WO2023276869A1 - Procédé de prédiction d'un pronostic après traitement avec un inhibiteur d'angiogenèse, et multithérapie anticancéreuse - Google Patents

Procédé de prédiction d'un pronostic après traitement avec un inhibiteur d'angiogenèse, et multithérapie anticancéreuse Download PDF

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WO2023276869A1
WO2023276869A1 PCT/JP2022/025259 JP2022025259W WO2023276869A1 WO 2023276869 A1 WO2023276869 A1 WO 2023276869A1 JP 2022025259 W JP2022025259 W JP 2022025259W WO 2023276869 A1 WO2023276869 A1 WO 2023276869A1
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igfbp
inhibitor
treatment
cancer
angiogenesis
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Japanese (ja)
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浩之 鈴木
英希 岩本
浩徳 古賀
拓司 鳥村
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学校法人 久留米大学
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/6851—Quantitative amplification
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer

Definitions

  • Cancer especially solid tumors, require angiogenesis for their development and growth.
  • angiogenesis inhibitors drugs that target them, ie, angiogenesis inhibitors.
  • anti-angiogenic drugs have brought beneficial results to many cancer patients, their maximum contribution has not been achieved due to problems such as the lack of biomarkers that are effective in predicting therapeutic effects and drug resistance. is.
  • One object of the present disclosure is to provide biomarkers, methods, compositions, and kits for predicting prognosis after treatment with angiogenesis inhibitors.
  • a further object of the present disclosure is to provide pharmaceutical compositions, kits and methods for treating cancer.
  • the present disclosure in one aspect, relates to biomarkers, including IGFBP-1, for predicting the prognosis of a subject with cancer following treatment with an angiogenesis inhibitor.
  • the present disclosure provides, in one aspect, a method for predicting the prognosis of a subject with cancer after treatment with an angiogenesis drug, comprising: IGFBP- after treatment with an angiogenesis drug in a sample obtained from said subject; 1 relates to a method comprising measuring a quantity.
  • the present disclosure in one aspect, relates to a composition comprising an IGFBP-1 detection reagent for predicting the prognosis of a subject with cancer after treatment with an angiogenesis inhibitor.
  • the present disclosure in one aspect, relates to a kit comprising an IGFBP-1 detection reagent for predicting the prognosis of a subject with cancer following treatment with an angiogenesis inhibitor.
  • the present disclosure provides, in one aspect, a pharmaceutical composition for treating cancer comprising: including angiogenesis inhibitors, combined with IGFBP-1 inhibitors, including an IGFBP-1 inhibitor combined with an angiogenesis inhibitor, or an angiogenesis inhibitor and an IGFBP-1 inhibitor; It relates to pharmaceutical compositions.
  • the present disclosure relates to a kit for treating cancer, the kit comprising a composition comprising an angiogenesis inhibitor and a composition comprising an IGFBP-1 inhibitor.
  • the present disclosure in one aspect, relates to a method for treating cancer comprising administering an angiogenesis inhibitor and an IGFBP-1 inhibitor to a subject in need of treatment.
  • the present disclosure provides biomarkers, methods, compositions, and kits for predicting prognosis after treatment with angiogenesis inhibitors. Additionally, the present disclosure provides pharmaceutical compositions, kits, and methods for treating cancer.
  • Figure 1 shows the CT values (top) and serum IGFBP-1 levels (ng/ml) (bottom) before and one month after lenvatinib treatment in 31 cases of advanced hepatocellular carcinoma.
  • Pre LEN indicates results before lenvatinib treatment
  • Post LEN indicates results after lenvatinib treatment.
  • Student's t-test **: p ⁇ 0.01.
  • comparisons between two groups were analyzed by Student's t-test, and comparisons between three or more groups were analyzed using one-way ANOVA.
  • * indicates p ⁇ 0.05
  • ** indicates p ⁇ 0.01.
  • FIG. 2 shows the correlation (Pearson correlation coefficient) between the rate of change in serum IGFBP-1 value and the rate of change in CT value in lenvatinib treatment.
  • Figure 3 shows the correlation between the serum IGFBP-1 level before lenvatinib treatment (top), the serum IGFBP-1 level after treatment (middle), or the rate of change in IGFBP-1 before and after treatment (bottom) and survival time (Log -rank test).
