含み、人工的に修飾又は置換された核酸、及び生体内で核酸へと変換される核酸前駆体を含む。
　人工的に修飾又は置換された核酸としては、５－置換ピリミジン、６－アザピリミジン、ならびにＮ－２、Ｎ－６およびＯ－６置換プリン（２－アミノプロピルアデニンを含めた）、５－プロピニルウラシルおよび５－プロピニルシトシンなどを含むものが挙げられる。また、人工的に修飾又は置換された核酸としては、核酸の２’位と４’位との間が連結され（架橋）され、環構造が２つ（二環式）となっている修飾された核酸（架橋核酸（ＢＮＡ））なども使用し得る。その他、ペプチド核酸、ロックト核酸、モルホリノ核酸、チオ核酸などの修飾核酸が使用され得る。
　「核酸」として、例えば、「アンチセンス核酸」、「リボザイム核酸」及び「ＲＮＡｉ活性を有する核酸」が挙げられる。
　「核酸」として、好ましくは「アンチセンス核酸」、及び「リボザイム核酸」が挙げられる。
　あるいは、「核酸」として、好ましくは「アンチセンス核酸」及び「ＲＮＡｉ活性を生じさせる核酸」が挙げられる。ＲＮＡｉ活性を生じさせる核酸としては、ｓｉＲＮＡ、ｓｈＲＮＡ、ｍｉＲＮＡ、短鎖もしくは長鎖の１もしくは２本鎖ＲＮＡ、またはそれらの修飾物等の１つ以上の組合せを挙げることができる。 "Nucleic acid" means a molecule in which nucleotides consisting of bases, sugars and phosphates are linked by phosphodiester bonds, and contains ribonucleic acid (RNA) and deoxyribonucleic acid (DNA), and is artificially modified or substituted nucleic acid. , And nucleic acid precursors that are converted to nucleic acids in vivo.
Artificially modified or substituted nucleic acids include 5-substituted pyrimidines, 6-azapyrimidines, and N-2, N-6 and O-6 substituted purines (including 2-aminopropyladenine), 5-propynyl. Included include uracil and 5-propynylcytosine and the like. Further, as the artificially modified or substituted nucleic acid, the 2'position and the 4'position of the nucleic acid are linked (crosslinked), and the nucleic acid has two ring structures (bicyclic type). Nucleic acid (crosslinked nucleic acid (BNA)) and the like can also be used. In addition, modified nucleic acids such as peptide nucleic acids, locked nucleic acids, morpholinon nucleic acids, and thionucleic acids can be used.
Examples of the "nucleic acid" include "antisense nucleic acid", "ribozyme nucleic acid" and "nucleic acid having RNAi activity".
Preferred examples of the "nucleic acid" include "antisense nucleic acid" and "ribozyme nucleic acid".
Alternatively, examples of the "nucleic acid" include "antisense nucleic acid" and "nucleic acid that causes RNAi activity". Examples of the nucleic acid that causes RNAi activity include one or more combinations of siRNA, shRNA, miRNA, short or long chain RNA, or modifications thereof.
　「抗ＮＦＫＢＩＺ抗体」とは、ＮＦＫＢＩＺを特異的に認識する抗体を意味し、ＮＦＫＢＩＺに対し結合活性を有する抗体を意味する。
　「ＮＦＫＢＩＺを特異的に認識する抗体」は、モノクローナル抗体及びポリクローナル抗体のいずれであってもよい。「ＮＦＫＢＩＺを特異的に認識する抗体」として好ましくは、ポリクローナル抗体が挙げられる。「ＮＦＫＢＩＺを特異的に認識する抗体」としてより好ましくは、哺乳動物由来のモノクローナル抗体が挙げられる。
　哺乳動物由来のモノクローナル抗体及びポリクローナル抗体は、動物の血中に産生されるもの、ハイブリドーマに産生されるもの、および遺伝子工学的手法により抗体遺伝子を含む発現ベクターで形質転換した宿主に産生されるもの、ファージディスプレイにより１兆個の分子からなる莫大なクローンライブラリーから最適抗体がスクリーニングされ、その遺伝子からCHO細胞により大量生産されるもの、及びヒトの抗体を生産するトランスジェニックマウスから直接得られるヒト抗体などが挙げられる。
　モノクローナル抗体およびポリクローナル抗体は当業者に公知の方法によって作製することができる。 The "anti-NFKBIZ antibody" means an antibody that specifically recognizes NFKBIZ, and means an antibody that has a binding activity to NFKBIZ.
The "antibody that specifically recognizes NFKBIZ" may be either a monoclonal antibody or a polyclonal antibody. Preferred examples of the "antibody that specifically recognizes NFKBIZ" include a polyclonal antibody. More preferably, a mammalian-derived monoclonal antibody is mentioned as the "antibody that specifically recognizes NFKBIZ".
Monoclonal and polyclonal antibodies derived from mammals are those produced in animal blood, those produced in hybridomas, and those produced in hosts transformed with an expression vector containing an antibody gene by genetic engineering techniques. Optimal antibodies are screened from a vast library of 1 trillion molecules by phage display and mass-produced by CHO cells from that gene, and humans obtained directly from transgenic mice that produce human antibodies. Examples include antibodies.
Monoclonal antibodies and polyclonal antibodies can be produced by methods known to those skilled in the art.
　「低分子化合物」とは、分子量が１万未満の「有機低分子化合物」又は「無機低分子化合物」を意味する。「低分子化合物」として好ましくは「有機低分子化合物」が挙げられる。
　「低分子化合物」の分子量として好ましくは、５０００以下であり、より好ましくは３０００以下であり、更に好ましくは２０００以下であり、最も好ましくは１０００以下が挙げられる。 The "low molecular weight compound" means an "organic low molecular weight compound" or an "inorganic low molecular weight compound" having a molecular weight of less than 10,000. The "low molecular weight compound" is preferably an "organic low molecular weight compound".
The molecular weight of the "low molecular weight compound" is preferably 5000 or less, more preferably 3000 or less, still more preferably 2000 or less, and most preferably 1000 or less.
　ＮＦＫＢＩＺインヒビター及び／又はレグネース１エンハンサーの好ましい態様として、低分子化合物である「Ｅ３リガーゼ阻害化合物」が挙げられる。 A preferred embodiment of the NFKBIZ inhibitor and / or Regnes 1 enhancer is a low molecular weight compound "E3 ligase inhibitor compound".
　「Ｅ３リガーゼ阻害化合物」として、例えば、国際公開２００６／１２９５８３に記載された化合物等が挙げられる。
　「Ｅ３リガーゼ阻害化合物」として具体的には、
４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）、（５－［［３－ジメチルアミノ）プロピル］アミノ］－３，１０－ジメチルピリミジノ［４，５－ｂ］キノリン－２，４（３Ｈ，１０Ｈ）－ジオン　ジヒドロクロライド（ＨＬＩ３７３、５０２１３７－９８－６）、及び
［（１Ｒ，２Ｒ，４Ｒ，６Ｒ，８Ｓ，９Ｅ，１１Ｒ）－８－ヒドロキシ－４，９－ジメチル－１４－メチリデン－１３－オキソ－５，１２－ジオキサトリサイクロ［９．３．０．０４，６］テトラデシ－９－エン－２－イル］２－メチルプロプ－２－エノエート（エリオフロリン、２７５４２－１７－２）が挙げられる。
「Ｅ３リガーゼ阻害化合物」として、最も好ましくは、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）が挙げられる。本開示において、ＧＳ１４３が、炎症性疾患から発生したがんに対して有効であることが見出されており（実施例）、ＧＳ１４３は炎症が伴わないがんに対しても高い蓋然性をもって有効であるといえる。 Examples of the "E3 ligase inhibitory compound" include the compounds described in International Publication 2006/129583.
Specifically, as an "E3 ligase inhibitor compound",
4- (3-Benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl) -benzoic acid (GS143), ( 5-[[3-Dimethylamino) propyl] Amino] -3,10-Dimethylpyrimidino [4,5-b] Quinoline-2,4 (3H, 10H) -dione dihydrochloride (HLI373, 502137-98- 6) and [(1R, 2R, 4R, 6R, 8S, 9E, 11R) -8-hydroxy-4,9-dimethyl-14-methylidene-13-oxo-5,12-dioxatricyclo [9. 3.0.0 4,6 ] Tetradec-9-ene-2-yl] 2-methylprop-2-enoate (eliofuroline, 27542-17-2).
The most preferable "E3 ligase inhibitor compound" is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-. 1-yl) -benzoic acid (GS143) can be mentioned. In the present disclosure, GS143 has been found to be effective against cancers arising from inflammatory diseases (Examples), and GS143 is also highly probable to be effective against non-inflammatory cancers. It can be said that there is.
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　「高分子化合物」とは、分子量が１万以上の化合物を意味する。
　「高分子化合物」として、例えば、「天然高分子」、「合成高分子」、及び「半合成高分子」が挙げられる。「高分子化合物」の別の分類として、「有機高分子」及び「無機高分子」が挙げられ、好ましくは「有機高分子」が挙げられる。
　「天然高分子」として、ポリアミン、一部の脂質、セルロース、アミロース、デンプン、キチン、天然ゴム、ポリペプチド、タンパク質、DNA、RNA、一部の脂質、リグニン、及びアスファルテン等が挙げられる。
　「合成高分子」として、ポリマーが挙げられる。
　「半合成高分子」として、人工セルロース等が挙げられる。 The "polymer compound" means a compound having a molecular weight of 10,000 or more.
Examples of the "polymer compound" include "natural polymer", "synthetic polymer", and "semi-synthetic polymer". As another classification of "polymer compound", "organic polymer" and "inorganic polymer" are mentioned, and "organic polymer" is preferable.
Examples of the "natural polymer" include polyamine, some lipids, cellulose, amylose, starch, chitin, natural rubber, polypeptides, proteins, DNA, RNA, some lipids, lignin, asphaltene and the like.
Examples of the "synthetic polymer" include polymers.
Examples of the "semi-synthetic polymer" include artificial cellulose and the like.
　本開示における「物質」は、水和物及び／又は溶媒和物の形で存在することもあるので、水和物及び／又は溶媒和物もまた本開示化合物に包含される。 Since the "substance" in the present disclosure may exist in the form of a hydrate and / or a solvate, the hydrate and / or the solvate is also included in the disclosed compounds.
　本開示における物質は、適宜、その製薬学的に許容される塩で用いられ得る。 The substances in the present disclosure may optionally be used in their pharmaceutically acceptable salts.
　「製薬学的に許容される塩」は、製薬学的に無毒な酸（無機酸及び有機酸を含む）から調整される塩を意味する。製薬学的に許容される塩としては、例えば、限定されないが、酢酸塩、アルギン酸塩、アントラニル酸塩、ベンゼンスルホン酸塩、安息香酸塩、カンファースルホン酸塩、クエン酸塩、エテンスルホン塩酸、ギ酸塩、フマル酸塩、グルコン酸塩、グルタミン酸塩、グルコレン酸塩、ガラクツロン酸塩、グリシド酸塩、臭化水素酸塩、塩酸塩、イセチオン酸塩、乳酸塩、マレイン酸塩、リンゴ酸塩、マンデル酸塩、メタンスルホン酸塩、ムチン酸塩、硝酸塩、パモ酸塩、パントテン酸塩、フェニル酢酸塩、プロピオン酸塩、リン酸塩、サリチル酸塩、ステアリン酸塩、コハク酸塩、スルファニル酸塩、硫酸塩、酒石酸塩、及びｐ－トルエンスルホン酸塩などが挙げられる。製薬学的に許容される塩として好ましくは、臭化水素酸塩、及び塩酸塩が挙げられる。製薬学的に許容される塩として最も好ましくは、塩酸塩が挙げられる。 "Pharmaceutically acceptable salt" means a salt prepared from a pharmaceutically non-toxic acid (including inorganic and organic acids). Pharmaceutically acceptable salts include, for example, but not limited to acetates, alginates, anthranylates, benzenesulfonates, benzoates, camphorsulfonates, citrates, ethenesulfonates, formic acids. Salt, fumarate, gluconate, glutamate, glucolenate, galacturonate, glycidate, hydrobromide, hydrochloride, ISEthionate, lactate, maleate, malate, mandel Acids, methanesulfonates, mutinates, nitrates, pamoates, pantothenates, phenylacetates, propionates, phosphates, salicylates, stearate, succinates, sulfanylates, sulfates Examples include salts, tartrates, and p-toluene sulfonates. Preferred examples of the pharmaceutically acceptable salt include hydrobromide salt and hydrochloride. The most preferred pharmaceutically acceptable salt is hydrochloride.
　（疾患）
　本開示は、上述のインヒビター及び／又はエンハンサーによるがんの治療を提供し得る。がんとして、とりわけ、慢性炎症に伴うがんが対象とされ得る。理論に拘束されることを望まないが、本明細書の実施例において、慢性炎症におけるがんのドライバー遺伝子が同定されており、上記インヒビター及び／又はエンハンサーが、かかるがんの抑制に有効であることが理解される。本開示は、下記に例示されるような特徴を有する疾患を対象とし得る。 (disease)
The present disclosure may provide treatment of cancer with the above-mentioned inhibitors and / or enhancers. Cancers, especially those associated with chronic inflammation, can be targeted. Without wishing to be bound by theory, in the examples herein, the driver genes for cancer in chronic inflammation have been identified and the inhibitors and / or enhancers described above are effective in controlling such cancers. Is understood. The present disclosure may cover diseases having characteristics such as those exemplified below.
　慢性炎症とは、組織異常が解消されているのにもかかわらず炎症物質、細胞などの活動が収束しない状態を意味する。慢性炎症性疾患として例えば、「炎症性腸疾患（ＩＢＤ；ｉｎｆｌａｍｍａｔｏｒｙ　ｂｏｗｅｌ　ｄｉｓｅａｓｅ）」が挙げられる。 Chronic inflammation means a state in which the activities of inflammatory substances, cells, etc. do not converge even though the tissue abnormality has been resolved. As a chronic inflammatory disease, for example, "inflammatory bowel disease (IBD; inflammatory bowel disease)" can be mentioned.
　「炎症性腸疾患」とは、消化管に炎症をおこす慢性炎症に係る疾患の総称で、免疫機構が異常をきたし、自己免疫細胞が腸の細胞を攻撃することで腸に炎症を起こす疾患を意味する。「炎症性腸疾患」の症状としては、「下痢」、「血便」、及び「腹痛」が挙げられる。
　「炎症性腸疾患」としては、「潰瘍性大腸炎（ＵＣ；Ｕｌｃｅｒａｔｉｖｅ　ｃｏｌｉｔｉｓ）」及び「クローン病（ＣＤ：Ｃｒｏｈｎ’ｓ　ｄｉｓｅａｓｅ）」が挙げられる。「炎症性腸疾患」として好ましくは、「潰瘍性大腸炎」が挙げられる。 "Inflammatory bowel disease" is a general term for diseases related to chronic inflammation that causes inflammation of the gastrointestinal tract, and is a disease that causes inflammation of the intestine by causing abnormalities in the immune system and autoimmune cells attacking intestinal cells. means. Symptoms of "inflammatory bowel disease" include "diarrhea", "bloody stool", and "abdominal pain".
Examples of the "inflammatory bowel disease" include "ulcerative colitis (UC)" and "Crohn's disease" (CD: Crohn's disease). Preferred examples of the "inflammatory bowel disease" include "ulcerative colitis".
　「潰瘍性大腸炎」とは、主に大腸粘膜に潰瘍やびらんができる原因不明の非特異性炎症性疾患を意味する。
　「潰瘍性大腸炎」としては、「潰瘍性（慢性）全大腸炎」、「潰瘍性（慢性）全大腸炎」、「潰瘍性（慢性）直腸Ｓ状結腸炎」、「炎症性ポリープ」、「左側大腸炎」、「その他の潰瘍性大腸炎」及び「原因不明の潰瘍性大腸炎」が挙げられる。
「潰瘍性大腸炎」の症状としては、「粘血便」、「下痢」、「発熱」・「体重減少」、「腹痛」及び「貧血」が挙げられる。
　「潰瘍性大腸炎」の合併症としては、「結節性紅斑」、「多発性関節炎」、「強直性脊椎炎」、「壊疽性膿皮症」、「肛門周囲炎・肛門膿瘍」、「肛門潰瘍・痔」、「中毒性巨大結腸症」、「穿孔」、「偽ポリポーシス（ポリープ）」、「歯肉炎」、「口内炎」、「凍瘡（足、指、耳）」、「浮腫（むくみ）」、「口渇」、及び「がん」が挙げられる。「潰瘍性大腸炎に伴う発がん」として、例えば、「潰瘍性大腸炎における腸炎関連性がん（ＣＡＣ；ｃｏｌｉｔｉｓ　ａｓｓｏｃｉａｔｅｄ　ｃａｒｃｉｎｏｍａ）」が挙げられる。 "Ulcerative colitis" means a non-specific inflammatory disease of unknown cause, which mainly causes ulcers and erosions on the mucosa of the large intestine.
"Ulcerative colitis" includes "ulcerative (chronic) colitis", "ulcerative (chronic) colitis", "ulcerative (chronic) rectal sigmoid colitis", "inflammatory polyp", Examples include "left side colitis", "other ulcerative colitis" and "ulcerative colitis of unknown cause".
Symptoms of "ulcerative colitis" include "mucous stool", "diarrhea", "fever" / "weight loss", "abdominal pain" and "anemia".
Complications of "ulcerative colitis" include "erythema nodosum", "polyarthritis", "chilblains", "pyoderma gangrenosum", "perianal inflammation / anorectal abscess", "anorectal abscess" Ulcerative colitis, addictive giant colitis, perforation, pseudopolyarthritis (polyp), gingitis, stomatitis, chilblains (feet, fingers, ears), edema , "Thirst", and "Cancer". Examples of the "carcinogenesis associated with ulcerative colitis" include "enterocolitis-related cancer (CAC) in ulcerative colitis".
　「クローン病」とは、主として口腔から肛門までの全消化管に、非連続性の慢性肉芽腫性炎症を生じる原因不明の炎症性疾患を意味する。
　「クローン病」としては、「小腸のクローン病」、「大腸のクローン病」、「その他のクローン病」及び「詳細不明のクローン病」が挙げられる。
　「クローン病」の症状としては、「腹痛」、「下痢」、「発熱」、「体重減少」、「肛門病変（痔瘻・裂肛・肛門潰瘍等）」及び「嘔吐」が挙げられる。
　「クローン病」の合併症としては、「関節症状（関節痛、関節炎）」、「皮膚症状（結節性紅斑、壊疽性膿皮症）」、「Ｓｗｅｅｔ病」、「眼症状（虹彩炎）」、「原発性硬化性胆管炎」及び「悪性腫瘍（大腸がん、回腸がん）」が挙げられる。 "Crohn's disease" means an inflammatory disease of unknown cause that causes discontinuous chronic granulomatous inflammation, primarily in the entire gastrointestinal tract from the oral cavity to the anus.
Examples of "Crohn's disease" include "Crohn's disease of the small intestine", "Crohn's disease of the large intestine", "Other Crohn's disease" and "Crohn's disease of unknown details".
Symptoms of "Crohn's disease" include "abdominal pain", "diarrhea", "fever", "weight loss", "anal fistula (anal fistula, anal fissure, anal ulcer, etc.)" and "vomiting".
Complications of "Crohn's disease" include "joint symptoms (arthralgia, arthritis)", "skin symptoms (erythema nodosum, pyoderma gangrenosum)", "Sweet disease", and "eye symptoms (iriditis)". , "Primary sclerosing cholangitis" and "malignant tumor (colon cancer, ileal cancer)".
　本開示における「がん」は悪性腫瘍を意味する。 "Cancer" in this disclosure means a malignant tumor.
　「がん」としては、例えば、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫が挙げられる。がんとして、上述のものを含めた群から選択される少なくとも一つを含むがんを本開示で対象とし得る。 "Cancer" includes, for example, colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, etc. Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, These include testicular tumors, testicular germ cell tumors, ovarian germ cell tumors, Wilms tumors, skin cancers, malignant melanomas, neuroblastomas, osteosarcomas, Ewing sarcomas, and soft sarcomas. The present disclosure may cover cancers that include at least one selected from the group including those described above.
　「がん」として、好ましくは、「大腸がん」があげられる。 The "cancer" is preferably "colon cancer".