  • FIG. 4 shows changes in tumor volume over time (left), gross observations of tumors (middle), and tumor weights (right) in hepatocellular carcinoma model mice administered with lenvatinib or sorafenib (day 14 of administration).
  • FIG. 5 shows serum IGFBP-1 levels (left) in hepatocellular carcinoma model mice administered with lenvatinib or sorafenib, and IGFBP-1 mRNA expression (middle) and protein expression (right) in tumors.
  • FIG. 6 shows the expression of IGFBP-1, CD31, and CA9 in tumor tissues of hepatocellular carcinoma model mice administered with lenvatinib or sorafenib.
  • FIG. 7 shows the expression of IGFBP-1 and CD31 in the liver of hepatocellular carcinoma model mice to which lenvatinib was administered.
  • the photograph on the left shows the results of immunostaining, and the graph on the right shows IGFBP-1-positive signal (%) per field of view (top) and the number of CD31-positive cells (bottom).
  • FIG. 8 shows the expression of IGFBP-1 mRNA in Hep-55.1C cells after administration of lenvatinib.
  • FIG. 9 shows IGFBP-1 mRNA (top) and protein (bottom) expression in Hep-55.1C cells cultured under normoxia or hypoxia conditions.
  • Figure 10 shows proliferation of HuH7 cells (left) or HepG2 cells (right) cultured for 48 hours in the presence of IGFBP-1 (0, 250, 500 ng/ml).
  • FIG. 11 shows vascular endothelial cell proliferation (top) and tube formation (bottom) in the presence of IGFBP-1.
  • FIG. 12 shows vascular endothelial cell proliferation (top) and tube formation (bottom) in the presence of lenvatinib and IGFBP-1.
  • FIG. 13 shows tube formation in the presence of an angiogenesis inhibitor selected from lenvatinib, sorafenib, a VEGFR inhibitor, or a FGFR inhibitor and IGFBP-1.
  • FIG. 14 shows the expression of IGFBP-1, HIF-1 ⁇ , and HIF-2 ⁇ in Hep-55.1C cells under normoxia and hypoxia conditions, and the expression of the HIF inhibitor YC-1 against this. show action.
  • FIG. 15 shows the expression of IGFBP-1, HIF-1 ⁇ , and HIF-2 ⁇ in HuH7 cells under normoxia and hypoxia conditions, and the effect of the HIF inhibitor YC-1 on this. .
  • FIG. 16 shows the expression of IGFBP-1, HIF-1 ⁇ , and HIF-2 ⁇ in HepG2 cells under normoxia and hypoxia conditions, and the effect of the HIF inhibitor YC-1 on this.
  • Figure 17 shows phosphorylation of FAK and ERK-1/2 by IGFBP-1 in HUVEC cells.
  • FIG. 18 shows HUVEC cell proliferation by IGFBP-1 in the presence of integrin ⁇ 5 ⁇ 1 inhibitor (left) or FAK inhibitor (right).
  • FIG. 19 shows tube formation by IGFBP-1 in the presence of integrin ⁇ 5 ⁇ 1 inhibitors or FAK inhibitors.
  • Figure 20 shows macroscopic tumor findings (upper) and tumor weight (lower left) after administration of lenvatinib (day 14) and changes in tumor volume over time (right) in hepatocellular carcinoma model mice implanted with IGFBP-1-deficient HuH7 cells. below).
  • IGFBP-1-KD indicates IGFBP-1 deficient tumors.
  • Figure 21 shows gross observations of tumors (upper) and tumor weights (lower left) after administration of lenvatinib (day 14) and changes in tumor volume over time (right) in hepatocellular carcinoma model mice implanted with IGFBP-1-deficient HepG2 cells. below).
  • IGFBP-1-KD indicates IGFBP-1 deficient tumors.
  • Figure 22 shows macroscopic findings (upper) and tumor weight (lower left) of tumors (day 14) and tumor volume over time after administration of lenvatinib, anti-IGFBP-1 antibody, or a combination thereof in hepatocellular carcinoma model mice. Changes (lower right) are shown.
  • FIG. 23 shows changes in tumor volume over time after administration of lenvatinib, an integrin ⁇ 5/ ⁇ 1 inhibitor, or a combination thereof in hepatocellular carcinoma model mice.
  • the present disclosure provides, in one aspect, a method for predicting the prognosis of a subject with cancer after treatment with an angiogenesis drug, comprising: IGFBP- after treatment with an angiogenesis drug in a sample obtained from said subject; 1 relates to a method comprising measuring a quantity.
  • IGFBP1 Insulin-like Growth Factor Binding Protein 1 binds to insulin-like growth factors (IGFs) (particularly IGF-I and IGF-II) and regulates their activity and distribution. It is a secretory protein known to IGFBP1 is also known to bind to integrin ⁇ 5/ ⁇ 1 on the cell membrane via its RGD (Arg-Gly-Asp) domain.
  • the Genbank Gene ID of human IGFBP1 is 3484, the amino acid sequence is disclosed in Genbank Accession No. NP_000587, and the mRNA sequence is disclosed in Genbank Accession No. NM_000596, respectively.
  • sample is, but is not limited to, for example, a blood sample or a cancer cell or cancer tissue sample.
  • Blood samples include whole blood, plasma and serum.
  • sample obtained from a subject is used in the sense of including a sample obtained from a subject that has undergone processing necessary for measurement, such as separation or concentration of proteins or nucleic acids, freezing, or fixation. Collection and subsequent processing of samples from subjects can be carried out as appropriate by those skilled in the art.
  • the sample is serum.
  • the subject is a mammal. Mammals include, for example, mice, rats, rabbits, cats, dogs, sheep, pigs, horses, cows, monkeys, and humans. In one embodiment, the subject is human.
  • the sample is obtained from the subject after treatment with an anti-angiogenic drug.
  • the sample may be, for example, 1-6 months, 1-3 months (eg, 1, 2, or 3 months), 1-5 weeks (eg, 1, 2, 3, 4, or 5 weeks), or 1 Obtained after ⁇ 7 days (eg, 1, 2, 3, 4, 5, 6, or 7 days) of treatment with an angiogenesis inhibitor.
  • Samples may be obtained at multiple time points after initiation of treatment. In one embodiment, the sample is obtained after one month of anti-angiogenic drug treatment. Additionally, a pre-treatment sample with an anti-angiogenic drug may also be obtained. In one embodiment, the sample is obtained prior to anti-angiogenic drug treatment and after one month of anti-angiogenic drug treatment.
  • the amount of IGFBP-1 can be the amount of IGFBP-1 protein or mRNA.
  • the amount of IGFBP-1 can be determined by using a substance that specifically binds to IGFBP-1 (e.g., antibody, aptamer (e.g., DNA aptamer, RNA aptamer, peptide aptamer)), or by using the nucleic acid sequence of IGFBP-1.
  • IGFBP-1-specific primers or probes e.g., primers that specifically amplify IGFBP-1 mRNA or cDNA, probes that specifically bind to IGFBP-1 mRNA or cDNA
  • the amount of IGFBP-1 is measured using an anti-IGFBP-1 antibody.
  • a person skilled in the art can appropriately prepare the aforementioned antibodies, aptamers, primers and probes based on the amino acid and nucleic acid sequences of IGFBP-1.
  • Measurement methods include ELISA (Enzyme-Linked Immunosorbent Assay), EIA (Enzyme Immuno Assay), RIA (Radioimmunoassay), immunological assays such as Western blot and dot blot, quantitative PCR, and mass spectrometry.
  • ELISA Enzyme-Linked Immunosorbent Assay
  • EIA Enzyme Immuno Assay
  • RIA Radioimmunoassay
  • immunological assays such as Western blot and dot blot, quantitative PCR, and mass spectrometry.
  • a person skilled in the art can appropriately process the sample obtained from the subject according to the measurement method.
  • the amount of IGFBP-1 after treatment with angiogenesis inhibitors or the rate of change in the amount of IGFBP-1 before and after treatment correlates with the prognosis of the subject, and the higher the amount of IGFBP-1 after treatment or the amount of IGFBP-1 before treatment The greater the post-treatment increase in IGFBP-1 levels, the worse the prognosis. Therefore, prognosis can be predicted by measuring the amount of IGFBP-1 after treatment with angiogenesis inhibitors.
  • prognosis means the medical outlook for the course of a subject with cancer after treatment with an angiogenesis inhibitor or the subject's life expectancy.