　「大腸がん」としては、「盲腸がん」、「結腸がん」、「直腸がん」、及び「肛門がん」が挙げられる。「大腸がん」として好ましくは、「結腸がん」、「直腸がん」、及び「肛門がん」が挙げられる。「大腸がん」としてより好ましくは、「結腸がん」及び「直腸がん」が挙げられる。「大腸がん」としてさらに好ましくは、「結腸がん」が挙げられる。大腸がんとして、盲腸がん、結腸がん、直腸がん、又は及び肛門がんからなる群より選択される少なくとも一つを含む大腸がんを本開示で対象とし得る。 Examples of "colorectal cancer" include "cecal cancer", "colon cancer", "rectal cancer", and "anal cancer". Preferred examples of "colorectal cancer" include "colon cancer", "rectal cancer", and "anal cancer". More preferably, "colorectal cancer" includes "colon cancer" and "rectal cancer". More preferably, "colon cancer" is mentioned. Colorectal cancers, including at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, or anal cancer, may be included in the present disclosure.
　「がん」として好ましくは、「慢性炎症に伴うがん」が挙げられる。「慢性炎症に伴うがん」とは、慢性炎症を発症後、その炎症に伴って発症するがんをいい、慢性炎症性疾患に合併したがんとして診断される。「慢性炎症に伴うがん」として、例えば、炎症性腸疾患に合併した大腸がん、逆流性食道炎に合併した食道がん、アルコール性肝炎に合併した肝がん、非アルコール性脂肪肝炎に合併した肝がん、慢性胃炎に合併した胃がん、慢性膵炎に合併した膵がん、及び原発性硬化性胆管炎に合併した胆管がんが挙げられる。 The "cancer" is preferably "cancer associated with chronic inflammation". "Cancer associated with chronic inflammation" refers to cancer that develops with the onset of chronic inflammation and is diagnosed as cancer associated with chronic inflammatory disease. "Cancer associated with chronic inflammation" includes, for example, pancreatic cancer associated with inflammatory bowel disease, esophageal cancer associated with reflux esophagitis, liver cancer associated with alcoholic hepatitis, and non-alcoholic steatohepatitis. Examples include liver cancer associated with liver cancer, gastric cancer associated with chronic gastric inflammation, pancreatic cancer associated with chronic pancreatitis, and cholangiocarcinoma associated with primary sclerosing cholangitis.
　「慢性炎症に伴うがん」として、好ましくは、炎症性腸疾患に合併した大腸がんが挙げられる。
　「慢性炎症に伴うがん」として、より好ましくは、潰瘍性大腸炎に合併した大腸がんが挙げられる。
　「慢性炎症に伴うがん」として、さらに好ましくは、「潰瘍性大腸炎における腸炎関連性がん（ＣＡＣ）」及び「潰瘍性大腸炎における大腸がん」が挙げられる。 The "cancer associated with chronic inflammation" preferably includes colon cancer associated with inflammatory bowel disease.
The "cancer associated with chronic inflammation" more preferably includes colon cancer associated with ulcerative colitis.
More preferably, "cancer associated with chronic inflammation" includes "enterocolitis-related cancer in ulcerative colitis (CAC)" and "colon cancer in ulcerative colitis".
　「腸炎関連性がん」又は「炎症性がん」とは、「炎症性腸疾患に合併した大腸がん」を意味する。 "Enterocolitis-related cancer" or "inflammatory cancer" means "colon cancer associated with inflammatory bowel disease".
　ＮＦＫＢＩＺの機能欠損変異は、マウス腸炎モデルにおいて組織の炎症性サイトカインの産生を抑制し、組織破壊と再生を伴う腸炎を緩和する。本開示において、１つの実施形態では、炎症性サイトカインの産生を抑制するための、ＮＦＫＢＩＺインヒビター及び／又はレグネース１エンハンサーを含む組成物、またはその使用が提供され得る。別の実施形態では、組織破壊と再生を伴う腸炎を緩和するための、ＮＦＫＢＩＺインヒビター及び／又はレグネース１エンハンサーを含む組成物、またはその使用が提供され得る。 The NFKBIZ deficient mutation suppresses the production of tissue inflammatory cytokines in a mouse enteritis model and alleviates enteritis associated with tissue destruction and regeneration. In the present disclosure, in one embodiment, a composition comprising an NFKBIZ inhibitor and / or a Regnes 1 enhancer for suppressing the production of inflammatory cytokines, or use thereof, may be provided. In another embodiment, a composition comprising an NFKBIZ inhibitor and / or a Regnes 1 enhancer, or use thereof, may be provided to alleviate enteritis associated with tissue destruction and regeneration.
　（予防／治療）
　本開示における、「予防」とは、対象となる疾患を発症していると診断をされていない人に対して本開示の有効成分を投与する行為であり、例えば、疾患の発症を防止することを目的とするものである。 (Prevention / Treatment)
In the present disclosure, "prevention" is an act of administering the active ingredient of the present disclosure to a person who has not been diagnosed as developing the target disease, for example, to prevent the onset of the disease. Is the purpose.
　本開示における、「治療」とは、医師により疾患を発症していると診断をされた人（患者）に対して本開示の有効成分を投与する行為であり、例えば、疾患や症状を軽減すること、癌腫を増大させないこと又は疾患発症前の状態に戻すことを目的とするものである。また、投与の目的が疾患や症状の悪化防止又は癌腫の増大防止であっても、投与されるのが患者であれば、治療行為である。 In the present disclosure, "treatment" is an act of administering the active ingredient of the present disclosure to a person (patient) diagnosed as having a disease by a doctor, for example, reducing the disease or symptom. The purpose is to prevent the growth of carcinoma or to return it to the state before the onset of the disease. Moreover, even if the purpose of administration is to prevent the exacerbation of diseases and symptoms or the growth of carcinoma, if the administration is to a patient, it is a therapeutic act.
　本開示のインヒビター及び／又はエンハンサーを投与する場合、その使用量は、症状、年齢、投与方法等によって異なるが、例えば、静脈内注射の場合には、成人に対して、１日当たり、下限として、０．０１ｍｇ（好ましくは０．１ｍｇ）、上限として、１０００ｍｇ（好ましくは１００ｍｇ）を、１回または数回に分けて、症状に応じて投与することにより効果が期待される。その投与スケジュールとしては、例えば単回投与、１日１回３日間連日投与、又は１日２回１週間連続投与、等を挙げることができる。さらに上記記載の各投与方法を、約１日間～約６０日間の間隔をあけて繰り返すこともできる。 When the inhibitor and / or enhancer of the present disclosure is administered, the amount used varies depending on the symptoms, age, administration method, etc., but for example, in the case of intravenous injection, the lower limit per day is set for adults. The effect is expected by administering 0.01 mg (preferably 0.1 mg) and, as the upper limit, 1000 mg (preferably 100 mg) in one or several divided doses according to the symptom. Examples of the administration schedule include single administration, once daily administration for 3 days, or twice daily administration for 1 week. Further, each of the above-described administration methods can be repeated at intervals of about 1 day to about 60 days.
　本開示のインヒビター及び／又はエンハンサーは、経口投与又は非経口投与により、直接又は適当な剤形を用いて製剤にし、投与することができる。剤形は、例えば、錠剤、カプセル剤、散剤、顆粒剤、液剤、懸濁剤、注射剤、貼付剤、ハップ剤等が挙げられるがこれに限らない。製剤は、薬学的に許容される添加剤を用いて、公知の方法で製造される。 The inhibitors and / or enhancers of the present disclosure can be formulated and administered directly or in an appropriate dosage form by oral administration or parenteral administration. Dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, haptics and the like. Formulations are made by known methods using pharmaceutically acceptable additives.
　添加剤としては、目的に応じて、賦形剤、崩壊剤、結合剤、流動化剤、滑沢剤、コーティング剤、溶解剤、溶解補助剤、増粘剤、分散剤、安定化剤、甘味剤、香料等を用いることができる。添加剤の具体例としては、例えば、乳糖、マンニトール、結晶セルロース、低置換度ヒドロキシプロピルセルロース、トウモロコシデンプン、部分α化デンプン、カルメロースカルシウム、クロスカルメロースナトリウム、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール、ステアリン酸マグネシウム、フマル酸ステアリルナトリウム、ポリエチレングリコール、プロピレングリコール、酸化チタン、タルク等が挙げられる。 Additives include excipients, disintegrants, binders, fluidizers, lubricants, coatings, solubilizers, solubilizers, thickeners, dispersants, stabilizers, and sweetness, depending on the purpose. Agents, fragrances and the like can be used. Specific examples of the additive include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl. Examples thereof include alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide and talc.
　本開示のインヒビター及び／又はエンハンサーは、非経口投与又は経口投与により投与しうるが、好ましくは経口的方法により投与される。 The inhibitors and / or enhancers of the present disclosure can be administered by parenteral administration or oral administration, but are preferably administered by an oral method.
　本開示において、被験者のがん細胞におけるＮＦＫＢＩＺの遺伝子発現及び／又はＮＦＫＢＩＺの活性を測定することで、ＮＦＫＢＩＺインヒビターの当該被験者への有効性を予測し得る。加えて、本開示において、ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇している被験者をがんを治療及び／又は予防するための医薬組成物又は方法の対象とすることができる。理論に拘束されることを望むものではないが、本明細書の実施例において、ＮＦＫＢＩＺの機能が抑制された場合に、がんの発生が抑制され、また、発生したがんの増殖が抑制されることが示されており、ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇している被験者を対象としてＮＦＫＢＩＺインヒビターを用い得ることが理解される。ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇していることは、（１）被験者より取得したがん細胞のＮＦＫＢＩＺ遺伝子の発現及び／又は活性を測定すること、（２）（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又は活性を、健常者より採取した細胞中の前記ＮＦＫＢＩＺ遺伝子の発現及び／又は活性（以下、対照値という）と比較すること、及び（３）（２）の結果に基づき、（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又は活性が、該対照値よりも大きい場合に、ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇していると判定することを含む工程で決定され得る。インヒビター、被験者、細胞種、および測定などに関する特徴として、本明細書の他の箇所に記載される特徴を必要に応じて採用し得る。 In the present disclosure, the effectiveness of the NFKBIZ inhibitor on the subject can be predicted by measuring the gene expression of NFKBIZ and / or the activity of NFKBIZ in the cancer cells of the subject. In addition, in the present disclosure, subjects with increased expression of NFKBIZ and / or increased activity of NFKBIZ shall be the subject of pharmaceutical compositions or methods for treating and / or preventing cancer. Can be done. Although not bound by theory, in the examples herein, when the function of NFKBIZ is suppressed, the development of cancer is suppressed and the growth of the developed cancer is suppressed. It is understood that the NFKBIZ inhibitor can be used in subjects with increased expression of NFKBIZ and / or increased activity of NFKBIZ. The increased expression of NFKBIZ and / or the increased activity of NFKBIZ means that (1) the expression and / or activity of the NFKBIZ gene in cancer cells obtained from the subject is measured, (2). Comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and (3) ( Based on the result of 2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ is increased. It can be determined in a process that includes determining that it is. Features described elsewhere herein may optionally be employed as features relating to inhibitors, subjects, cell types, measurements, and the like.
　本開示において、被験者のがん細胞におけるレグネース１の発現及び／又は活性を測定することで、レグネース１エンハンサーの当該被験者への有効性を予測し得る。加えて、本開示において、レグネース１の発現が低下している、及び／又はレグネース１の活性が低下している被験者をがんを治療及び／又は予防するための医薬組成物又は方法の対象とすることができる。理論に拘束されることを望むものではないが、本明細書の実施例において、レグネース１エンハンサーが、炎症性疾患から発生したがんに対して有効であることが見出されており（実施例）、レグネース１の発現が低下している、及び／又はレグネース１の活性が低下している被験者を対象としてレグネース１エンハンサーを用い得ることが理解される。レグネース１発現が低下している、及び／又はレグネース１の活性が低下していることは、（１）被験者より取得したがん細胞のレグネース１の発現及び／又は活性を測定すること、（２）（１）で定量したレグネース１の発現及び／又は活性を、健常者より採取した細胞中のレグネース１の発現及び／又は活性（以下、対照値という）と比較すること、及び（３）（２）の結果に基づき、（１）で定量したレグネース１の発現及び／又は活性が、対照値よりも小さい場合に、レグネース１の発現及び／又は活性が低下していると判定することを含む工程で決定され得る。エンハンサー、被験者、細胞種、および測定などに関する特徴として、本明細書の他の箇所に記載される特徴を必要に応じて採用し得る。 In the present disclosure, the effectiveness of the Legnes 1 enhancer on the subject can be predicted by measuring the expression and / or activity of Legnes 1 in the cancer cells of the subject. In addition, in the present disclosure, subjects with reduced expression of Legnes 1 and / or reduced activity of Legnes 1 are subject to pharmaceutical compositions or methods for treating and / or preventing cancer. can do. Although not bound by theory, in the examples herein, the Legnes 1 enhancer has been found to be effective against cancers arising from inflammatory diseases (Examples). ), It is understood that the Legnese 1 enhancer can be used for subjects with reduced expression of Legnes 1 and / or decreased activity of Legnes 1. Decreased expression of legnes 1 and / or decreased activity of legnes 1 means that (1) measurement of legnes 1 expression and / or activity of cancer cells obtained from a subject, (2) ) To compare the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and (3) ( Based on the result of 2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it includes determining that the expression and / or activity of legnes 1 is decreased. It can be determined in the process. Features described elsewhere herein may be incorporated as needed as features relating to enhancers, subjects, cell types, measurements and the like.
　（１）本開示のインヒビター及び／又はエンハンサーの有効量を投与することと、（２）（ｉ）他の抗がん剤の有効量を投与すること、（ｉｉ）ホルモン療法剤の有効量を投与すること、（ｉｉｉ）他の炎症性腸疾患治療剤の有効量を投与すること、及び（ｉｖ）非薬剤療法からなる群からなる群から選ばれる１～４種とを組み合わせることにより、より効果的にがんを予防／治療することができる。非薬剤療法としては、例えば、手術、放射線療法、遺伝子治療、温熱療法、凍結療法、レーザー灼熱療法、血球成分除去療法（白血球除去療法、顆粒球除去療法）などが挙げられ、これらを２種以上組み合わせることもできる。 (1) Administering effective amounts of the inhibitors and / or enhancers of the present disclosure, (2) (i) Administering effective amounts of other anticancer agents, (ii) Effective amounts of hormone therapy agents. By administering (iii) an effective amount of another therapeutic agent for inflammatory bowel disease, and (iv) combining with 1 to 4 species selected from the group consisting of non-drug therapies. Can effectively prevent / treat cancer. Examples of non-drug therapies include surgery, radiotherapy, gene therapy, hyperthermia, cryotherapy, laser burning therapy, blood cell component removal therapy (leukocyte removal therapy, granulocyte removal therapy), and two or more of these. It can also be combined.
　本開示のインヒビター及び／又はエンハンサーは、その効果の増強を目的として、他の薬物と併用して用いることができる。具体的には、本開示のインヒビター及び／又はエンハンサーは、ホルモン療法剤、化学療法剤、免疫療法剤または細胞増殖因子ならびにその受容体作用を阻害する薬剤等の薬物と併用して用いることができる。以下、本開示のインヒビター及び／又はエンハンサーと併用し得る薬物を併用薬物と略記する。 The inhibitors and / or enhancers of the present disclosure can be used in combination with other drugs for the purpose of enhancing their effects. Specifically, the inhibitors and / or enhancers of the present disclosure can be used in combination with drugs such as hormone therapies, chemotherapeutic agents, immunotherapeutic agents or cell growth factors and agents that inhibit their receptor action. .. Hereinafter, drugs that can be used in combination with the inhibitors and / or enhancers of the present disclosure are abbreviated as concomitant drugs.
　本開示のインヒビター及び／又はエンハンサーは単剤として使用しても優れた抗がん作用を示すが、さらに前記併用薬物の一つまたは幾つかと併用（多剤併用）することによって、その効果をより一層増強または患者のＱＯＬを改善させることができる。 The inhibitors and / or enhancers of the present disclosure show excellent anticancer activity even when used as a single agent, but the effect can be further enhanced by using in combination with one or several of the above-mentioned concomitant drugs (multi-drug combination). It can be further enhanced or the patient's QOL can be improved.
　「ホルモン療法剤」としては、例えば、ホスフェストロール、ジエチルスチルベストロール、クロロトリアニセン、酢酸メドロキシプロゲステロン、酢酸メゲストロール、酢酸クロルマジノン、酢酸シプロテロン、ダナゾール、ジエノゲスト、アソプリスニル、アリルエストレノール、ゲストリノン、ノメゲストール、タデナン、メパルトリシン、ラロキシフェン、オルメロキシフェン、レボルメロキシフェン、抗エストロゲン（例えば、クエン酸タモキシフェン、クエン酸トレミフェン等）、ピル製剤、メピチオスタン、テストロラクトン、アミノグルテチイミド、ＬＨ－ＲＨ誘導体（ＬＨ－ＲＨアゴニスト（例えば、酢酸ゴセレリン、ブセレリン、リュープロレリンなど）、ＬＨ－ＲＨアンタゴニスト）、ドロロキシフェン、エピチオスタノール、スルホン酸エチニルエストラジオール、アロマターゼ阻害剤（例えば、塩酸ファドロゾール、アナストロゾール、レトロゾール、エキセメスタン、ボロゾール、フォルメスタンなど）、フルタミド、ビカルタミド、ニルタミド、アンドロゲン受容体拮抗剤（例えば、アパルタミド、エンザルタミド）、アンドロゲン合成阻害剤（例えば、アビラテロンなど）、副腎皮質ホルモン系薬剤（例えば、デキサメタゾン、プレドニゾロン、ベタメタゾン、トリアムシノロンなど）、レチノイド、及びレチノイドの代謝を遅らせる薬剤（例えば、リアロゾールなど）などが挙げられる。 Examples of the "hormonal therapeutic agent" include phosfestol, diethylstillbestrol, chlorotrianisen, medroxyprogesterone acetate, megestrol acetate, chlormaginone acetate, ciproterone acetate, danazol, dienogest, asoprisnil, allylestradiol, and guest. Linon, nomegestol, tadenan, mepartricin, raloxifene, olmeroxyphene, revolmeroxyphene, anti-estrogen (eg, tamoxyphene citrate, tremiphen citrate, etc.), pills, mepitiostane, testrolactone, aminoglutetiimide, LH- RH derivatives (LH-RH agonists (eg, goselelin acetate, busererin, leuprolerin, etc.), LH-RH antagonists), raloxifene, epithiostanol, ethinylestradiol sulfonate, aromatase inhibitors (eg, fadrozol hydrochloride, ana) Strozol, retrozol, exemestane, borozol, formestane, etc.), flutamide, bicalutamide, niltamide, androgen receptor antagonists (eg, appartamide, enzalutamide), androgen synthesis inhibitors (eg, avilateron, etc.) Examples include dexamethasone, prednisolone, betamethazone, triamsinolone, etc., retinoids, and agents that slow the metabolism of retinoids (eg, rialozol, etc.).
　「化学療法剤」としては、例えば、アルキル化剤、代謝拮抗剤、抗がん性抗生物質、植物由来抗がん剤、分子標的治療剤、免疫調節剤、その他の化学療法剤などが用いられる。代表的な例を次に記載する。 Examples of the "chemotherapeutic agent" include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, molecular-targeted therapeutic agents, immunomodulators, and other chemotherapeutic agents. .. A typical example is described below.
　「アルキル化剤」としては、例えば、ナイトロジェンマスタード、塩酸ナイトロジェンマスタード－Ｎ－オキシド、クロラムブチル、シクロフォスファミド、イホスファミド、チオテパ、カルボコン、トシル酸インプロスルファン、ブスルファン、塩酸ニムスチン、ミトブロニトール、メルファラン、ダカルバジン、ラニムスチン、リン酸エストラムスチンナトリウム、トリエチレンメラミン、カルムスチン、ロムスチン、ストレプトゾジン、ピポブロマン、エトグルシド、カルボプラチン、シスプラチン、ミボプラチン、ネダプラチン、オキサリプラチン、アルトレタミン、アンバムスチン、塩酸ジブロスピジウム、フォテムスチン、プレドニムスチン、プミテパ、リボムスチン、テモゾロミド、チオテパ、トレオスルファン、トロフォスファミド、ジノスタチンスチマラマー、アドゼレシン、システムスチン、ビゼレシン及びそれらのＤＤＳ製剤などが挙げられる。 Examples of the "alkylating agent" include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosfamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, and mel. Farang, dacarbazine, lanimustin, sodium estramustin phosphate, triethylene melamine, carmustin, romustin, streptozogen, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustin, dibrospidine hydrochloride , Prednimustin, Pumitepa, Ribomustin, Temozolomide, Thiotepa, Treosulfan, Trophosfamide, Dinostatin stimalamar, Adzelesin, Cisplatin, Busulfan and their DDS preparations.
　「代謝拮抗剤」としては、例えば、メルカプトプリン、６－メルカプトプリンリボシド、チオイノシン、メトトレキサート、ペメトレキセド、エオシタビン、シタラビン、シタラビンオクフォスファート、塩酸アンシタビン、５－ＦＵ系薬剤（例えば、フルオロウラシル、テガフール、ＵＦＴ、ドキシフルリジン、カルモフール、ガロシタビン、エミテフール、カペシタビンなど）、アミノプテリン、ネルザラビン、ロイコポリンカルシウム、タブロイド、ブトシン、フォリネイトカルシウム、レボフォリネイトカルシウム、クラドリビン、エミテフール、フルダラビン、ゲムシタビン、ヒドロキシカルパミド、ペントスタチン、ピリトレキシム、イドキシウリジン、ミトグアゾン、チアゾフリン、アンバムスチン、ベンダムスチン、及びそれらのＤＤＳ製剤などが挙げられる。 Examples of the "antimetabolite" include mercaptopurine, 6-mercaptopurine riboside, thioinosin, methotrexate, pemetrexed, eocitabine, cytarabine, cytarabine octofusphate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, etc.). UFT, doxiflulysine, carmofur, gallositabin, emitefur, capecitabine, etc.), aminopterin, nerzarabin, leukoporin calcium, tabloid, butocin, forinate calcium, levofolinate calcium, cladribine, emitefur, fludalabine, gemcitabine, hydroxycarpamid , Pyritrexim, idoxyuridine, mitogazone, thiazofurin, ambamustin, bendamstin, and DDS preparations thereof.
　「抗がん性抗生物質」としては、例えば、アクチノマイシンＤ、アクチノマイシンＣ、マイトマイシンＣ、クロモマイシンＡ３、塩酸ブレオマイシン、硫酸ブレオマイシン、硫酸ペプロマイシン、塩酸ダウノルビシン、塩酸ドキソルビシン、塩酸アクラルビシン、塩酸ピラルビシン、塩酸エピルビシン、ネオカルチノスタチン、ミスラマイシン、ザルコマイシン、カルチノフィリン、ミトタン、塩酸ゾルビシン、塩酸ミトキサントロン、塩酸イダルビシン、及びそれらのＤＤＳ製剤などが挙げられる。 Examples of the "anticancer antibiotic" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, acralubicin hydrochloride, pyrarubicin hydrochloride, and hydrochloric acid. Examples thereof include epirubicin, neocartinostatin, misramycin, zarkomycin, cartinophylline, mittan, sorbicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and DDS preparations thereof.
　「植物由来抗がん剤」としては、例えば、エトポシド、リン酸エトポシド、硫酸ビンブラスチン、硫酸ビンクリスチン、硫酸ビンデシン、テニポシド、パクリタキセル、ドセタクセル、DJ-927、ビノレルビン、イリノテカン、トポテカン、及びそれらのＤＤＳ製剤などが挙げられる。 Examples of the "plant-derived anticancer agent" include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, bindecine sulfate, teniposide, paclitaxel, docetaxel, DJ-927, vinorelbine, irinotecan, topotecan, and their DDS preparations. Can be mentioned.
　「分子標的治療剤」としては、例えば、イマチニブ、ゲフィチニブ、エルロチニブ、ソラフェニブ、ダサチニブ、スニチニブ、ニロチニブ、ラパチニブ、パゾパニブ、ルキソリチニブ、クリゾチニブ、ベムラフェニブ、バンデタニブ、ポナチニブ、カボザンチニブ、トファシチニブ、レゴラフェニブ、ボスチニブ、アキシチニブ、ダブラフェニブ、トラメチニブ、ニンテダニブ、イデラリシブ、セリチニブ、レンバチニブ、パルボシクリブ、アレクチニブ、アファチニブ、オシメルチニブ、リボシクリブ、アベマシクリブ、ブリガチニブ、ネラチニブ、コパンリシブ、コビメチニブ、イブルチニブ、アカラブルチニブ、エンコラフェニブ、ビニメチニブ、バリシチニブ、フォスタマチニブ、ロルラチニブ、エルダフィチニブ、エントレクチニブ、ダコミチニブ、シロリムス、エベロリムス、テムシロリムス、オラパリブ、ルカパリブ、ニラパリブ、ベネトクラックス、アザシチジン、デシタビン、ボリノスタット、パノビノスタット、ロミデプシン、ボルテゾミブ、カルフィルゾミブ、及びイキサゾミブなどが挙げられる。 "Molecular targeted therapies" include, for example, imatinib, gefitinib, erlotinib, sorafenib, dasatinib, snitinib, nirotinib, laparib, pazopanib, luxolitinib, crizotinib, bemurafenib, bandetanib, ponatib nib, vemurafenib, bandetanib, ponatib. , Trametinib, nintedanib, Iderarishibu, Serichinibu, lenvatinib, Paruboshikuribu, Arekuchinibu, AFATINIB, Oshimeruchinibu, Riboshikuribu, Abemashikuribu, Burigachinibu, neratinib, Kopanrishibu, cobimetinib, Iburuchinibu, Akaraburuchinibu, Enkorafenibu, Binimechinibu, Barishichinibu, Fosutamachinibu, Rorurachinibu, Erudafichinibu, Entorekuchinibu, Dakomichinibu , Sirolimus, Eberolimus, Temsirolimus, Olaparib, Lucaparib, Nilaparib, Vemurafenib, Azacitidine, Decitabin, Borinostat, Panobinostat, Lomidepsin, Bortezomib, Calfilzomib, and Ixazomib.
　「免疫調節剤」としては、例えば、レナリドミド及びポマリドミドなどが挙げられる。 Examples of the "immunmodulator" include lenalidomide and pomalidomide.
　「その他の化学療法剤」としては、例えば、ソブゾキサンなどが挙げられる。 Examples of "other chemotherapeutic agents" include sobzoxane.
　「免疫療法剤（ＢＲＭ）」としては、例えば、ピシバニール、クレスチン、シゾフィラン、レンチナン、ウベニメクス、インターフェロン、インターロイキン、マクロファージコロニー刺激因子、顆粒球コロニー刺激因子、エリスロポイエチン、リンホトキシン、ＢＣＧワクチン、コリネバクテリウムパルブム、レバミゾール、ポリサッカライドＫ、プロコダゾール、抗ＣＴＬＡ４抗体、抗ＰＤ－１抗体、抗ＰＤ－Ｌ１抗体、Ｔｏｌｌ－ｌｉｋｅ　Ｒｅｃｅｐｔｏｒｓ作動薬（例えば、ＴＬＲ７作動薬、ＴＬＲ８作動薬、ＴＬＲ９作動薬など）が挙げられる。 Examples of the "immunotherapeutic agent (BRM)" include pisibanil, crestin, cisophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulator, granulocyte colony stimulator, erythropoietin, phosphotoxin, BCG vaccine, corinebacterium Umpalbum, levamisol, polysaccharide K, prochodazole, anti-CTLA4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, Toll-like Receptors agonist (for example, TLR7 agonist, TLR8 agonist, TLR9 agonist, etc.) Can be mentioned.
　細胞増殖因子ならびにその受容体の作用を阻害する薬剤における細胞増殖因子としては、細胞増殖を促進する物質であれば、どのようなものでもよく、通常、分子量が２０，０００以下のペプチドで、受容体との結合により低濃度で作用が発揮される因子があげられる。具体的には、ＥＧＦ（ｅｐｉｄｅｒｍａｌ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）またはそれと実質的に同一の活性を有する物質（例えば、ＴＧＦａｌｐｈａなど）、インスリンまたはそれと実質的に同一の活性を有する物質（例えば、インスリン、ＩＧＦ（ｉｎｓｕｌｉｎ－ｌｉｋｅ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）－１、ＩＧＦ－２など）、ＦＧＦ（ｆｉｂｒｏｂｌａｓｔ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）またはそれと実質的に同一のアッセイを有する物質（例えば、酸性ＦＧＦ、塩基性ＦＧＦ、ＫＧＫ（ｋｅｒａｔｉｎｏｃｙｔｅ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）、ＦＧＦ－１０など）、及び、その他の細胞増殖因子（例えば、ＣＳＦ（ｃｏｌｏｎｙ　ｓｔｉｍｕｋａｔｉｎｇ　ｆａｃｔｏｒ）、ＥＰＯ（ｅｒｙｔｈｒｏｐｏｉｅｔｉｎ）、ＩＬ－２（ｉｎｔｅｒｌｅｕｋｉｎ－２）、ＮＧＦ（ｎｅｒｖｅ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）、ＰＤＧＦ（ｐｌａｔｅｌｅｔ－ｄｅｒｉｖｅｄ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）、ＴＧＦ－ｂｅｔａ（ｔｒａｎｓｆｏｒｍｉｎｇ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ　ｂｅｔａ）、ＨＧＦ（ｈｅｐａｔｏｃｙｔｅ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）、ＶＥＧＦ（ｖａｓｃｕｌａｒ　ｅｎｄｏｔｈｅｌｉａｌ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）、へレグリン、アンジオポエチンなど）が挙げられる。 The cell growth factor in the drug that inhibits the action of the cell growth factor and its receptor may be any substance as long as it promotes cell growth, and is usually accepted by a peptide having a molecular weight of 20,000 or less. Factors that exert their effects at low concentrations by binding to the body. Specifically, EGF (epidermal growth factor) or a substance having substantially the same activity as it (for example, TGFalpha), insulin or a substance having substantially the same activity as it (for example, insulin, IGF (insulin-)). (like growth factor) -1, IGF-2, etc.), FGF (fibroblast growth factor) or a substance having substantially the same assay (for example, acidic FGF, basic FGF, KGK (keratinocite growth factor), FGF-10. Etc.) and other cell growth factors (for example, CSF (colory stemming factor), EPO (erythropoitin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derivted) Examples include TGF-beta (transforming growth factor beta), HGF (hepatotic growth factor), VEGF (vascular endotherial growth factor), hergulin, angiopoetin, etc.).
　本開示の物質は、その効果の増強、及び／又は合併症を治療することを目的として、「他の炎症性腸疾患治療剤」と併用して用いることができる。以下、本開示の物質と併用し得る「他の炎症性腸疾患治療剤」と略記する。 The substance of the present disclosure can be used in combination with "another therapeutic agent for inflammatory bowel disease" for the purpose of enhancing its effect and / or treating complications. Hereinafter, it is abbreviated as "another therapeutic agent for inflammatory bowel disease" that can be used in combination with the substance of the present disclosure.
　「他の炎症性腸疾患治療剤」としては、サリチル酸、サラゾスルファピリジン、メサラジン、プレドニゾロン、ベタメタゾン、ブデソニド、メチルプレドニゾロン、ハイドロコルチゾン、インフリキシマブ、アダリムマブ、ウステキヌマブ、セルトリズマブ、ゴリムマブ、タクロリムス、アザチオプリン、メルカプトプリン、シクロスポリン、トファシチニブ、及びベドリズマブが挙げられる。 "Other inflammatory bowel disease treatments" include salicylic acid, salazosulfapyridine, mesalazine, prednisolone, betamethasone, budesonide, methylprednisolone, hydrocortisone, infliximab, adalimumab, ustekinumab, sertrizumab, golimumab, tacrolimus, azathioprine. , Cyclosporine, tofacitinib, and vedrizumab.
　本開示の物質、及び併用薬剤の投与期間は限定されず、これらを投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。また、本開示の物質と併用薬剤の合剤としてもよい。併用薬剤の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本開示の物質と併用薬剤の配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせなどにより適宜選択することができる。例えば投与対象がヒトである場合、本開示の化合物１重量部に対し、併用薬剤を０．０１～１００重量部用いればよい。また、その副作用抑制の目的として、制吐剤、睡眠導入剤、抗痙攣薬などの薬剤（併用薬剤）と組み合わせて用いることができる。 The administration period of the substance of the present disclosure and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or at different times. In addition, it may be a mixture of the substance of the present disclosure and a concomitant drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the substance of the present disclosure and the concomitant drug can be appropriately selected depending on the administration target, administration route, target disease, symptom, combination and the like. For example, when the administration target is a human, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the compound of the present disclosure. In addition, for the purpose of suppressing the side effects, it can be used in combination with drugs (combined drugs) such as antiemetics, sleep-inducing agents, and anticonvulsants.
　理論に拘束されることを望むものではないが、本明細書の実施例において、ＮＦＫＢＩＺの機能が抑制された場合に、がんの発生が抑制され、また、発生したがんの増殖が抑制されることが示されており、任意のＮＦＫＢＩＺインヒビターが本開示において用いられ得ることが理解される。ＮＦＫＢＩＺは、アンキリンリピートドメインを介したＮＦκ－Ｂタンパク質との相互作用により炎症反応において機能することから、ＮＦＫＢＩＺインヒビターを用いて、ＮＦＫＢＩＺの発現量を減少させること、ＮＦＫＢＩＺの安定性を低下させること、ＮＦＫＢＩＺの核内移行を阻害すること、ＮＦＫＢＩＺとｐ５０との結合を阻害すること、ＮＦＫＢＩＺを含む複合体よりなる転写因子が特定のＤＮＡ配列と相互作用することなどによって、いずれの場合にも、がんの発生が抑制され得、または、発生したがんの増殖が抑制され得ることが理解される。 Although not bound by theory, in the examples herein, when the function of NFKBIZ is suppressed, the development of cancer is suppressed and the growth of the developed cancer is suppressed. It is understood that any NFKBIZ inhibitor can be used in the present disclosure. Since NFKBIZ functions in the inflammatory response by interacting with the NFκ-B protein via the ankyrin repeat domain, NFKBIZ inhibitors can be used to reduce the expression level of NFKBIZ and reduce the stability of NFKBIZ. In any case, by inhibiting the nuclear translocation of NFKBIZ, inhibiting the binding of NFKBIZ to p50, and the interaction of a transcription factor consisting of a complex containing NFKBIZ with a specific DNA sequence, It is understood that the development of cancer can be suppressed or the growth of the developed cancer can be suppressed.
　さらに、理論に拘束されることを望むものではないが、本明細書の実施例において、レグネース１の発現量を増加させた場合に、ＮＦＫＢＩＺの発現が低下することが示されており、上述のとおり、レグネース１の活性を増強することによってがんの発生が抑制され得、または、発生したがんの増殖が抑制され得ることが理解される。レグネース１の活性の増強として、レグネース１の発現量を増加させること、またはレグネース１の分解を減少させる（レグネース１を安定化するか、またはレグネース１を分解する物質（分解酵素など）を阻害する等）ことなどによって、いずれの場合にも、がんの発生が抑制され得、または、発生したがんの増殖が抑制され得ることが理解される。 Furthermore, although not desired to be bound by theory, it has been shown in the examples herein that increasing the expression level of Legnes 1 reduces the expression of NFKBIZ, as described above. As described above, it is understood that the development of cancer can be suppressed or the growth of the developed cancer can be suppressed by enhancing the activity of Legnes 1. As an enhancement of the activity of legnes 1, the expression level of legnes 1 is increased, or the degradation of legnes 1 is reduced (stabilizes legnes 1 or inhibits substances that degrade legnes 1 (such as degrading enzymes). Etc.) It is understood that the development of cancer can be suppressed or the growth of the developed cancer can be suppressed in any case.
（スクリーニング）
　本開示の一実施形態は、がんを治療及び／又は予防する物質を選別するスクリーニングする方法を提供し得る。これは、少なくとも部分的には、本発明者らによりＮＦＫＢＩＺインヒビターが、がんに対して格別な増殖抑制効果を示すことを見出したことに基づいている。 (screening)
One embodiment of the present disclosure may provide a method of screening to screen for substances that treat and / or prevent cancer. This is based, at least in part, on the finding by the present inventors that the NFKBIZ inhibitor exhibits a particular growth inhibitory effect on cancer.
　がんの治療及び／又は予防剤をスクリーニングする方法は、（１）がん細胞に治療及び／又は予防剤候補を作用させずに、遺伝子発現及び／又は活性を測定する工程、（２）当該がん細胞に当該治療及び／又は予防剤候補を作用させた後に、遺伝子発現及び／又は活性を測定する工程、及び（３）（２）の結果が、（１）の結果よりも小さい又は大きい場合に、当該治療及び／又は予防剤を、がんの治療及び／又は予防剤であると判定する工程を含み得る。遺伝子としては、ＮＦＫＢＩＺ、またはレグネース１などの本明細書に記載される遺伝子を対象とし得る。インヒビター、エンハンサー、被験者、細胞種、および測定などに関する特徴として、本明細書の他の箇所に記載される特徴を必要に応じて採用し得る。 Methods for screening for therapeutic and / or prophylactic agents for cancer include (1) measuring gene expression and / or activity without allowing therapeutic and / or prophylactic agent candidates to act on cancer cells, (2) relevant. The steps of measuring gene expression and / or activity after applying the therapeutic and / or prophylactic agent candidate to cancer cells, and the results of (3) and (2) are smaller or larger than the results of (1). In some cases, the treatment and / or prophylaxis may include the step of determining that the treatment and / or prophylaxis is a cancer treatment and / or prophylaxis. As the gene, a gene described in the present specification such as NFKBIZ or Legnes 1 can be targeted. Features described elsewhere herein may optionally be employed as features relating to inhibitors, enhancers, subjects, cell types, measurements, and the like.
　一実施形態では、方法は、ＮＦＫＢＩＺインヒビターをスクリーニングする方法として特徴付けられ、（１）がん細胞にインヒビター候補を作用させずに、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、（２）当該がん細胞に当該インヒビター候補を作用させた後に、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、及び（３）（２）の結果が、（１）の結果よりも小さい場合に、当該インヒビター候補を、ＮＦＫＢＩＺインヒビターであると判定する工程を含み得る。一実施形態では、方法は、ＮＦＫＢＩＺの発現量を減少させる物質、及び／又はＮＦＫＢＩＺの機能を抑制する物質をスクリーニングする方法として特徴付けられ、（１）がん細胞に被験物質を作用させずに、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、（２）当該がん細胞に当該被験物質を作用させた後に、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、（３）（２）の結果が、（１）の結果よりも小さい場合に、当該被験物質を、ＮＦＫＢＩＺの発現量を減少させる物質、及び／又はＮＦＫＢＩＺの機能を抑制する物質であると判定する工程を含み得る。 In one embodiment, the method is characterized as a method of screening for NFKBIZ inhibitors, (1) measuring gene expression and / or activity of NFKBIZ without allowing the candidate inhibitor to act on cancer cells, (2). After the cancer cell is allowed to act on the inhibitor candidate, the step of measuring the gene expression and / or activity of NFKBIZ, and when the results of (3) and (2) are smaller than the result of (1). The inhibitor candidate may include a step of determining that it is an NFKBIZ inhibitor. In one embodiment, the method is characterized as a method of screening for substances that reduce the expression level of NFKBIZ and / or suppress the function of NFKBIZ, (1) without allowing the test substance to act on the cancer cells. , The step of measuring the gene expression and / or activity of NFKBIZ, (2) the step of measuring the gene expression and / or activity of NFKBIZ after allowing the test substance to act on the cancer cells, (3) (2) When the result of (1) is smaller than the result of (1), the test substance may include a step of determining that the test substance is a substance that reduces the expression level of NFKBIZ and / or a substance that suppresses the function of NFKBIZ.
　一実施形態では、方法は、レグネース１エンハンサーをスクリーニングする方法として特徴付けられ、（１）がん細胞にエンハンサー候補を作用させずに、レグネース１の発現及び／又は活性を測定する工程、（２）当該がん細胞に当該エンハンサー候補を作用させた後に、レグネース１の発現及び／又は活性を測定する工程、（３）（２）の結果が、（１）の結果よりも大きい場合に、当該エンハンサー候補を、レグネース１エンハンサーであると判定する工程を含み得る。一実施形態では、方法は、レグネース１の活性を増強する物質をスクリーニングする方法として特徴付けられ、（１）がん細胞に被験物質を作用させずに、レグネース１の活性を測定する工程、（２）当該がん細胞に当該被験物質を作用させた後に、レグネース１の活性を測定する工程、（３）（２）の結果が、（１）の結果よりも大きい場合に、当該被験物質を、レグネース１の活性を増強する物質であると判定する工程を含み得る。 In one embodiment, the method is characterized as a method of screening a legnes 1 enhancer, (1) measuring the expression and / or activity of legnes 1 without allowing the enhancer candidate to act on the cancer cells, (2). ) The step of measuring the expression and / or activity of Legnes 1 after allowing the enhancer candidate to act on the cancer cells, when the results of (3) and (2) are larger than the results of (1). The enhancer candidate may include a step of determining that it is a Legnes 1 enhancer. In one embodiment, the method is characterized as a method of screening for a substance that enhances the activity of Legnes 1, (1) measuring the activity of Legnes 1 without allowing the test substance to act on the cancer cells, (1). 2) The step of measuring the activity of Legnes 1 after allowing the test substance to act on the cancer cells. When the results of (3) and (2) are larger than the results of (1), the test substance is used. , The step of determining that the substance enhances the activity of Legnes 1 may be included.
　以下に実施例を挙げて本開示を詳細に説明するが、本開示は何らこれらに限定されるものではない。 The present disclosure will be described in detail with reference to examples below, but the present disclosure is not limited thereto.
実施例１Example 1
　潰瘍性大腸炎（ＵＣ）で認められるドライバー変異の検出Detection of driver mutations found in ulcerative colitis (UC)
（１）検体の採取
　潰瘍性大腸炎でない被験者（非ＵＣ被験者）からの検体は、内視鏡的を用いて外科的に大腸粘膜から採取した。検体はメチレンブルー染色後に実体顕微鏡下で評価し、異常陰窩巣などの形成異常の陰窩の病変を含む検体を除外した。
　潰瘍性大腸炎である被験者（ＵＣ被験者）から得た全ての検体は、半分を全エキソームシークエンス（Ｗｈｏｌｅ　Ｅｘｏｍｅ　Ｓｅｑｕｅｎｃｉｎｇ（ＷＥＳ））解析のためのサンプリングに用い、残りの半分を病理的な評価のために用いた。一部の検体に関しては、全体をWES解析のためのサンプリングのために用い、病理評価は別の近接する粘膜の検体を用いて行った。病理評価はＲｉｄｄｅｌｌの分類（Ｒｉｄｄｅｌｌ，Ｒ．Ｈ．ｅｔ　ａｌ．Ｈｕｍａｎ　Ｐａｔｈｏｌｏｇｙ　１４：９３１（１９８３））に基づき２人の病理医によって行い、検体を「正常（ｎｏｎ－ｄｙｓｐｌａｓｉａ）」、「低度異形成」、「高度異形成」及び「がん」である４つのグループに分類した。内視鏡生検で入手した検体は、単一の陰窩サンプルならびにバルクの陰窩サンプルを得るために、およそ４ｍｍ２の大きさに切断した。手術検体からは、直径２．５ｍｍ（４．９ｍｍ２）のパンチ生検（ＢＰ－２５Ｆ、カイインダストリーズ）を用いてサンプルを採取した。これらのサンプルは、氷冷した２０ｍＭ　ＥＤＴＡ（エチレンジアミン四酢酸）を含有するＰＢＳ（リン酸緩衝生理食塩水）中で２０分間インキュベートすることにより上皮を粘膜下層から分離させたのち、上皮をピンセットで機械的に単離し、そこから単一陰窩もしくはバルクの陰窩を採取した。位置を記録した陰窩の集団を得るために、最初に上皮表面にアクリル接着剤を塗布することで粘膜における陰窩の構造を固定した。２０ｍＭ　ＥＤＴＡで処理したのち、接着剤の下にある陰窩の集団をひとまとめに粘膜下層からはがし取るか、粘膜下層から押し出した。最後に、それぞれの陰窩を、場所の記録と計数をおこないながら単離した。がん組織の解析に関しては、がん細胞をホルマリン固定パラフィン包埋（ＦＦＰＥ）検体から実体顕微鏡下で単離し、そこからＤＮＡを抽出した。 (1) Collection of Specimens Specimens from subjects without ulcerative colitis (non-UC subjects) were surgically collected from the large intestine mucosa using an endoscope. Specimens were evaluated under a stereomicroscope after staining with methylene blue, and specimens containing dysplasia crypt lesions such as abnormal crypt foci were excluded.
For all specimens obtained from subjects with ulcerative colitis (UC subjects), half were used for sampling for whole exome sequencing (WES) analysis and the other half were used for pathological evaluation. Used for For some specimens, the whole was used for sampling for WES analysis and pathological assessment was performed using another specimen of adjacent mucosa. Pathological evaluation was performed by two pathologists based on Riddell's classification (Riddell, RH et al. Human Pathology 14: 931 (1983)), and the samples were "normal (non-dysplasia)" and "low degree dysplasia". It was divided into four groups: "formation", "severe dysplasia" and "cancer". Specimens obtained by endoscopic biopsy were cut to a size of approximately 4 mm 2 to obtain a single crypt sample as well as a bulk crypt sample. Samples were taken from the surgical specimens using a punch biopsy (BP-25F, Kai Industries) with a diameter of 2.5 mm (4.9 mm 2 ). These samples were separated from the submucosa by incubation in PBS (phosphate buffered saline) containing ice-cooled 20 mM EDTA (ethylenediaminetetraacetic acid) for 20 minutes, and then the epithelium was machined with tweezers. Isolation was performed, and a single crypt or a bulk crypt was collected from the crypt. To obtain a well-positioned crypt population, the crypt structure in the mucosa was first fixed by applying an acrylic adhesive to the epithelial surface. After treatment with 20 mM EDTA, the population of crypts underneath the adhesive was either stripped from the submucosa or extruded from the submucosa. Finally, each crypt was isolated with location recording and counting. For analysis of cancer tissue, cancer cells were isolated from formalin-fixed paraffin-embedded (FFPE) specimens under a stereomicroscope and DNA was extracted from them.
（２）全エキソームシークエンス（Ｗｈｏｌｅ　Ｅｘｏｍｅ　Ｓｅｑｕｅｎｃｉｎｇ，　ＷＥＳ）
　上記（１）で単離した単一陰窩から抽出したゲノムＤＮＡを２つの溶液に分け、それぞれ独立してＲＥＰＬＩ－ｇ　Ｓｉｎｇｌｅ　Ｃｅｌｌ　Ｋｉｔ（Ｑｉａｇｅｎ）を用いて、全ゲノム増幅（ＷＧＡ）を行った。増幅したＤＮＡは、ＷＥＳ、又はその後の検証に用いた。その他の検体は、ゲノムＤＮＡとＲＮＡをＡｌｌ　Ｐｒｅｐ　ＤＮＡ／ＲＮＡ　Ｍｉｃｒｏ　Ｋｉｔ（Ｑｉａｇｅｎ）を用いて同時に抽出した。末梢血あるいはＦＦＰＥがん検体から顕微解剖により単離した正常固有筋層からは、Ｇｅｎｔｒａ　Ｐｕｒｅｇｅｎｅ　Ｋｉｔ（Ｑｉａｇｅｎ）を用いてＤＮＡを抽出し、生殖系列コントロールとして用いた。
　ＷＥＳライブラリはＳｕｒｅＳｅｌｅｃｔ　Ｈｕｍａｎ　Ａｌｌ　Ｅｘｏｎ　Ｖ５　（Ａｇｉｌｅｎｔ　Ｔｅｃｈｎｏｌｏｇｉｅｓ）もしくはｘＧｅｎ　Ｅｘｏｍｅ　Ｒｅｓｅａｒｃｈ　Ｐａｎｅｌ（ＩＤＴ）を用いて調製し、濃縮したエキソン断片はＨｉＳｅｑ　２５００あるいはＮｏｖａＳｅｑ　６０００（Ｉｌｌｕｍｉｎａ）上で１００－１５０ｂｐペアエンドモードで、既報と同様にシークエンスした（Ｙｏｓｈｉｄａ，Ｋ．ｅｔ　ａｌ．Ｎａｔｕｒｅ　４７８：６４（２０１１））。目標シークエンス深度は１００ｘであり、実際の深度は１３３ｘであった。１０１人の個人からの生殖系列コントロールの平均深度は１４０ｘであった。変異検出はＧｅｎｏｍｏｎ２パイプラインバージョン２．６（ｈｔｔｐｓ：／／ｇｅｎｏｍｏｎ．ｒｅａｄｔｈｅｄｏｃｓ．ｉｏ／ｊａ／ｌａｔｅｓｔ／）を用いて、既報と同様に行った（Ｙｏｋｏｙａｍａ，Ａ．ｅｔ　ａｌ．Ｎａｔｕｒｅ　５６５：３１２　（２０１９））。
　要約すると、シークエンスリードはヒトゲノム参照配列（ｈｇ１９）に対してＢｕｒｒｏｗｓ－Ｗｈｅｅｌｅｒ　Ａｌｉｇｎｅｒバージョン０．７．８を用いてデフォルトのパラメータ設定でアライメントした。ＰＣＲデュプリケートはｂｉｏｂａｍｂａｍバージョン０．０．１９１（ｈｔｔｐｓ：／／ｇｉｔｈｕｂ．ｃｏｍ／ｇｔ１／ｂｉｏｂａｍｂａｍ）を用いて除外した。体細胞変異は、多型およびシークエンスエラーを除外することにより検出した。このために、Ｇｅｎｏｍｏｎ２を用いて、まずクオリティの低い、信頼できないリードならびにバリアントを、（ｉ）マッピングクオリティ＜２０、（ｉｉ）塩基クオリティ＜１５のしきい値を用いて除外した。十分な数のリード（総リード数≧８、バリアントリード≧３）及びバリアントアレル頻度（ＶＡＦ）≧０．０５（新鮮あるいはＦＦＰＥ検体）、≧０．２５（単一陰窩ＷＧＡ検体）、＜０．０２（生殖系列対照検体）でサポートされ、ストランド比≠０もしくは１であるバリアントに限定したあと、それらのバリアントがエラーと想定されるＶＡＦより有意に高いＶＡＦで観察されているかを調べた（新鮮検体、ＦＦＰＥ検体、ＷＧＡ検体についてそれぞれＰ　≦　１０－４、１０－３．５、１０－４）。ここで、その有意性は、ＥＢＣａｌｌアルゴリズム（Ｓｈｉｒａｉｓｈｉ，Ｙ．ｅｔ　ａｌ．Ｎｕｃｌｅｉｃ　ａｃｉｄｓ　ｒｅｓｅａｒｃｈ　４１：ｅ８９（２０１３））によって、末梢血検体（ｎ＝２０）のＷＥＳデータを用いて決定された経験的なＶＡＦ分布に基づいて評価した。生殖系列バリアントに関しては、ＶＡＦを、同一症例の対照検体におけるＶＡＦとフィッシャー検定により比較することで除外した（新鮮検体、ＦＦＰＥ検体、ＷＧＡ検体についてそれぞれＰ　≦　１０－１、１０－１、１０－２）。この処理により残存している他のシークエンスエラーも除外した。 (2) Whole Exome Sequencing (WES)
The genomic DNA extracted from the single crypt isolated in (1) above was divided into two solutions, and whole genome amplification (WGA) was performed independently using REPLI-g Single Cell Kit (Qiagen). .. The amplified DNA was used for WES or subsequent validation. For other samples, genomic DNA and RNA were simultaneously extracted using All Prep DNA / RNA MicroKit (Qiagen). DNA was extracted from the normal muscularis layer isolated from peripheral blood or FFPE cancer specimens by microdissection using the Gentra Puregene Kit (Qiagen) and used as a germline control.
The WES library was prepared using SureSelect Human All Exon V5 (Agilent Technologies) or xGen Exome Research Panel (IDT), and the concentrated exon fragments were prepared using HiSeq 2500 or NovaSeq 6000 (Illumina) in HiSeq 2500 or NovaSeq 6000 (Illumina). It was sequenced in the same manner (Yoshida, K. et al. Nature 478: 64 (2011)). The target sequence depth was 100x and the actual depth was 133x. The average depth of germline control from 101 individuals was 140x. Mutation detection was performed in the same manner as previously reported using Genomen2 pipeline version 2.6 (https://genomon.readedocs.io/ja/latest/) (Yokoyama, A. et al. Nature 565: 312 (2019). )).
In summary, sequence reads were aligned with the human genome reference sequence (hg19) using Burrows-Wheeler Aligner version 0.7.8 with default parameter settings. PCR duplication was excluded using biobambam version 0.0.191 (https://github.com/gt1/biobambam). Somatic mutations were detected by excluding polymorphisms and sequence errors. To this end, Genomon2 was used to first exclude low quality, unreliable reads and variants using thresholds of (i) mapping quality <20, (ii) base quality <15. Sufficient number of reads (total number of reads ≥ 8, variant reads ≥ 3) and variant allergen frequency (VAF) ≥ 0.05 (fresh or FFPE sample), ≥ 0.25 (single crypt WGA sample), <0 After limiting to variants supported by .02 (germline control specimens) with a strand ratio of ≠ 0 or 1, it was investigated whether those variants were observed with a VAF significantly higher than the assumed error VAF (. For fresh samples, FFPE samples, and WGA samples, P ≤ 10 -4 , 10-3.5 , 10 -4 ), respectively. Here, its significance was determined empirically by the EBCall algorithm (Shiraishi, Y. et al. Nucleic acids research 41: e89 (2013)) using WES data of a peripheral blood sample (n = 20). Evaluation was made based on the VAF distribution. For germline variants, VAF was excluded by comparing VAF and Fisher's exact test in control specimens of the same case (P ≤ 10 -1 , 10 -1 , 10 -2 for fresh, FFPE, and WGA specimens, respectively). ). Other sequence errors remaining by this process were also excluded.
（３）有意な変異を伴う（ドライバー）遺伝子の解析
　有意な変異を伴う遺伝子（ドライバー遺伝子）を、ｄＮ／ｄＳ法を用いて調べた。ｄＮ／ｄＳは、全ての反復性に変異を認める遺伝子に関して、ｄＮｄＳｃｖソフトウェア（ｈｔｔｐｓ：／／ｇｉｔｈｕｂ．ｃｏｍ／ｉｍ３ｓａｎｇｅｒ／ｄｎｄｓｃｖ）を用いて計算した。外科的に切除した大腸検体に関しては、サンプルを１ｃｍ格子に沿って取得したため、同じクローン由来の変異が複数のサンプルで検出されうる。そのような同じクローンに属する変異の複数回の観察は、解析前に補正する必要があった。そのために、まずサンプルを、「ＶＡＦ≧０．２５」である４個以上の変異を共有するサンプルから成るサンプルセットにクラスター化し、それ以外のサンプルは独立したサンプルとして扱った。その後、症例において検出されたそれぞれの変異について、サンプルセットに含まれるのか、独立サンプルに含まれるのかを、最も高いＶＡＦを有するサンプルによって決定した。潰瘍性大腸炎患者（ＵＣ患者）の正常粘膜（１５２のサンプルを含む３６サンプルセットと２４３の独立サンプル）ならびに非高変異（ｎｏｎｈｙｐｅｒｍｕｔａｔｅｄ）腸炎関連性大腸がん（ｃｏｌｉｔｉｓ－ａｓｓｏｃｉａｔｅｄ　ｃａｎｃｅｒ（ＣＡＣ）、本研究と外部データを合わせて８９サンプル）から得られた変異に対して、ｄＮｄＳｃｖを独立に適用し、有意な変異を認め（ｑ＜０．０５）、かつ、４％以上の正常粘膜あるいはＣＡＣサンプルで変異が認められる１４と９の遺伝子を、それぞれＵＣとＣＡＣのドライバーとみなした。潰瘍性大腸炎に係る正常粘膜（ＵＣ正常粘膜）においては、ＩＬ－１７シグナル経路に属し、タンパク質短縮型の変異を有する遺伝子もドライバーとみなした。合計で２０遺伝子をＵＣ正常粘膜におけるドライバーとみなした。 (3) Analysis of (driver) gene with significant mutation A gene (driver gene) with significant mutation was examined using the dN / dS method. dN / dS was calculated using dNdScv software (https://github.com/im3sanger/dndscv) for genes with mutations in all repeats. For surgically resected colon specimens, since the samples were obtained along a 1 cm grid, mutations from the same clone could be detected in multiple samples. Multiple observations of such mutations belonging to the same clone had to be corrected prior to analysis. To that end, the samples were first clustered into a sample set consisting of samples sharing 4 or more mutations with "VAF ≥ 0.25", and the other samples were treated as independent samples. Then, for each mutation detected in the case, whether it was included in the sample set or in the independent sample was determined by the sample with the highest VAF. Normal mucosa of patients with ulcerative colitis (UC patients) (36 sample sets including 152 samples and 243 independent samples) and nonhypermutated enterocolitis-related colon cancer (CAC), book DNdScv was independently applied to the mutations obtained from 89 samples (89 samples combined from the study and external data), and significant mutations were observed (q <0.05), and 4% or more of normal mucosa or CAC samples. The 14 and 9 genes that were mutated in were considered drivers of UC and CAC, respectively. In the normal mucosa (UC normal mucosa) associated with ulcerative colitis, a gene belonging to the IL-17 signal pathway and having a protein-shortened mutation was also regarded as a driver. A total of 20 genes were considered drivers in UC normal mucosa.
（４）細胞株を用いた実験
　ＨｅＬａ細胞株は１０％　ＦＢＳ（ウシ胎児血清）及び１００μＭ　２－メルカプトエタノール（２１４１８－４２、ナカライテスク）を添加したＤＭＥＭ培地（０８４５９－６４、ナカライテスク）を用いて維持した。ＨＴ２９ならびにＨＣＴ１１６細胞株は１０％　ＦＢＳを添加したＤＭＥＭ培地を用いて維持した。レグネース１をコードするヒトＺＣ３Ｈ１２Ａ遺伝子の全長野生型あるいはＣ末端短縮型変異（Ｗ４５３＊）を有するｃＤＮＡを、ｐｃＤＮＡ３．１（＋）（Ｖ７９０２０、ＴｈｅｒｍｏＦｉｓｈｅｒ）に、Ｎ末端Ｍｙｃタグ配列とともに挿入した。Ｓ４３８Ｌ変異Ｒｅｇｎａｓｅ－１はＱｕｉｋＣｈａｎｇｅ　Ｌｉｇｈｔｎｉｎｇ　Ｓｉｔｅ－Ｄｉｒｅｃｔｅｄ　Ｍｕｔａｇｅｎｅｓｉｓ　Ｋｉｔ　（２１０５１９，　Ａｇｉｌｅｎｔ）を用いて作成した。プラスミドＤＮＡは、ＨｅＬａ細胞にリポフェクタミン２０００（Ｌｉｐｏｆｅｃｔａｍｉｎｅ　２０００；１１６６８５００、Ｔｈｅｒｍｏ　Ｆｉｓｈｅｒ）を用いてメーカーのプロトコールに従って導入した。ＨｅＬａ細胞は組換えヒトＩＬ－１７Ａ（５７０５０２、Ｂｉｏｌｅｇｅｎｄ）を用いて刺激した。細胞は溶解バッファー（２０ｍＭ　Ｔｒｉｓ－ＨＣｌ（ｐＨ＝７．４）、１５０ｍＭ　ＮａＣｌ、０．５％　ＮＰ－４０、ｃＯｍｐｌｅｔｅ　Ｍｉｎｉ（ＥＤＴＡ－ｆｒｅｅ、１１８３６１７０００１、Ｒｏｃｈｅ）、２００　ｕｎｉｔｓ／ｍｌ　ＲＮａｓｅＯＵＴ（１０７７７０１９、ＴｈｅｒｍｏＦｉｓｈｅｒ））を用いて溶解した。溶解サンプルは７．５％　ＰＡＧＥゲル（Ｅ－Ｔ７．５Ｌ、ＡＴＴＯ）で分離し、Ｉｍｍｕｎ－Ｂｌｏｔ　ＰＶＤＦ　ｍｅｍｂｒａｎｅｓ　（１６２０１７７、Ｂｉｏ－Ｒａｄ）に転写した。
　免疫ブロット解析には以下の抗体を用いた：
ｍｏｎｏｃｌｏｎａｌ　ａｎｔｉ－ｃ－Ｍｙｃ（Ｍ４４３９，　Ｓｉｇｍａ－Ａｌｄｒｉｃｈ）、
ｍｏｎｏｃｌｏｎａｌ　ａｎｔｉ－ｂｅｔａ－Ａｃｔｉｎ（ｓｃ－４７７７８，　Ｓａｎｔａ　Ｃｒｕｚ）、
ａｎｔｉ－ｍｏｕｓｅ　ＩｇＧ　ＨＲＰ（ＮＡ９３１０－１ＭＬ，ＧＥ　Ｈｅａｌｔｈｃａｒｅ）。
　バンド強度はＡｍｅｒｓｈａｍ　Ｉｍａｇｅｒ　６００　Ａｎａｌｙｓｉｓ　Ｓｏｆｔｗａｒｅ（ＧＥ　Ｈｅａｌｔｈｃａｒｅ）を用いて分析した。 (4) Experiment using cell line HeLa cell line uses DMEM medium (08459-64, Nacalai Tesque) supplemented with 10% FBS (fetal bovine serum) and 100 μM 2-mercaptoethanol (21418-42, Nacalai Tesque). And maintained. The HT29 and HCT116 cell lines were maintained in DMEM medium supplemented with 10% FBS. A cDNA having a full-length wild-type or C-terminal shortened mutation (W453 *) of the human ZC3H12A gene encoding Legnes 1 was inserted into cDNA 3.1 (+) (V79020, Thermo Fisher) together with an N-terminal Myc tag sequence. The S438L mutant Regnase-1 was created using the QuikChange Lightning Site-Directed Mutagenesis Kit (210319, Agilent). The plasmid DNA was introduced into HeLa cells using Lipofectamine 2000 (116668500, Thermo Fisher) according to the manufacturer's protocol. HeLa cells were stimulated with recombinant human IL-17A (570502, BioLegend). The cells are lysis buffer (20 mM Tris-HCl (pH = 7.4), 150 mM NaCl, 0.5% NP-40, singlete Mini (EDTA-free, 118363170001, Roche), 200 units / ml RNaseOUT (10777019, Thermo Fisher). ) Was used to dissolve. Dissolved samples were separated on a 7.5% PAGE gel (ET7.5L, ATTO) and transferred to Immun-Blot PVDF membranes (162177, Bio-Rad).
The following antibodies were used for immunoblot analysis:
Monoclonal anti-c-Myc (M4439, Sigma-Aldrich),
Monoclonal anti-beta-Actin (sc-47778, Santa Cruz),
anti-mouse IgG HRP (NA9310-1ML, GE Healthcare).
Band intensities were analyzed using Amersham Imager 600 Analysis Software (GE Healthcare).
（５）結果
　採取した大腸粘膜から上皮を分離後、個々の陰窩について、直接全ゲノム増幅（ＷＧＡ）を行ったＤＮＡ試料を用いて全エキソームシーケンス（ＷＥＳ）を実施し、体細胞変異を検出した。潰瘍性大腸炎でない被験者（非ＵＣ被験者）の健常な小腸および大腸粘膜に関してＷＥＳ解析を行い、年齢（０歳～８６歳）と良好に相関した１５８８個の体細胞変異を同定した（図１）。炎症が大腸上皮に与える影響を調べるため、潰瘍性大腸炎患者（ＵＣ患者）から採取した正常粘膜から小腸および大腸の陰窩を単離して解析したところ、ＵＣ患者の正常粘膜においては１陰窩あたりの体細胞変異数は非ＵＣ被験者の正常粘膜と比べ３倍以上に増加し、有意に多かった（図１）。
　ＵＣ患者の正常粘膜で検出された遺伝子変異を解析したところ、ＮＦＫＢＩＺ、ＰＩＧＲ、ＺＣ３Ｈ１２Ａ、ＴＲＡＦ３ＩＰ２、ＨＮＲＮＰＦ、ＡＲＩＤ１Ａ、ＡＲＩＤ１Ｂ、ＫＲＡＳ、ＴＰ５３、ＲＮＦ４３、ＥＴＶ６、ＦＢＸＷ７、ＢＣＯＲ及びＢＣＯＲＬ１の１４遺伝子に対する変異が有意に正の選択を受けており、ドライバー変異と考えられた（「ｄＮ／ｄＳ＞１．０」かつ「ｑ＜０．０５」）。これらのうち、ほとんどの遺伝子に対する変異は、蛋白質の短縮を起こすことから、機能喪失型変異と考えられた。例外は、ＺＣ３Ｈ１２Ａ、ＨＮＲＮＰＦならびにＫＲＡＳ遺伝子であり、これらの遺伝子はミスセンス変異が一部のアミノ酸に集中するホットスポットを形成していたことから、機能獲得型変異と考えられた（図２）。
　これらのドライバー変異の共存排他関係を評価したところ、ＮＦＫＢＩＺ、ＰＩＧＲ、ＺＣ３Ｈ１２Ａ及びＴＲＡＦ３ＩＰ２遺伝子は相互に排他的であった（図３）。ＴＲＡＦ３ＩＰ２はＩＬ－１７シグナル経路のアダプター蛋白質として機能することが知られていたため、ＩＬ－１７シグナル経路に着目して解析したところ、ＩＬ１７ＲＡ、ＩＬ１７ＲＣ、ＴＲＡＦ５、ＲＥＬＡ、ＭＡＰＫ１４及びＢＴＲＣ遺伝子においても蛋白質短縮型変異が見つかり、先の解析で見つかっていたドライバー変異と合わせるとＮＦＫＢＩＺ、ＰＩＧＲ、ＺＣ３Ｈ１２Ａ、ＴＲＡＦ３ＩＰ２、ＩＬ１７ＲＡ、ＩＬ１７ＲＣ、ＴＲＡＦ５、ＲＥＬＡ及びＭＡＰＫ１４の９遺伝子がＩＬ－１７シグナル経路に属していた（図４）。
　以上の解析結果から、ＵＣ粘膜では、ＩＬ－１７シグナル経路に属する遺伝子への頻繁な変異が認められ、いずれの変異もＩＬ－１７シグナル経路の活性化を抑制する方向の変異であることが判明した。
　解析で同定されたＺＣ３Ｈ１２Ａ（レグネース１）のホットスポット変異がレグネース１タンパク質に与える影響を実験的に検討した。ＺＣ３Ｈ１２Ａのミスセンス変異のホットスポットはＩＫＫ複合体によって認識されリン酸化されるＤＳＧｘｘＳ配列部に集中しており、中でもリン酸化される４３８番のセリン残基のミスセンス変異が最も多く観察された（図２）。ＤＳＧｘｘＳ配列部は炎症性の刺激によりリン酸化されたのち、ユビキチン化酵素であるβ－ＴｒＣＰによって認識され、続いてポリユビキチン化を経てレグネース１の分解が促進されると報告されている（非特許文献８）。従って、ＵＣ粘膜におけるレグネース１の変異は、レグネース１の安定性を増すことでレグネース１蛋白質の発現量を上げると考えられる。レグネース１はＩＬ－１７シグナル経路を含む炎症性のシグナルを負に制御するため、レグネース１の変異も他の変異と同様にＩＬ－１７シグナル経路の活性化を抑制することが示唆された。 (5) Results After separating the epithelium from the collected large intestine mucosa, whole exome sequencing (WES) was performed on each crypt using a DNA sample that had been directly subjected to whole genome amplification (WGA), and somatic mutation was performed. Detected. WES analysis was performed on healthy small intestine and large intestine mucosa of subjects without ulcerative colitis (non-UC subjects), and 1588 somatic mutations that were well correlated with age (0 to 86 years) were identified (Fig. 1). .. In order to investigate the effect of inflammation on the large intestine epithelium, the crypts of the small and large intestines were isolated and analyzed from the normal mucosa collected from patients with ulcerative colitis (UC patients). The number of somatic cell mutations per unit increased more than 3 times compared to the normal mucosa of non-UC subjects, which was significantly higher (Fig. 1).
Analysis of gene mutations detected in the normal mucosa of UC patients revealed significant mutations in 14 genes of NFKBIZ, PIGR, ZC3H12A, TRAF3IP2, HNRNPF, ARID1A, ARID1B, KRAS, TP53, RNF43, ETV6, FBXW7, BCOR and BCORL1. Was positively selected and was considered to be a driver mutation ("dN / dS>1.0" and "q <0.05"). Of these, mutations for most genes were considered to be loss-of-function mutations because they caused protein shortening. The exceptions were the ZC3H12A, HNRNPF and KRAS genes, which were considered function-acquired mutations because they formed hotspots where missense mutations were concentrated in some amino acids (Fig. 2).
When the coexistence and exclusion relationships of these driver mutations were evaluated, the NFKBIZ, PIGR, ZC3H12A and TRAF3IP2 genes were mutually exclusive (Fig. 3). Since TRAF3IP2 was known to function as an adapter protein for the IL-17 signal pathway, analysis focusing on the IL-17 signal pathway revealed that the IL17RA, IL17RC, TRAF5, RELA, MAPK14 and BTRC genes were also shortened proteins. Mutations were found, and when combined with the driver mutations found in the previous analysis, nine genes, NFKBIZ, PIGR, ZC3H12A, TRAF3IP2, IL17RA, IL17RC, TRAF5, RELA and MAPK14, belonged to the IL-17 signaling pathway (Fig. 4). ..
From the above analysis results, frequent mutations to genes belonging to the IL-17 signal pathway were observed in the UC mucosa, and it was found that all mutations are mutations in the direction of suppressing activation of the IL-17 signal pathway. did.
The effect of the hotspot mutation of ZC3H12A (Legnes 1) identified in the analysis on the Legnes 1 protein was experimentally investigated. The hot spots for missense mutations in ZC3H12A are concentrated in the DSGxxS sequence, which is recognized and phosphorylated by the IKK complex, with the most missense mutations in the phosphorylated serine residue at position 438 being observed (Fig. 2). ). It has been reported that the DSGxxS sequence is phosphorylated by an inflammatory stimulus, then recognized by the ubiquitinizing enzyme β-TrCP, and subsequently undergoes polyubiquitination to promote the degradation of Legnes 1 (non-patent). Document 8). Therefore, it is considered that the mutation of Legnes 1 in the UC mucosa increases the expression level of Legnes 1 protein by increasing the stability of Legnes 1. Since legnes 1 negatively regulates inflammatory signals, including the IL-17 signaling pathway, it was suggested that mutations in legnes 1 suppress the activation of the IL-17 signaling pathway as well as other mutations.
実施例２
　ＵＣとがんのドライバー変異の比較 Example 2
Comparison of UC and cancer driver mutations
（１）外部データセット
　孤発性大腸がん（ｓｐｏｒａｄｉｃ　ｃｏｌｏｒｅｃｔａｌ　ｃａｎｃｅｒ（ｓＣＲＣ））患者由来の腫瘍、及び生殖系列検体のペアのＷＥＳデータ（ｂａｍファイル）は、Ｔｈｅ　Ｃａｎｃｅｒ　Ｇｅｎｏｍｅ　Ａｔｌａｓ（ＴＣＧＡ）　Ｄａｔａ　Ｐｏｒｔａｌ（ｈｔｔｐｓ：／／ｐｏｒｔａｌ．ｇｄｃ．ｃａｎｃｅｒ．ｇｏｖ／）からダウンロードした。ｂａｍファイルはｂｉｏｂａｍｂａｍを用いてｆａｓｔｑ形式に変換し、同じパイプラインを用いて本研究で取得した新鮮検体に適用した方法で変異検出をおこなった。正確性のために、腫瘍からＷＧＡを用いて得られた配列データは除外した。高変異性（ｈｙｐｅｒ－ｍｕｔａｔｅｄ）腫瘍（≧１２変異／１０６塩基）も解析から除外した。
（２）結果
　ＵＣに関しては、罹患７年を超える頃から発がん率が上昇し、腸炎関連性大腸がん（Ｃｏｌｉｔｉｓ－ａｓｓｏｃｉａｔｅｄ　ｃａｎｃｅｒ（ＣＡＣ））に移行することが知られている。ＵＣ患者で認められた正常粘膜の遺伝子変異をＣＡＣで認められる遺伝子変異と比較するため、ＣＡＣのＷＥＳ解析を行った。ＣＡＣで高度に変異する遺伝子として、ＴＰ５３、ＫＲＡＳ、ＲＮＦ４３、ＡＰＣ、ＳＭＡＤ４が検出されたが、ＩＬ－１７シグナル経路の遺伝子変異はＰＩＧＲを除いてほとんど観察されなかった（図５）。驚くべきことに、ＵＣ正常粘膜で最も頻繁に観察されるＮＦＫＢＩＺ変異はＣＡＣでは９６例中１例も観察されなかった（図５、図２）。ＴＣＧＡに格納されている高変異性（ｈｙｐｅｒ－ｍｕｔａｔｅｄ）タイプを除く孤発性大腸がん（ｓｐｏｒａｄｉｃ　ＣＲＣ（ｓＣＲＣ））の３５６例とも比較したところ、ＮＦＫＢＩＺの変異は２例のみで、加えてこれらは全てミスセンス変異であり蛋白短縮型（機能欠損型）変異ではなかった。また、ＺＣ３Ｈ１２Ａに対する変異も、ＣＡＣおよびｓＣＲＣにおいてほとんど認められなかった（図５、図２）。
　この結果は、ＵＣ正常粘膜からＣＡＣへの進化の過程で、ＮＦＫＢＩＺの機能欠損変異は強い陰性選択を受けている可能性を示唆するものと考えられた。すなわち、ＮＦＫＢＩＺの機能の欠損を起こした大腸上皮細胞は、がん化することができない、もしくは、がん化しても増殖ができない、あるいはその両方を伴うと考えられた。このことは、ＮＦＫＢＩＺを抑制することで、がんの発生の抑制の効果、ならびに、発生したがんの増殖を抑制する効果があることを示唆した。 (1) External data set The WES data (bam file) of a pair of tumors derived from patients with sporadic colorectal cancer (sCRC) and germline specimens is the The Cancer Genome Atlas (TCGA) Data Portal ( It was downloaded from https: //portal.gdc.cancer.gov/). The bum file was converted to FASTQ format using biobambam, and mutation detection was performed using the same pipeline by the method applied to the fresh sample obtained in this study. For accuracy, sequence data obtained using WGA from tumors was excluded. Highly mutated tumors (≧ 12 mutations / 10 6 bases) were also excluded from the analysis.
(2) Results Regarding UC, it is known that the carcinogenic rate increases from about 7 years after illness and shifts to enteritis-associated cancer (CAC). A WES analysis of CAC was performed to compare the gene mutations in normal mucosa found in UC patients with those found in CAC. TP53, KRAS, RNF43, APC, and SMAD4 were detected as highly mutated genes in CAC, but gene mutations in the IL-17 signaling pathway were hardly observed except for PIGR (Fig. 5). Surprisingly, the most frequently observed NFKBIZ mutation in UC normal mucosa was not observed in CAC in 1 of 96 cases (FIGS. 5 and 2). When compared with 356 cases of sporadic colorectal cancer (spolar CRC (sCRC)) excluding the hyper-mutated type stored in TCGA, only 2 cases had mutations in NFKBIZ, and in addition, these Are all missense mutations, not protein shortening (function-deficient) mutations. In addition, mutations to ZC3H12A were hardly observed in CAC and sCRC (FIGS. 5 and 2).
This result was considered to suggest that the function-deficient mutation of NFKBIZ may have undergone a strong negative selection in the process of evolution from UC normal mucosa to CAC. That is, it was considered that the colonic epithelial cells in which the function of NFKBIZ was deficient could not become cancerous, and even if they became cancerous, they could not proliferate, or both. This suggests that suppressing NFKBIZ has an effect of suppressing the development of cancer and an effect of suppressing the growth of the developed cancer.
実施例３
　ＮＦＫＢＩＺのがんにおける役割の検証 Example 3
Verification of the role of NFKBIZ in cancer
（１）ＮＦＫＢＩＺノックダウンの大腸がん細胞株に対する影響の解析
　ＨＴ２９およびＨＣＴ１１６細胞株に対して、ＮＦＫＢＩＺを標的としたｓｈＲＮＡ（「ｓｈＮＦＫＢＩＺ　１」及び「ｓｈＮＦＫＢＩＺ　２」）あるいは非標的配列（ＳＨＣ００２、Ｓｉｇｍａ）を含むｐＬＫＯ．１－ＥＧＦＰレンチウイルスを感染させた。遺伝子ノックダウン効果の測定のためのＲＮＡは感染３日後に抽出した。ノックダウン効果はリアルタイムＰＣＲ法により評価した。感染２日後に、３０００個の細胞を９６ウェルプレートのそれぞれのウェルに播種し、細胞増殖を２４時間間隔でＣｅｌｌ　Ｃｏｕｎｔｉｎｇ　Ｋｉｔ－８（ＣＫ０４、同仁化学研究所）を用いてメーカーのプロトコールに従って測定した。ｓｈＲＮＡ配列を表１に、ＰＣＲプライマー配列を表２に示す。 (1) Analysis of the effect of NFKBIZ knockdown on colorectal cancer cell lines For HT29 and HCT116 cell lines, FGFZ-targeted shRNA ("SHNFKBIZ 1" and "shNFKBIZ 2") or non-target sequences (SHC002, Sigma) ) Including pLKO. Infected with 1-EGFP wrench virus. RNA for measuring the gene knockdown effect was extracted 3 days after infection. The knockdown effect was evaluated by the real-time PCR method. Two days after infection, 3000 cells were seeded in each well of a 96-well plate and cell proliferation was measured at 24-hour intervals using Cell Counting Kit-8 (CK04, Dojin Chemical Laboratory) according to the manufacturer's protocol. .. The shRNA sequences are shown in Table 1, and the PCR primer sequences are shown in Table 2.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
（２）ＮＦＫＢＩＺノックアウトの腸炎関連性大腸がんモデルに対する影響の解析
　以下の遺伝子改変したＣ５７ＢＬ／６マウスを用いた。ＶｉｌＣｒｅ　ｍｉｃｅ（００４５８６）およびＲ２６－ＬａｃＺマウス（００３３０９）はＴｈｅ　Ｊａｃｋｓｏｎ　Ｌａｂｏｒａｔｏｒｙから入手した。Ｎｆｋｂｉｚ　ｆｌｏｘマウス（Ｏｋｕｍａ，　Ａ．　ｅｔ　ａｌ．Ｉｍｍｕｎｉｔｙ　３８：４５０（２０１３）、ＲＢＲＣ０６４１０）は理研バイオリソース研究センターから入手した。ＶｉｌＣｒｅＥＲマウス（ｅｌ　Ｍａｒｊｏｕ，　Ｆ．　ｅｔ　ａｌ．　３９：１８６（２００４））はＳｙｌｖｉｅ　Ｒｏｂｉｎｅから譲渡された。Ｎｆｋｂｉｚｆｌ／ｆｌＶｉｌＣｒｅ（コンディショナルノックアウト、ｃＫＯ）およびＮｆｋｂｉｚｆｌ／ｆｌ（対照）の同腹仔は、８週齢において１２ｍｇ／ｇ体重のアゾキシメタン（ＡＯＭ）（Ａ５４８６、ＳＩＧＭＡ）を腹腔に注射し、その後、３サイクルの２％デキストラン硫酸ナトリウムを投与した（１サイクルは５日間のデキストラン硫酸ナトリウム（ＤＳＳ）と、それに続く１６日間の水の投与）。３サイクルのＤＳＳの完了後、マウスは屠殺し、大腸を長軸方向に切開したのち、大腸における腫瘍の大きさと数を測定した。生じた腫瘍はＨＥ染色ならびにβ－カテニンあるいはＫｉ－６７の免疫組織化学によって病理学的に評価した。各マウスに関して、体重、大腸の長さ、および腸炎の組織学的スコアを記録した。腸炎の組織学的スコアに関しては、ＨＥ染色スライドのランダムに選択した５つの高倍率視野において、既報に従い上皮の損傷と炎症細胞の浸潤を０から１２まででスコア化し（Ｇｏｔｏ，　Ｎ．　ｅｔ　ａｌ．　Ｃａｎｃｅｒ　Ｒｅｓ　７７：３４４２　（２０１７））、その平均を解析に用いた。 (2) Analysis of Effect of NFKBIZ Knockout on Enteritis-Related Colorectal Cancer Model The following genetically modified C57BL / 6 mice were used. VilCremice (004586) and R26-LacZ mice (003309) were obtained from The Jackson Laboratory. Nfkbiz flox mice (Okuma, A. et al. Immunity 38: 450 (2013), RBRC06410) were obtained from the RIKEN BioResource Research Center. VilCre ER mice (el Marjou, F. et al. 39: 186 (2004)) were assigned by Sylvie Robine. Littermates of Nfkbiz fl / fl VilCre (conditional knockout, cKO) and Nfkbiz fl / f (control) were injected intraperitoneally with 12 mg / g body of azoxymethane (AOM) (A5486, SIGMA) at 8 weeks of age. Three cycles of 2% sodium dextran sulfate were administered (one cycle was 5 days of sodium dextran sulfate (DSS) followed by 16 days of water administration). After completion of 3 cycles of DSS, the mice were sacrificed, the large intestine was incised in the longitudinal direction, and then the size and number of tumors in the large intestine were measured. Tumors developed were pathologically evaluated by HE staining and immunohistochemistry of β-catenin or Ki-67. For each mouse, body weight, colorectal length, and histological scores of enteritis were recorded. For histological scores of enteritis, epithelial damage and inflammatory cell infiltration were scored from 0 to 12 in five randomly selected high-power fields on the HE-stained slide (Goto, N. et al. Cancer Res 77: 3442 (2017)), the average of which was used in the analysis.
（３）結果
　ＮＦＫＢＩＺが発生したがんの増殖に与える影響を検証するために、ヒト大腸がん細胞株であるＨＴ２９とＨＣＴ１１６に、ＮＦＫＢＩＺを標的としたｓｈＲＮＡを発現するレンチウイルスを感染させ、ＮＦＫＢＩＺ遺伝子のノックダウンを試みた。その結果、対照となる非標的配列ｓｈＲＮＡと比較して、ＮＦＫＢＩＺのノックダウンによって強く細胞株の増殖が抑制された（図６）。この結果によって、ＮＦＫＢＩＺを抑制することで大腸がん細胞の増殖を抑制できることが実証された。
　さらに、ＮＦＫＢＩＺが腫瘍の発生に与える影響を検証するために、Ｎｆｋｂｉｚｆｌ／ｆｌ；ＶｉｌＣｒｅマウス（コンディショナルＫＯマウス（ｃＫＯマウス））と、対照となるＮｆｋｂｉｚｆｌ／ｆｌマウスを用いて、慢性ＤＳＳ腸炎負荷条件下でのＡＯＭ投与によって誘発される炎症性腫瘍モデル（図７）における腫瘍発生を調べた。その結果、対照マウスと比べて、ＮＦＫＢＩＺ　ｃＫＯマウスでは有意に腫瘍発生が抑制される結果となった（図８、図９）。この結果によって、ＮＦＫＢＩＺの機能を抑制することで大腸がんの腫瘍の発生を抑制できることが実証された。 (3) Results In order to verify the effect of NFKBIZ on the growth of the developed cancer, HT29 and HCT116, which are human colon cancer cell lines, are infected with NFKBIZ-targeted shRNA-expressing lentivirus, and NFKBIZ An attempt was made to knock down the gene. As a result, the proliferation of cell lines was strongly suppressed by knockdown of NFKBIZ as compared with the control non-target sequence shRNA (Fig. 6). From this result, it was demonstrated that the proliferation of colorectal cancer cells can be suppressed by suppressing NFKBIZ.
In addition, to examine the effect of NFKBIZ on tumor development, chronic DSS enteritis using Nfkbiz fl / fl ; VilCre mice (conditional KO mice (cKO mice)) and control Nfkbiz fl / fl mice. Tumor development in an inflammatory tumor model (Fig. 7) induced by AOM administration under stress conditions was investigated. As a result, the tumor development was significantly suppressed in the NFKBIZ cKO mouse as compared with the control mouse (FIGS. 8 and 9). From this result, it was demonstrated that the development of colorectal cancer tumor can be suppressed by suppressing the function of NFKBIZ.
実施例４
　Ｅ３リガーゼ阻害剤ＧＳ１４３によるＮＦＫＢＩＺ遺伝子発現抑制試験 Example 4
NFKBIZ gene expression suppression test with E3 ligase inhibitor GS143
（１）細胞培養および試薬添加
　１ｘ１０6　個のＨＴ２９細胞株を、１．８ｍＬ/ウェルの培地を分注した６ウェルプレートに播種した。３７℃で５％ＣＯ２存在の条件下にて２４時間培養したのち、各々のプレートについて、ＧＳ１４３のＤＭＳＯ溶液を終濃度が１μＭ、５μＭ、１０μＭ、又は２０μＭとなるように添加した（終容積２．０ｍＬ）。コントロールとしてＧＳ１４３を含まないＤＭＳＯ溶液を同様に培地で希釈し添加した。さらに２４時間後培養した。 (1) Cell culture and addition of reagents 1x10 6 HT29 cell lines were seeded on a 6-well plate dispensed with 1.8 mL / well medium. After culturing at 37 ° C. in the presence of 5% CO 2 for 24 hours, a DMSO solution of GS143 was added to each plate so that the final concentration was 1 μM, 5 μM, 10 μM, or 20 μM (final volume 2). .0 mL). As a control, a DMSO solution containing no GS143 was similarly diluted with medium and added. After another 24 hours, the cells were cultured.
（２）細胞培養および試薬添加
　上述の細胞から核酸抽出装置であるＭａｘｗｅｌｌ（プロメガ社製）および　Ｍａｘｗｅｌｌ（Ｒ）　１６　ＬＥＶ　ｓｉｍｐｌｙＲＮＡ　Ｐｕｒｉｆｉｃａｔｉｏｎ　Ｋｉｔｓ（プロメガ社製）を用い、添付のプロトコルに従ってＲＮＡを調製した。即ち、ＧＳ１４３添加後、２４時間培養した細胞をＰＢＳ（ＧＩＢＣＯ社製）で１回洗浄後、トリプシンーＥＤＴＡを０．５ｍＬ添加し、３７℃で５％ＣＯ２存在の条件下にて３分程度培養することで細胞を剥離した。キット添付の１－Ｔｈｉｏｇｌｙｃｅｒｏｌ／Ｈｏｍｏｇｅｎｉｚａｔｉｏｎ　Ｓｏｌｕｔｉｏｎを２００μＬに細胞を懸濁後、さらにキット添付のｌｙｓｉｓ　ｂｕｆｆｅｒを２００μＬを添加し、１５秒間ボルテックスすることで細胞ライセートを調製した。キット添付のカートリッジに４００μＬの細胞ライセートを添加し、該カートリッジをＭａｘｗｅｌｌにセット後、ＲＮＡを自動調製した。ＲＮＡはＮａｎｏＤｒｏｐ（Ｔｈｅｒｍｏ　ｓｃｉｅｎｔｉｆｉｃ社製）で濃度を測定した。５００ｎｇのＲＮＡを鋳型としてｉＳｃｒｉｐｔＴＭ　Ｒｅｖｅｒｓｅ　Ｔｒａｎｓｃｒｉｐｔｉｏｎ　Ｓｕｐｅｒｍｉｘ　ｆｏｒ　ＲＴ－ｑＰＣＲ（バイオラッド社製）を用い、ｃＤＮＡを合成した。合成したｃＤＮＡ、ヒトＮＦＫＢＩＺもしくはヒトＡＣＴＢ遺伝子特異的なプライマー（Ｏｒｉｇｅｎｅ社製）、及びｉＴａｑ　Ｕｎｉｖｅｒｓａｌ　ＳＹＢＲ（Ｒ）　Ｇｒｅｅｎ　Ｓｕｐｅｒｍｉｘ（バイオラッド社製）を用いてプロトコルに従いリアルタイムＰＣＲ反応溶液を調製し、ＣＦＸ３８４（バイオラッド社製）で反応させ、該反応物を検出、定量した。各サンプルにおけるヒトＮＦＫＢＩＺの発現量をヒトＡＣＴＢの発現量で補正した値を、それぞれのサンプルにおけるＮＦＫＢＩＺ発現レベルとし、さらに各サンプルにおけるＮＦＫＢＩＺ発現量をＤＭＳＯ添加コントロールサンプルにおけるＮＦＫＢＩＺ発現量により補正した値を相対ｍＲＮＡ発現量（ＮＦＫＢＩＺ／ＡＣＴＢ）として算出した（図１０）。 (2) Cell Culture and Addition of Reagents RNA was prepared from the above-mentioned cells using Maxwell (manufactured by Promega) and Maxwell (R) 16 LEV simplicity RNA Purification Kits (manufactured by Promega), which are nucleic acid extractors, according to the attached protocol. That is, after adding GS143, cells cultured for 24 hours were washed once with PBS (manufactured by GIBCO), 0.5 mL of trypsin-EDTA was added, and the cells were cultured at 37 ° C. for about 3 minutes under the condition of 5% CO 2 presence. The cells were detached by doing so. After suspending the cells in 200 μL of 1-Thioglycerol / Homogenesis Solution attached to the kit, 200 μL of lysis buffer attached to the kit was further added, and the cells were vortexed for 15 seconds to prepare cell lysates. 400 μL of cell lysate was added to the cartridge attached to the kit, the cartridge was set in Maxwell, and RNA was automatically prepared. The concentration of RNA was measured with NanoDrop (manufactured by Thermo Scientific). CDNA was synthesized using 500 ng of RNA as a template using iScript TM Reverse Transcription Supermix for RT-qPCR (manufactured by Bio-Rad). A real-time PCR reaction solution was prepared according to the protocol using the synthesized cDNA, human NFKBIZ or human ACTB gene-specific primer (manufactured by Origine), and iTaq Universal SYBR (R) Green Supermix (manufactured by Bio-Rad), and CFX384 (CFX384). The reaction was carried out with Bio-Rad), and the reaction product was detected and quantified. The value obtained by correcting the expression level of human NFKBIZ in each sample by the expression level of human ACTB was defined as the NFKBIZ expression level in each sample, and the value obtained by correcting the expression level of NFKBIZ in each sample by the expression level of NFKBIZ in the DMSO-added control sample was used. It was calculated as the relative mRNA expression level (NFKBIZ / ACTB) (FIG. 10).
（３）結果
　図１０に示される通り、ＧＳ１４３（１０μＭ以上の濃度）は、ＨＴ２９細胞（ヒト結腸腺癌細胞）のＮＦＫＢＩＺの発現を有意に抑制した。 (3) Results As shown in FIG. 10, GS143 (concentration of 10 μM or more) significantly suppressed the expression of NFKBIZ in HT29 cells (human colon adenocarcinoma cells).
実施例５
　E３リガーゼ阻害剤ＧＳ１４３によるレグネース１発現の安定化確認試験 Example 5
Stabilization confirmation test of Legnes 1 expression by E3 ligase inhibitor GS143
（１）ウエスタンブロットによる発現確認
　実施例４と同様にＧＳ１４３を添加し、２４時間培養した細胞を、セルスクレーパーで回収し、ＰＢＳで１回洗浄した。既報のプロトコルに従い、ウエスタンブロットによってレグネース１の発現を検出した。即ち、上述の細胞ペレットを５０μＬの１％　ＳＤＳを含むＬｙｓｉｓ　ｂｕｆｆｅｒ（ナカライテスク製）で懸濁し、十分にボルテックスをしたのち、氷上で１５分間インキュベートした。その後、１００００ｇ、１５分、４℃にて遠心処理をし、上清を細胞ライセートとして回収した。タンパク質濃度をＢＣＡ　Ｐｒｏｔｅｉｎ　Ａｓｓａｙ（Ｔｈｅｒｍｏｆｉｓｈｅｒ製）で測定し、１レーン当たり、２０μｇとなるようにＳＤＳ－ＰＡＧＥに供した。ＳＤＳ－ＰＡＧＥのゲルはＡｎｙ　ｋＤミニプロティアンＴＧＸプレキャストゲル（バイオラッド、４５６９０３３）を用いた。レグネース１の発現は抗レグネース１抗体（ＧｅｎｅＴｅｘ社製、ＧＴＸ１１０８０７）にて、ローディングコントロールのβ－チューブリンの発現は抗β－チューブリン抗体（Ｃｅｌｌ　Ｓｉｇｎａｌｉｎｇ　Ｔｅｃｈｎｏｌｏｇｙ社製、２１２８Ｓ）にて検出した（図１１）。 (1) Confirmation of expression by Western blotting GS143 was added in the same manner as in Example 4, and cells cultured for 24 hours were collected with a cell scraper and washed once with PBS. The expression of Legnes 1 was detected by Western blotting according to the previously reported protocol. That is, the above-mentioned cell pellet was suspended in Lysis buffer (manufactured by Nacalai Tesque) containing 50 μL of 1% SDS, vortexed sufficiently, and then incubated on ice for 15 minutes. Then, the cells were centrifuged at 10000 g for 15 minutes at 4 ° C., and the supernatant was collected as cell lysates. The protein concentration was measured by BCA Protein Assay (manufactured by Thermo Fisher) and subjected to SDS-PAGE so as to be 20 μg per lane. As the gel for SDS-PAGE, Any kD miniprotian TGX precast gel (Bio-Rad, 4569033) was used. The expression of Legnes 1 was detected with an anti-Regnes 1 antibody (GTX110807, manufactured by GeneTex), and the expression of β-tubulin in the loading control was detected with an anti-β-tubulin antibody (2128S, manufactured by Cell Signaling Technology) (Fig. 11).
（２）結果
　図１１で示される通り、実施例５にてＮＦＫＢＩＺの発現低下が認められた１０μＭ以上のＧＳ１４３濃度にてレグネース１の発現量の増加が認められ、実施例５におけるＮＦＫＢＩＺ発現の抑制が、Ｅ３リガーゼ阻害に起因したレグネース１発現の安定化に起因していることが示唆された。 (2) Results As shown in FIG. 11, a decrease in the expression of NFKBIZ was observed in Example 5, and an increase in the expression level of Legnes 1 was observed at a GS143 concentration of 10 μM or more, and the expression of NFKBIZ was suppressed in Example 5. However, it was suggested that it was due to the stabilization of Legnes 1 expression due to the inhibition of E3 ligase.
実施例６
　Ｅ３リガーゼ阻害剤ＧＳ１４３による細胞増殖抑制試験 Example 6
Cell growth inhibition test with E3 ligase inhibitor GS143
（１）細胞増殖抑制試験
　５００個のＨＴ２９細胞株を９０μＬ／ウェルの培地を分注した９６ウェルプレートに播種した。３７℃で５％ＣＯ２存在の条件下にて２４時間培養したのち、各々のプレートに終濃度が１．２５μＭ、２．５μＭ、５μＭ、１０μＭ、２０μＭとなるようにＧＳ１４３を添加し（終容積１００μＬ）、さらに３日間培養した。その後、１０μＬのａｌａｍａｒＢｌｕｅ（Ｒ）Ｃｅｌｌ　Ｖｉａｂｉｌｉｔｙ　Ｒｅａｇｅｎｔ（Ｔｈｅｒｍｏｆｉｓｈｅｒ製）を添加し、１～２時間、３７℃で５％ＣＯ２存在の条件下にて培養し、各サンプルの蛍光強度（励起波長／蛍光波長：５４０－５７０／５８０－６１０　ｎｍ）を蛍光プレートリーダーで測定した。ＤＭＳＯコントロールサンプルにおける蛍光強度にて補正した値を細胞生存率（％）として算出した（図１２）。 (1) Cell Growth Inhibition Test 500 HT29 cell lines were seeded on a 96-well plate dispensed with 90 μL / well medium. After culturing at 37 ° C. in the presence of 5% CO 2 for 24 hours, GS143 was added to each plate so that the final concentrations were 1.25 μM, 2.5 μM, 5 μM, 10 μM, and 20 μM (final volume). 100 μL), and further cultured for 3 days. Then, 10 μL of alamarBlue (R) Cell Viability Reagent (manufactured by Thermovisher) was added and cultured for 1 to 2 hours at 37 ° C. under the condition of 5% CO 2 presence, and the fluorescence intensity (excitation wavelength / fluorescence) of each sample was obtained. Wavelength: 540-570 / 580-610 nm) was measured with a fluorescent plate reader. The value corrected by the fluorescence intensity in the DMSO control sample was calculated as the cell viability (%) (FIG. 12).
（２）結果
　図１２で示される通り、ＧＳ１４３は特に１０μＭ以上の濃度において、強力な細胞増殖抑制効果を示した。当該１０μＭ以上の濃度は、実施例８及び実施例９にてレグネース１の発現安定化及び、それに伴うＮＦＫＢＩＺ発現抑制が認められた濃度であることから、Ｅ３リガーゼ阻害剤は、レグネース１の発現を安定化し、ＮＦＫＢＩＺの発現を低下させることで、大腸がん細胞株の細胞増殖を阻害することを見出した。 (2) Results As shown in FIG. 12, GS143 showed a strong cell growth inhibitory effect especially at a concentration of 10 μM or more. Since the concentration of 10 μM or more is the concentration at which the expression stabilization of legnes 1 and the accompanying suppression of NFKBIZ expression were observed in Examples 8 and 9, the E3 ligase inhibitor caused the expression of legnes 1. It has been found that by stabilizing and reducing the expression of NFKBIZ, it inhibits cell proliferation of colorectal cancer cell lines.
実施例７：治療例
（１）患者の選別
　被験者のがんが、慢性炎症に伴うがんであることを、大腸内視鏡検査、注腸造影検査やＣＴ検査、ＭＲＩ検査などによって診断する。炎症状態は、被験者の血液の炎症パラメータの変化やがん組織の炎症病変の広がりや程度によって測定する。
（２）製剤
　被験者を治療するための、ＮＦＫＢＩＺインヒビター及び／又はレグネース１エンハンサーを含む製剤を提供する。薬剤はＧＳ１４３（実施例７）のように調製する。
（３）治療
　被験者のがんの種類、病態の進行度、ＧＳ１４３の適合性、治療履歴、健康状態などを勘案し、薬剤治療が適切と判断された場合に、ＧＳ１４３を投与する。
（４）結果
　被験者の腫瘍の縮小や消失、炎症状態の軽快などがＧＳ１４３投与により達成されることで治療効果が評価される。 Example 7: Treatment example (1) Selection of patients The subject's cancer is diagnosed as being associated with chronic inflammation by colonoscopy, enema contrast examination, CT examination, MRI examination, or the like. The inflammatory state is measured by changes in the inflammatory parameters of the subject's blood and the extent and extent of inflammatory lesions in the cancerous tissue.
(2) Formulation A preparation containing an NFKBIZ inhibitor and / or a Regnes 1 enhancer for treating a subject is provided. The drug is prepared as in GS143 (Example 7).
(3) Treatment Considering the type of cancer of the subject, the degree of progression of the pathological condition, the suitability of GS143, the treatment history, the health condition, etc., GS143 is administered when the drug treatment is judged to be appropriate.
(4) Results The therapeutic effect is evaluated by achieving the reduction or disappearance of the tumor of the subject and the alleviation of the inflammatory state by the administration of GS143.
実施例８：治療剤製造
　ＮＦＫＢＩＺインヒビターとして、ＧＳ１４３を使用し、以下の組成で混合し、内服用の錠剤を調製する。
Figure JPOXMLDOC01-appb-T000004
 Example 8: Therapeutic agent production GS143 is used as an NFKBIZ inhibitor and mixed with the following composition to prepare tablets for internal use.
Figure JPOXMLDOC01-appb-T000004
実施例９：ＮＦＫＢＩＺの腸炎における役割の検討
（１）方法
以下の遺伝子改変したＣ５７ＢＬ／６マウスを用いた。ＶｉｌＣｒｅ　ｍｉｃｅ（００４５８６）およびＲ２６－ＬａｃＺマウス（００３３０９）はＴｈｅ　Ｊａｃｋｓｏｎ　Ｌａｂｏｒａｔｏｒｙから入手した。Ｎｆｋｂｉｚ　ｆｌｏｘマウス（Ｏｋｕｍａ，　Ａ．　ｅｔ　ａｌ．Ｉｍｍｕｎｉｔｙ　３８：４５０（２０１３）、ＲＢＲＣ０６４１０）は理研バイオリソース研究センターから入手した。ＶｉｌＣｒｅＥＲマウス（ｅｌ　Ｍａｒｊｏｕ，　Ｆ．　ｅｔ　ａｌ．　３９：１８６（２００４））はＳｙｌｖｉｅ　Ｒｏｂｉｎｅから譲渡された。Ｎｆｋｂｉｚｆｌ／ｆｌＶｉｌＣｒｅ（コンディショナルノックアウト、ｃＫＯ、ｎ　＝　３）およびＮｆｋｂｉｚｆｌ／ｆｌ（対照、ｎ　＝　３）の同腹仔に対して、５日間の１．５％デキストラン硫酸ナトリウム（ＤＳＳ）の投与を行った２日後に、腸粘膜からＲＮＡを抽出し、リアルタイムＰＣＲ法によって炎症性サイトカインなどの遺伝子の発現量を測定した。
（２）結果
ＮｆｋｂｉｚコンディショナルノックアウトマウスにおけるＤＳＳ投与後の腸粘膜における種々の炎症性サイトカインの遺伝子発現量は、コントロールマウスと比較して有意に低下した（図１３）。このことは、ＮＦＫＢＩＺの機能の抑制が腸炎を緩和することを示唆した。 Example 9: Examination of the role of NFKBIZ in enteritis (1) Method The following genetically modified C57BL / 6 mice were used. VilCremice (004586) and R26-LacZ mice (003309) were obtained from The Jackson Laboratory. Nfkbiz flox mice (Okuma, A. et al. Immunity 38: 450 (2013), RBRC06410) were obtained from the RIKEN BioResource Research Center. VilCre ER mice (el Marjou, F. et al. 39: 186 (2004)) were assigned by Sylvie Robine. Administration of 1.5% sodium dextran sulfate (DSS) for 5 days to litters of Nfkbiz fl / fl VilCre (conditional knockout, cKO, n = 3) and Nfkbiz fl / fl (control, n = 3). Two days after the above, RNA was extracted from the intestinal mucosa, and the expression level of genes such as inflammatory cytokines was measured by a real-time PCR method.
(2) Results The gene expression levels of various inflammatory cytokines in the intestinal mucosa after DSS administration in Nfkbiz conditional knockout mice were significantly reduced as compared with control mice (Fig. 13). This suggested that suppression of the function of NFKBIZ alleviated enteritis.
　（注記）
　以上のように、本開示の好ましい実施形態を用いて本開示を例示してきたが、本開示は、この実施形態に限定して解釈されるべきものではない。本開示は、特許請求の範囲によってのみその範囲が解釈されるべきであることが理解される。当業者は、本開示の具体的な好ましい実施形態の記載から、本開示の記載および技術常識に基づいて等価な範囲を実施することができることが理解される。本明細書において引用した特許、特許出願および文献は、その内容自体が具体的に本明細書に記載されているのと同様にその内容が本明細書に対する参考として援用されるべきであることが理解される。本願は、日本国特許庁に２０１９年８月５日に出願された特願第２０１９－１４３８９５号に対して優先権主張をするものであり、同出願の内容自体は具体的に本明細書に記載されているのと同様にその内容が本明細書に対する参考として援用されるべきであることが理解される。 (Note)
As described above, the present disclosure has been illustrated using the preferred embodiments of the present disclosure, but the present disclosure should not be construed as being limited to this embodiment. It is understood that the present disclosure should be construed only by the claims. It will be understood from those skilled in the art that the description of the specific preferred embodiments of the present disclosure will enable equivalent scope to be implemented based on the description of the present disclosure and common general technical knowledge. The patents, patent applications and documents cited herein are to be incorporated by reference in their content as they are specifically described herein. Understood. This application claims priority to Japanese Patent Application No. 2019-143895 filed with the Japan Patent Office on August 5, 2019, and the content of the application itself is specifically described in the present specification. It is understood that its content should be incorporated as a reference to this specification as it is described.
　本発明に係るＮＦＫＢＩＺインヒビターは、慢性炎症に伴うがんに対して、極めて有用である。また本発明のスクリーニング方法は、がんの治療または予防薬の候補物質となる、ＮＦＫＢＩＺインヒビターを探索するために有用である。 The NFKBIZ inhibitor according to the present invention is extremely useful for cancer associated with chronic inflammation. In addition, the screening method of the present invention is useful for searching for an NFKBIZ inhibitor that is a candidate substance for a therapeutic or prophylactic drug for cancer.
配列番号１：ｓｈＮＦＫＢＩＺ　１　標的配列
配列番号２：ｓｈＮＦＫＢＩＺ　１配列
配列番号３：ｓｈＮＦＫＢＩＺ　２　標的配列
配列番号４：ｓｈＮＦＫＢＩＺ　２配列
配列番号５：ＮＦＫＢＩＺ　フォワードプライマー
配列番号６：ＮＦＫＢＩＺ　リバースプライマー
配列番号７：１８Ｓ　ｒＲＮＡ　フォワードプライマー
配列番号８：１８Ｓ　ｒＲＮＡ　リバースプライマー SEQ ID NO: 1: shNFKBIZ 1 Target SEQ ID NO: 2: shNFKBIZ 1 SEQ ID NO: 3: shNFKBIZ 2 Target SEQ ID NO: 4: shNFKBIZ 2 SEQ ID NO: 5: NFKBIZ Forward primer SEQ ID NO: 6: NFKBIZ Reverse primer SEQ ID NO: 7:18 Forward primer SEQ ID NO: 8: 18S rRNA Reverse primer

Claims (161)

  1. 　ＮＦＫＢＩＺインヒビターを含む、がんを治療及び／又は予防するための医薬組成物。 A pharmaceutical composition for treating and / or preventing cancer, which comprises an NFKBIZ inhibitor.
  2. 　前記がんが、慢性炎症に伴うがんである、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the cancer is a cancer associated with chronic inflammation.
  3. 　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、請求項２に記載の医薬組成物。 The pharmaceutical composition according to claim 2, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  4. 　前記炎症性腸疾患が、潰瘍性大腸炎である、請求項３に記載の医薬組成物。 The pharmaceutical composition according to claim 3, wherein the inflammatory bowel disease is ulcerative colitis.
  5. 　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、請求項１～４のいずれか一項に記載の医薬組成物。 The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer. , Esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis Claim 1 comprising at least one selected from the group consisting of embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. The pharmaceutical composition according to any one of 4 to 4.
  6. 　前記がんが、大腸がんである、請求項５に記載の医薬組成物。 The pharmaceutical composition according to claim 5, wherein the cancer is colorectal cancer.
  7. 　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、請求項６に記載の医薬組成物。 The pharmaceutical composition according to claim 6, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  8. 　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、請求項１～７のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 7, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  9. 　前記インヒビターが、ＮＦＫＢＩＺの発現を減少させる、及び／又はＮＦＫＢＩＺの機能を抑制するものである、請求項１～８のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 8, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
  10. 　前記インヒビターが、ＮＦＫＢＩＺの核内移行を阻害するものである、請求項１～９のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 9, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
  11. 　前記インヒビターが、ＮＦＫＢＩＺとｐ５０との結合を阻害するものである、請求項１～１０のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 10, wherein the inhibitor inhibits the binding between NFKBIZ and p50.
  12. 　前記インヒビターが、ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することを阻害するものである、請求項１～１１のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 11, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence.
  13. 　前記インヒビターが、Ｅ３リガーゼ阻害活性を有する、請求項１～１２のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 12, wherein the inhibitor has an E3 ligase inhibitory activity.
  14. 　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、請求項１～１３のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 13, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  15. 　前記インヒビターが、核酸である、請求項１４に記載の医薬組成物。 The pharmaceutical composition according to claim 14, wherein the inhibitor is a nucleic acid.
  16. 　前記インヒビターが、抗ＮＦＫＢＩＺ抗体である、請求項１４に記載の医薬組成物。 The pharmaceutical composition according to claim 14, wherein the inhibitor is an anti-NFKBIZ antibody.
  17. 　前記インヒビターが、低分子化合物である、請求項１４に記載の医薬組成物。 The pharmaceutical composition according to claim 14, wherein the inhibitor is a low molecular weight compound.
  18. 　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、請求項１７に記載の医薬組成物。 The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl) -benzoic acid. The pharmaceutical composition according to claim 17, which is an acid (GS143).
  19. 　レグネース１エンハンサーを含む、がんを治療及び／又は予防するための医薬組成物。 A pharmaceutical composition for treating and / or preventing cancer, which comprises a Legnes 1 enhancer.
  20. 　前記がんが、慢性炎症に伴うがんである、請求項１９に記載の医薬組成物。 The pharmaceutical composition according to claim 19, wherein the cancer is a cancer associated with chronic inflammation.
  21. 　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、請求項２０に記載の医薬組成物。 The pharmaceutical composition according to claim 20, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  22. 　前記炎症性腸疾患が、潰瘍性大腸炎である、請求項２１に記載の医薬組成物。 The pharmaceutical composition according to claim 21, wherein the inflammatory bowel disease is ulcerative colitis.
  23. 　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、請求項１９～２２のいずれか一項に記載の医薬組成物。 The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer. , Esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis 19. Claim 19 comprising at least one selected from the group consisting of embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. The pharmaceutical composition according to any one of 22 to 22.
  24. 　前記がんが、大腸がんである、請求項２３に記載の医薬組成物。 The pharmaceutical composition according to claim 23, wherein the cancer is colorectal cancer.
  25. 　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、請求項２４に記載の医薬組成物。 The pharmaceutical composition according to claim 24, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  26. 　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、請求項１９～２５のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 19 to 25, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  27. 　前記エンハンサーが、レグネース１の活性を増強するものである、請求項１９～２６のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 19 to 26, wherein the enhancer enhances the activity of Legnes 1.
  28. 　前記エンハンサーが、レグネース１分解酵素を阻害するものである、請求項１９～２７のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 19 to 27, wherein the enhancer inhibits a legnes monodegrading enzyme.
  29. 　前記レグネース１分解酵素が、レグネース１リン酸化酵素、又はレグネース１ユビキチン化酵素である、請求項２８に記載の医薬組成物。 The pharmaceutical composition according to claim 28, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  30. 　前記エンハンサーが、Ｅ３リガーゼ阻害活性を有する、請求項２９に記載の医薬組成物。 The pharmaceutical composition according to claim 29, wherein the enhancer has an E3 ligase inhibitory activity.
  31. 　前記エンハンサーが、核酸、抗体、低分子化合物、又は高分子化合物である、請求項１９～３０のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 19 to 30, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  32. 　前記エンハンサーが、核酸である、請求項３１に記載の医薬組成物。 The pharmaceutical composition according to claim 31, wherein the enhancer is a nucleic acid.
  33. 　前記エンハンサーが、抗体である、請求項２６に記載の医薬組成物。 The pharmaceutical composition according to claim 26, wherein the enhancer is an antibody.
  34. 　前記エンハンサーが、低分子化合物である、請求項２６に記載の医薬組成物。 The pharmaceutical composition according to claim 26, wherein the enhancer is a low molecular weight compound.
  35. 　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、請求項３４に記載の医薬組成物。 The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl) -benzoic acid. The pharmaceutical composition according to claim 34, which is an acid (GS143).
  36. 　Ｅ３リガーゼインヒビターを含む、がんを治療及び／又は予防するための医薬組成物。 A pharmaceutical composition for treating and / or preventing cancer, which comprises an E3 ligase inhibitor.
  37. 　前記がんが、慢性炎症に伴うがんである、請求項３６に記載の医薬組成物。 The pharmaceutical composition according to claim 36, wherein the cancer is a cancer associated with chronic inflammation.
  38. 　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、請求項３７に記載の医薬組成物。 The pharmaceutical composition according to claim 37, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  39. 　前記炎症性腸疾患が、潰瘍性大腸炎である、請求項３８に記載の医薬組成物。 The pharmaceutical composition according to claim 38, wherein the inflammatory bowel disease is ulcerative colitis.
  40. 　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、請求項３６～３９のいずれか一項に記載の医薬組成物。 The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer. , Esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis 36. Claim 36, comprising at least one selected from the group consisting of embryonic cell tumors, ovarian embryonic cell tumors, Wilms tumors, skin cancers, malignant melanomas, neuroblastomas, osteosarcoma, Ewing sarcoma, and soft sarcoma. The pharmaceutical composition according to any one of 39 to 39.
  41. 　前記がんが、大腸がんである、請求項４０に記載の医薬組成物。 The pharmaceutical composition according to claim 40, wherein the cancer is colorectal cancer.
  42. 　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、請求項４１に記載の医薬組成物。 The pharmaceutical composition according to claim 41, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  43. 　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、請求項３６～４２のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 36 to 42, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  44. 　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、請求項３６～４３のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 36 to 43, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  45. 　前記インヒビターが、核酸である、請求項４４に記載の医薬組成物。 The pharmaceutical composition according to claim 44, wherein the inhibitor is a nucleic acid.
  46. 　前記インヒビターが、抗Ｅ３リガーゼ抗体である、請求項４４に記載の医薬組成物。 The pharmaceutical composition according to claim 44, wherein the inhibitor is an anti-E3 ligase antibody.
  47. 　前記インヒビターが、低分子化合物である、請求項４４に記載の医薬組成物。 The pharmaceutical composition according to claim 44, wherein the inhibitor is a low molecular weight compound.
  48. 　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、請求項４７に記載の医薬組成物。 The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl) -benzoic acid. The pharmaceutical composition according to claim 47, which is an acid (GS143).
  49. 　ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇している被験者に投与されることを特徴とする、ＮＦＫＢＩＺインヒビターを有効成分として含む、がんを治療及び／又は予防するための医薬組成物。 For treating and / or preventing cancer, comprising an NFKBIZ inhibitor as an active ingredient, characterized in that it is administered to a subject with elevated expression of NFKBIZ and / or increased activity of NFKBIZ. Pharmaceutical composition.
  50. 　前記ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇している被験者が、
    （１）該被験者より取得したがん細胞のＮＦＫＢＩＺ遺伝子の発現及び／又は活性を測定する工程、
    （２）（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又は活性を、健常者より採取した細胞中の前記ＮＦＫＢＩＺ遺伝子の発現及び／又は活性（以下、対照値という）と比較する工程、及び
    （３）（２）の結果に基づき、（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又は活性が、該対照値よりも大きい場合に、ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇していると判定する工程
    を含む工程で決定されることを特徴とする、請求項４９に記載の組成物。     The subject in which the expression of NFKBIZ is increased and / or the activity of NFKBIZ is increased is
    (1) A step of measuring the expression and / or activity of the NFKBIZ gene in cancer cells obtained from the subject.
    (2) A step of comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ. 49. The composition according to claim 49, wherein the composition is determined in a step including a step of determining that is increasing.
  51. 　前記がんが、慢性炎症に伴うがんである、請求項４９又は５０に記載の組成物。 The composition according to claim 49 or 50, wherein the cancer is a cancer associated with chronic inflammation.
  52. 　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、請求項５１に記載の組成物。 The composition according to claim 51, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  53. 　前記炎症性腸疾患が、潰瘍性大腸炎である、請求５２に記載の組成物。 The composition according to claim 52, wherein the inflammatory bowel disease is ulcerative colitis.
  54. 　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、請求項４９～５３のいずれか一項に記載の組成物。 The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer. , Esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis 49. It comprises at least one selected from the group consisting of embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. 5. The composition according to any one of 53.
  55. 　前記がんが、大腸がんである、請求項５４に記載の組成物。 The composition according to claim 54, wherein the cancer is colorectal cancer.
  56. 　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、請求項５５に記載の組成物。 The composition according to claim 55, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  57. 　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、請求項３６～４３のいずれか一項に記載の組成物。 The composition according to any one of claims 36 to 43, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  58. 　前記インヒビターが、ＮＦＫＢＩＺの発現を減少させる、及び／又はＮＦＫＢＩＺの機能を抑制するものである、請求項４９～５７のいずれか一項に記載の組成物。 The composition according to any one of claims 49 to 57, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
  59. 　前記インヒビターが、ＮＦＫＢＩＺの核内移行を阻害するものである、請求項４９～５８のいずれか一項に記載の組成物。 The composition according to any one of claims 49 to 58, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
  60. 　前記インヒビターが、ＮＦＫＢＩＺとｐ５０との結合を阻害するものである、請求項４９～５９のいずれか一項に記載の組成物。 The composition according to any one of claims 49 to 59, wherein the inhibitor inhibits the binding between NFKBIZ and p50.
  61. 　前記インヒビターが、ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することを阻害するものである、請求項４９～６０のいずれか一項に記載の組成物。 The composition according to any one of claims 49 to 60, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence.
  62. 　前記インヒビターが、Ｅ３リガーゼ阻害活性を有する、請求項４９～６１のいずれか一項に記載の組成物。 The composition according to any one of claims 49 to 61, wherein the inhibitor has an E3 ligase inhibitory activity.
  63. 　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、請求項４９～６２のいずれか一項に記載の組成物。 The composition according to any one of claims 49 to 62, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  64. 　前記インヒビターが、核酸である、請求項６３に記載の組成物。 The composition according to claim 63, wherein the inhibitor is a nucleic acid.
  65. 　前記インヒビターが、抗ＮＦＫＢＩＺ抗体である、請求項６３に記載の組成物。 The composition according to claim 63, wherein the inhibitor is an anti-NFKBIZ antibody.
  66. 　前記インヒビターが、低分子化合物である、請求項６３に記載の組成物。 The composition according to claim 63, wherein the inhibitor is a low molecular weight compound.
  67. 　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、請求項６６に記載の組成物。 The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl) -benzoic acid. The composition according to claim 66, which is an acid (GS143).
  68. 　被験者のがん細胞におけるＮＦＫＢＩＺの遺伝子発現及び／又はＮＦＫＢＩＺの活性を測定することを含む、ＮＦＫＢＩＺインヒビターの該被験者への有効性を予測する方法。 A method of predicting the efficacy of an NFKBIZ inhibitor on a subject, including measuring the gene expression and / or activity of NFKBIZ in the subject's cancer cells.
  69. 　前記がん細胞におけるＮＦＫＢＩＺの遺伝子発現及び／又はＮＦＫＢＩＺの活性の測定が、
    （１）前記被験者より取得したがん細胞のＮＦＫＢＩＺ遺伝子の発現及び／又はＮＦＫＢＩＺの活性を測定する工程、
    （２）（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又はＮＦＫＢＩＺの活性を、健常者より採取した細胞中の前記ＮＦＫＢＩＺ遺伝子の発現及び／又はＮＦＫＢＩＺの活性（以下、対照値という）と比較する工程、及び
    （３）（２）の結果に基づき、（１）で定量したＮＦＫＢＩＺ遺伝子の発現及び／又はＮＦＫＢＩＺの活性が、該対照値よりも大きい場合に、ＮＦＫＢＩＺの発現が亢進している、及び／又はＮＦＫＢＩＺの活性が上昇していると判定する工程
    を含む工程で決定される、請求項６８に記載の方法。     Measurement of NFKBIZ gene expression and / or NFKBIZ activity in the cancer cells
    (1) A step of measuring the expression of the NFKBIZ gene and / or the activity of NFKBIZ in cancer cells obtained from the subject.
    (2) The expression and / or NFKBIZ activity of the NFKBIZ gene quantified in (1) is compared with the expression and / or NFKBIZ activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject. Based on the steps and the results of (3) and (2), the expression of NFKBIZ is enhanced when the expression of the NFKBIZ gene and / or the activity of NFKBIZ quantified in (1) is larger than the control value. The method of claim 68, which is determined in a step comprising determining that the activity of NFKBIZ is increased and / or NFKBIZ.
  70. 　前記がんが、慢性炎症に伴うがんである、請求項６８または６９に記載の方法。 The method according to claim 68 or 69, wherein the cancer is a cancer associated with chronic inflammation.
  71. 　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、請求項６８～７０のいずれか一項に記載の方法。 The method according to any one of claims 68 to 70, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  72. 　前記炎症性腸疾患が、潰瘍性大腸炎である、請求項７１に記載の方法。 The method according to claim 71, wherein the inflammatory bowel disease is ulcerative colitis.
  73. 　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、請求項６８～７２のいずれか一項に記載の方法。 The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer. , Esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis Claim 68, comprising at least one selected from the group consisting of embryonic cell tumors, ovarian embryonic cell tumors, Wilms tumors, skin cancers, malignant melanomas, neuroblastomas, osteosarcomas, Ewing sarcomas, and soft sarcomas. The method according to any one of 7 to 72.
  74. 　前記がんが、大腸がんである、請求項７３に記載の方法。 The method according to claim 73, wherein the cancer is colorectal cancer.
  75. 　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、請求項７４に記載の方法。 The method according to claim 74, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  76. 　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、請求項６８～７５のいずれか一項に記載の方法。 The method according to any one of claims 68 to 75, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  77. 　前記インヒビターが、ＮＦＫＢＩＺの発現を減少させる、及び／又はＮＦＫＢＩＺの機能を抑制するものである、請求項６８～７６のいずれか一項に記載の方法。 The method according to any one of claims 68 to 76, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
  78. 　前記インヒビターが、ＮＦＫＢＩＺの核内移行を阻害するものである、請求項６８～７７のいずれか一項に記載の方法。 The method according to any one of claims 68 to 77, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
  79. 　前記インヒビターが、ＮＦＫＢＩＺとｐ５０との結合を阻害するものである、請求項６８～７８のいずれか一項に記載の方法。 The method according to any one of claims 68 to 78, wherein the inhibitor inhibits the binding between NFKBIZ and p50.
  80. 　前記インヒビターが、ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することを阻害するものである、請求項６８～７９のいずれか一項に記載の方法。 The method according to any one of claims 68 to 79, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence.
  81. 　前記インヒビターが、Ｅ３リガーゼ阻害活性を有する、請求項６８～８０のいずれか一項に記載の方法。 The method according to any one of claims 68 to 80, wherein the inhibitor has an E3 ligase inhibitory activity.
  82. 　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、請求項６８～８１のいずれか一項に記載の方法。 The method according to any one of claims 68 to 81, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  83. 　前記インヒビターが、核酸である、請求項８２に記載の方法。 The method according to claim 82, wherein the inhibitor is nucleic acid.
  84. 　前記インヒビターが、抗ＮＦＫＢＩＺ抗体である、請求項８２に記載の方法。 The method according to claim 82, wherein the inhibitor is an anti-NFKBIZ antibody.
  85. 　前記インヒビターが、低分子化合物である、請求項８２に記載の方法。 The method according to claim 82, wherein the inhibitor is a low molecular weight compound.
  86. 前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、請求項８５に記載の方法。 The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl) -benzoic acid. The method of claim 85, which is an acid (GS143).
  87. 　ＮＦＫＢＩＺインヒビターをスクリーニングする方法であって、
    （１）がん細胞にインヒビター候補を作用させずに、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、
    （２）該がん細胞に該インヒビター候補を作用させた後に、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、及び
    （３）（２）の結果が、（１）の結果よりも小さい場合に、該インヒビター候補を、ＮＦＫＢＩＺインヒビターであると判定する工程、
    を含む、方法。     A method of screening for NFKBIZ inhibitors,
    (1) A step of measuring the gene expression and / or activity of NFKBIZ without allowing an inhibitor candidate to act on cancer cells.
    (2) The step of measuring the gene expression and / or activity of NFKBIZ after allowing the inhibitor candidate to act on the cancer cells, and when the results of (3) and (2) are smaller than the results of (1). In addition, a step of determining the inhibitor candidate as an NFKBIZ inhibitor,
    Including methods.
  88. 　がんの治療及び／又は予防剤をスクリーニングする方法であって、
    （１）がん細胞に治療及び／又は予防剤候補を作用させずに、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、
    （２）該がん細胞に該治療及び／又は予防剤候補を作用させた後に、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、及び
    （３）（２）の結果が、（１）の結果よりも小さい場合に、該治療及び／又は予防剤候補を、がんの治療及び／又は予防剤であると判定する工程、
    を含む、方法。     A method of screening for cancer treatment and / or prophylaxis.
    (1) A step of measuring gene expression and / or activity of NFKBIZ without allowing a therapeutic and / or prophylactic agent candidate to act on cancer cells.
    (2) The steps of measuring the gene expression and / or activity of NFKBIZ after allowing the therapeutic and / or prophylactic agent candidate to act on the cancer cells, and the results of (3) and (2) are the results of (1). A step of determining the therapeutic and / or prophylactic agent candidate as a cancer therapeutic and / or prophylactic agent if the result is smaller than the result.
    Including methods.
  89. 　ＮＦＫＢＩＺの発現量を減少させる物質、及び／又はＮＦＫＢＩＺの機能を抑制する物質をスクリーニングする方法であって、
    （１）がん細胞に被験物質を作用させずに、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、
    （２）該がん細胞に該被験物質を作用させた後に、ＮＦＫＢＩＺの遺伝子発現及び／又は活性を測定する工程、
    （３）（２）の結果が、（１）の結果よりも小さい場合に、該被験物質を、ＮＦＫＢＩＺの発現量を減少させる物質、及び／又はＮＦＫＢＩＺの機能を抑制する物質であると判定する工程、
    を含む、方法。     A method for screening a substance that reduces the expression level of NFKBIZ and / or a substance that suppresses the function of NFKBIZ.
    (1) A step of measuring the gene expression and / or activity of NFKBIZ without allowing a test substance to act on cancer cells.
    (2) A step of measuring the gene expression and / or activity of NFKBIZ after allowing the test substance to act on the cancer cells.
    (3) When the result of (2) is smaller than the result of (1), it is determined that the test substance is a substance that reduces the expression level of NFKBIZ and / or a substance that suppresses the function of NFKBIZ. Process,
    Including methods.
  90. 　前記がんが、慢性炎症に伴うがんである、請求項８７～８９のいずれか一項に記載の方法。 The method according to any one of claims 87 to 89, wherein the cancer is a cancer associated with chronic inflammation.
  91. 　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、請求項９０に記載の方法。 The method according to claim 90, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  92. 　前記炎症性腸疾患が、潰瘍性大腸炎である、請求項９１に記載の方法。 The method according to claim 91, wherein the inflammatory bowel disease is ulcerative colitis.
  93. 　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、請求項８７～９２のいずれか一項に記載の方法。 The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer. , Esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis Claim 87, comprising at least one selected from the group consisting of embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. 9. The method according to any one of 92.
  94. 　前記がんが、大腸がんである、請求項９３に記載の方法。 The method according to claim 93, wherein the cancer is colorectal cancer.
  95. 　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、請求項９４に記載の方法。 The method of claim 94, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  96. 　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、請求項８７～９５のいずれか一項に記載の方法。 The method according to any one of claims 87 to 95, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  97. 　前記インヒビターが、ＮＦＫＢＩＺの発現を減少させる、及び／又はＮＦＫＢＩＺの機能を抑制するものである、請求項８７～９６のいずれか一項に記載の方法。 The method according to any one of claims 87 to 96, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
  98. 　前記インヒビターが、ＮＦＫＢＩＺの核内移行を阻害するものである、請求項８７～９７のいずれか一項に記載の方法。 The method according to any one of claims 87 to 97, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
  99. 　前記インヒビターが、ＮＦＫＢＩＺとｐ５０との結合を阻害するものである、請求項８７～９８のいずれか一項に記載の方法。 The method according to any one of claims 87 to 98, wherein the inhibitor inhibits the binding between NFKBIZ and p50.
  100. 　前記インヒビターが、ＮＦＫＢＩＺを含む複合体よりなる転写因子が、特定のＤＮＡ配列と相互作用することを阻害するものである、請求項８７～９９のいずれか一項に記載の方法。 The method according to any one of claims 87 to 99, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence.
  101. 　前記インヒビターが、Ｅ３リガーゼ阻害活性を有する、請求項８７～１００のいずれか一項に記載の方法。 The method according to any one of claims 87 to 100, wherein the inhibitor has an E3 ligase inhibitory activity.
  102. 　前記インヒビターが、核酸、抗体、低分子化合物、又は高分子化合物である、請求項８７～１０１のいずれか一項に記載の方法。 The method according to any one of claims 87 to 101, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  103. 　前記インヒビターが、核酸である、請求項１０２に記載の方法。 The method according to claim 102, wherein the inhibitor is nucleic acid.
  104. 　前記インヒビターが、抗ＮＦＫＢＩＺ抗体である、請求項１０２に記載の方法。 The method of claim 102, wherein the inhibitor is an anti-NFKBIZ antibody.
  105. 　前記インヒビターが、低分子化合物である、請求項１０２に記載の方法。 The method according to claim 102, wherein the inhibitor is a low molecular weight compound.
  106. 　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、請求項１０５に記載の方法。 The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl) -benzoic acid. The method of claim 105, which is an acid (GS143).
  107. 　レグネース１の発現が低下している、及び／又はレグネース１の活性が低下している被験者に投与されることを特徴とする、レグネース１エンハンサーを含む、がんを治療及び／又は予防するための医薬組成物。 For treating and / or preventing cancer, including the Legnes 1 Enhancer, which is administered to a subject with reduced expression of Legnes 1 and / or decreased activity of Legnes 1. Pharmaceutical composition.
  108. 　前記レグネース１発現が低下している、及び／又はレグネース１の活性が低下している被験者が、
    （１）該被験者より取得したがん細胞のレグネース１の発現及び／又は活性を測定する工程、
    （２）（１）で定量したレグネース１の発現及び／又は活性を、健常者より採取した細胞中の前記レグネース１の発現及び／又は活性（以下、対照値という）と比較する工程、及び
    （３）（２）の結果に基づき、（１）で定量したレグネース１の発現及び／又は活性が、対照値よりも小さい場合に、レグネース１の発現及び／又は活性が低下していると判定する工程
    を含む工程で決定されることを特徴とする、請求項１０７に記載の組成物。     Subjects with reduced expression of Legnes 1 and / or decreased activity of Legnes 1
    (1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject.
    (2) A step of comparing the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased. The composition according to claim 107, which is determined by a step including a step.
  109. 　前記がんが、慢性炎症に伴うがんである、請求項１０７又は１０８に記載の組成物。 The composition according to claim 107 or 108, wherein the cancer is a cancer associated with chronic inflammation.
  110. 　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、請求項１０９に記載の組成物。 The composition according to claim 109, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  111. 　前記炎症性腸疾患が、潰瘍性大腸炎である、請求項１１０に記載の組成物。 The composition according to claim 110, wherein the inflammatory bowel disease is ulcerative colitis.
  112. 　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、請求項１０７～１１１のいずれか一項に記載の組成物。 The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer. , Esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis Claim 107, comprising at least one selected from the group consisting of embryonic cell tumors, ovarian embryonic cell tumors, Wilms tumors, skin cancers, malignant melanomas, neuroblastomas, osteosarcomas, Ewing sarcomas, and soft sarcomas. The composition according to any one of 1 to 111.
  113. 　前記がんが、大腸がんである、請求項１１２に記載の組成物。 The composition according to claim 112, wherein the cancer is colorectal cancer.
  114. 　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、請求項１１３に記載の組成物。 The composition according to claim 113, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  115. 　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、請求項１０７～１１４のいずれか一項に記載の組成物。 The composition according to any one of claims 107 to 114, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  116. 　前記エンハンサーが、レグネース１の活性を増強するものである、請求項１０７～１１５のいずれか一項に記載の組成物。 The composition according to any one of claims 107 to 115, wherein the enhancer enhances the activity of Legnes 1.
  117. 　前記エンハンサーが、レグネース１分解酵素を阻害するものである、請求項１０７～１１６のいずれか一項に記載の組成物。 The composition according to any one of claims 107 to 116, wherein the enhancer inhibits a legnes monodegrading enzyme.
  118. 　前記レグネース１分解酵素が、レグネース１リン酸化酵素、又はレグネース１ユビキチン化酵素である、請求項１１７に記載の組成物。 The composition according to claim 117, wherein the legnes 1-degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  119. 　前記エンハンサーが、Ｅ３リガーゼ阻害活性を有する、請求項１０７～１１８のいずれか一項に記載の組成物。 The composition according to any one of claims 107 to 118, wherein the enhancer has an E3 ligase inhibitory activity.
  120. 　前記エンハンサーが、核酸、抗体、低分子化合物、又は高分子化合物である、請求項１０７～１１９のいずれか一項に記載の組成物。 The composition according to any one of claims 107 to 119, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  121. 　前記エンハンサーが、核酸である、請求項１２０に記載の組成物。 The composition according to claim 120, wherein the enhancer is a nucleic acid.
  122. 　前記エンハンサーが、抗体である、請求項１２０に記載の組成物。 The composition according to claim 120, wherein the enhancer is an antibody.
  123. 　前記エンハンサーが、低分子化合物である、請求項１２０に記載の組成物。 The composition according to claim 120, wherein the enhancer is a low molecular weight compound.
  124. 　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、請求項１２３に記載の組成物。 The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl) -benzoic acid. The composition according to claim 123, which is an acid (GS143).
  125. 　被験者のがん細胞におけるレグネース１の発現及び／又は活性を測定することを含む、レグネース１エンハンサーの該被験者への有効性を予測する方法。 A method of predicting the efficacy of a Legnese 1 enhancer on a subject, including measuring the expression and / or activity of Legnes 1 in the subject's cancer cells.
  126. 　前記がん細胞におけるレグネース１の発現及び／又は活性の測定が、
    （１）前記被験者より取得したがん細胞のレグネース１の発現及び／又は活性を測定する工程、
    （２）（１）で定量したレグネース１の発現及び／又は活性を、健常者より採取した細胞中の前記レグネース１の発現及び／又は活性（以下、対照値という）と比較する工程、及び
    （３）（２）の結果に基づき、（１）で定量したレグネース１の発現及び／又は活性が、対照値よりも小さい場合に、レグネース１の発現及び／又は活性が低下していると判定する工程
    を含む工程で決定される、請求項１２５に記載の方法。     Measurement of the expression and / or activity of Legnes 1 in the cancer cells
    (1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject.
    (2) A step of comparing the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased. 125. The method of claim 125, which is determined in a process comprising the process.
  127. 　前記がんが、慢性炎症に伴うがんである、請求項１２５又は１２６に記載の方法。 The method according to claim 125 or 126, wherein the cancer is a cancer associated with chronic inflammation.
  128. 　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、請求項１２７に記載の方法。 The method according to claim 127, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  129. 　前記炎症性腸疾患が、潰瘍性大腸炎である、請求項１２８に記載の方法。 The method according to claim 128, wherein the inflammatory bowel disease is ulcerative colitis.
  130. 　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、請求項１２５～１２９のいずれか一項に記載の方法。 The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer. , Esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis Claim 125, comprising at least one selected from the group consisting of embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. The method according to any one of 129.
  131. 　前記がんが、大腸がんである、請求項１３０に記載の方法。 The method according to claim 130, wherein the cancer is colorectal cancer.
  132. 　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、請求項１３１に記載の方法。 13. The method of claim 131, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  133. 　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、請求項１２５～１３２のいずれか一項に記載の方法。 The method according to any one of claims 125 to 132, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  134. 　前記エンハンサーが、レグネース１の活性を増強するものである、請求項１２５～１３３のいずれか一項に記載の方法。 The method according to any one of claims 125 to 133, wherein the enhancer enhances the activity of Legnes 1.
  135. 　前記エンハンサーが、レグネース１分解酵素を阻害するものである、請求項１２５～１３４のいずれか一項に記載の方法。 The method according to any one of claims 125 to 134, wherein the enhancer inhibits a legnes monodegrading enzyme.
  136. 　前記レグネース１分解酵素が、レグネース１リン酸化酵素、又はレグネース１ユビキチン化酵素である、請求項１３５に記載の方法。 The method according to claim 135, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  137. 　前記エンハンサーが、Ｅ３リガーゼ阻害活性を有する、請求項１２５～１３６のいずれか一項に記載の方法。 The method according to any one of claims 125 to 136, wherein the enhancer has an E3 ligase inhibitory activity.
  138. 　前記エンハンサーが、核酸、抗体、低分子化合物、又は高分子化合物である、請求項１２５～１３７のいずれか一項に記載の方法。 The method according to any one of claims 125 to 137, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  139. 　前記エンハンサーが、核酸である、請求項１３８に記載の方法。 The method according to claim 138, wherein the enhancer is a nucleic acid.
  140. 　前記エンハンサーが、抗体である、請求項１３８に記載の方法。 The method according to claim 138, wherein the enhancer is an antibody.
  141. 　前記エンハンサーが、低分子化合物である、請求項１３８に記載の方法。 The method according to claim 138, wherein the enhancer is a low molecular weight compound.
  142. 　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、請求項１４１に記載の方法。 The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl) -benzoic acid. The method of claim 141, which is an acid (GS143).
  143. 　レグネース１エンハンサーをスクリーニングする方法であって、
    （１）がん細胞にエンハンサー候補を作用させずに、レグネース１の発現及び／又は活性を測定する工程、
    （２）該がん細胞に該エンハンサー候補を作用させた後に、レグネース１の発現及び／又は活性を測定する工程、
    （３）（２）の結果が、（１）の結果よりも大きい場合に、該エンハンサー候補を、レグネース１エンハンサーであると判定する工程、
    を含む、方法。     A method of screening for Legnes 1 enhancers
    (1) A step of measuring the expression and / or activity of Legnes 1 without allowing an enhancer candidate to act on cancer cells.
    (2) A step of measuring the expression and / or activity of Legnes 1 after allowing the enhancer candidate to act on the cancer cells.
    (3) A step of determining the enhancer candidate as a legnace 1 enhancer when the result of (2) is larger than the result of (1).
    Including methods.
  144. 　がんの治療及び／又は予防剤をスクリーニングする方法であって、
    （１）がん細胞に治療及び／又は予防剤を作用させずに、レグネース１の発現及び／又は活性を測定する工程、
    （２）該がん細胞に該治療及び／又は予防剤候補を作用させた後に、レグネース１の発現及び／又は活性を測定する工程、
    （３）（２）の結果が、（１）の結果よりも大きい場合に、該治療及び／又は予防剤候補を、がんの治療及び／又は予防剤であると判定する工程、
    を含む、方法。     A method of screening for cancer treatment and / or prophylaxis.
    (1) A step of measuring the expression and / or activity of Legnes 1 without allowing a therapeutic and / or preventive agent to act on cancer cells.
    (2) A step of measuring the expression and / or activity of Legnes 1 after allowing the cancer cell to act on the therapeutic and / or prophylactic agent candidate.
    (3) A step of determining a candidate for a therapeutic and / or prophylactic agent as a therapeutic and / or prophylactic agent for cancer when the result of (2) is larger than the result of (1).
    Including methods.
  145. 　レグネース１の活性を増強する物質をスクリーニングする方法であって、
    （１）がん細胞に被験物質を作用させずに、レグネース１の活性を測定する工程、
    （２）該がん細胞に該被験物質を作用させた後に、レグネース１の活性を測定する工程、（３）（２）の結果が、（１）の結果よりも大きい場合に、該被験物質を、レグネース１の活性を増強する物質であると判定する工程、
    を含む、方法。     A method of screening for substances that enhance the activity of Legnes 1.
    (1) A step of measuring the activity of Legnes 1 without allowing a test substance to act on cancer cells.
    (2) A step of measuring the activity of Legnes 1 after allowing the test substance to act on the cancer cells. When the results of (3) and (2) are larger than the results of (1), the test substance. , A step of determining that the substance enhances the activity of Legnes 1.
    Including methods.
  146. 　前記がんが、慢性炎症に伴うがんである、請求項１４３～１４５のいずれか一項に記載の方法。 The method according to any one of claims 143 to 145, wherein the cancer is a cancer associated with chronic inflammation.
  147. 　前記慢性炎症に伴うがんが、炎症性腸疾患に合併したがんである、請求項１４６に記載の方法。 The method according to claim 146, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  148. 　前記炎症性腸疾患が、潰瘍性大腸炎である、請求項１４７に記載の方法。 The method according to claim 147, wherein the inflammatory bowel disease is ulcerative colitis.
  149. 　前記がんが、大腸がん、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、骨髄異形成症候群、脳腫瘍、頭頸部がん、食道がん、甲状腺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、膀胱がん、前立腺がん、尿路上皮がん、腎がん、腎細胞がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、皮膚がん、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング肉腫、及び軟部肉腫からなる群より選択される少なくとも一つを含む、請求項１４３～１４８のいずれか一項に記載の方法。 The cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer. , Esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis 143, which comprises at least one selected from the group consisting of embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. The method according to any one of 148.
  150. 　前記がんが、大腸がんである、請求項１４９に記載の方法。 The method according to claim 149, wherein the cancer is colorectal cancer.
  151. 　前記大腸がんが、盲腸がん、結腸がん、直腸がん、及び肛門がんからなる群より選択される少なくとも一つを含む、請求項１５０に記載の方法。 The method according to claim 150, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  152. 　前記がんが、潰瘍性大腸炎における腸炎関連性がんである、請求項１４３～１５１のいずれか一項に記載の方法。 The method according to any one of claims 143 to 151, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  153. 　前記エンハンサーが、レグネース１の活性を増強するものである、請求項１４３～１５２のいずれか一項に記載の方法。 The method according to any one of claims 143 to 152, wherein the enhancer enhances the activity of Legnes 1.
  154. 　前記エンハンサーが、レグネース１分解酵素を阻害するものである、請求項１４３～１５３のいずれか一項に記載の方法。 The method according to any one of claims 143 to 153, wherein the enhancer inhibits a legnes monodegrading enzyme.
  155. 　前記レグネース１分解酵素が、レグネース１リン酸化酵素、又はレグネース１ユビキチン化酵素である、請求項１５４に記載の方法。 The method according to claim 154, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  156. 　前記エンハンサーが、Ｅ３リガーゼ阻害活性を有する、請求項１４３～１５５のいずれか一項に記載の方法。 The method according to any one of claims 143 to 155, wherein the enhancer has an E3 ligase inhibitory activity.
  157. 　前記エンハンサーが、核酸、抗体、低分子化合物、又は高分子化合物である、請求項１４３～１５６のいずれか一項に記載の方法。 The method according to any one of claims 143 to 156, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  158. 　前記エンハンサーが、核酸である、請求項１５７に記載の方法。 The method according to claim 157, wherein the enhancer is a nucleic acid.
  159. 　前記エンハンサーが、抗体である、請求項１５７に記載の方法。 The method according to claim 157, wherein the enhancer is an antibody.
  160. 　前記エンハンサーが、低分子化合物である、請求項１５７に記載の方法。 The method according to claim 157, wherein the enhancer is a low molecular weight compound.
  161. 　前記低分子化合物が、４－（３－ベンジル－４－（５－（２－フルオローフェニル）－フラン－２－イルメチレン）－５－オキソ－４，５－ジヒドロピラゾール－１－イル）－安息香酸（ＧＳ１４３）である、請求項１６０に記載の方法。 The low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl) -benzoic acid. The method of claim 160, which is an acid (GS143).
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