  • the prognostic prediction is prediction of overall survival or progression-free survival. Poor prognosis can mean short overall or progression-free survival, and good prognosis can mean long overall or progression-free survival.
  • the method of the present disclosure includes comparing the amount of IGFBP-1 after treatment with an anti-angiogenic drug to a reference value.
  • the reference value separates a group of subjects with cancer after treatment with an angiogenesis inhibitor into a group with a good prognosis after treatment and a group with a poor prognosis with a statistically significant difference.
  • the reference value should be a percentage (e.g., 10%, 20%, 30%, 40%, or 50%) that separates the top IGFBP-1 levels for each subject in the subject group after treatment with an angiogenesis inhibitor. can be any value.
  • the subject is predicted to have a poor prognosis after treatment with an anti-angiogenic drug if the amount of IGFBP-1 after treatment with an anti-angiogenic drug is greater than or equal to the reference value or is higher than the reference value. be. In one embodiment, the subject is predicted to have a favorable prognosis after treatment with an anti-angiogenic drug if the amount of IGFBP-1 following treatment with an anti-angiogenic drug is less than or equal to the reference value or is lower than the reference value. be done. In one embodiment, the reference value is a value within the range of 30000 ng/mL to 60000 ng/ml or 40000 ng/mL to 50000 ng/ml.
  • the methods of the present disclosure comprise comparing the percent change in IGFBP-1 amount after anti-angiogenic drug treatment to IGFBP-1 amount before treatment with a reference value.
  • the reference value separates a group of subjects with cancer after treatment with an angiogenesis inhibitor into a group with a good prognosis after treatment and a group with a poor prognosis with a statistically significant difference.
  • can be the rate of change in the amount of IGFBP-1 that can be Statistical significance may be analyzed by any test method. Test methods include, for example, log-rank test.
  • the reference value is a constant percentage (e.g., 10%, 20%, 30%, 40%, or 50%) of the top percent change in IGFBP-1 levels for each subject in a group of subjects after treatment with an angiogenesis inhibitor. %) may be used. In one embodiment, the reference value is a value within the range of 1.5-3 or 2-2.5. In one embodiment, the subject is predicted to have a poor prognosis after treatment with an anti-angiogenic drug if the percent change is greater than or equal to the reference value or higher than the reference value. In one embodiment, the subject is predicted to have a favorable prognosis after treatment with an anti-angiogenic drug if the percent change is less than or equal to the reference value or is lower than the reference value.
  • the amount of IGFBP-1 after treatment with angiogenesis inhibitors may be compared with multiple reference values. For example, the prognosis of each subject in the subject group after treatment with an angiogenesis inhibitor is ranked into 3 or more stages, and 2 or more IGFBP-1 amounts that can separate each ranked group with a statistically significant difference Alternatively, its rate of change may be used as a reference value. This can predict the prognostic rank of a subject after treatment with an angiogenesis inhibitor. Statistical significance may be analyzed by any test method. Test methods include, for example, log-rank test.
  • the reference value is a constant percentage from the top of the IGFBP-1 amount or its rate of change for each subject in the subject group after treatment with an angiogenesis inhibitor (e.g., 10%, 20%, 30%, 40%, or 50%) can be separated from each other.
  • an angiogenesis inhibitor e.g., 10%, 20%, 30%, 40%, or 50%
  • IGFBP-1 is expressed in tumors and secreted into the blood by hypoxic stimulation, and IGFBP-1 has been shown to enhance the proliferation and tube formation of vascular endothelial cells. It is suggested to be involved in resistance to drugs that induce ischemia or hypoxia. Therefore, the disclosed methods can be used for prognosis after treatment with angiogenesis inhibitors that induce tumor ischemia or hypoxia.
  • Cancers include liver cancer (including hepatocellular carcinoma and intrahepatic cholangiocarcinoma), esophageal cancer, gastric cancer, small bowel cancer, colon cancer, pancreatic cancer, lung cancer (including non-small cell lung cancer), breast cancer, germ cell cancer, and gallbladder cancer. , head and neck cancer, skin cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, uterine cancer, cervical cancer, ovarian cancer, thyroid cancer, gallbladder cancer, brain tumor, thymic cancer, malignant melanoma, leukemia, myelodysplasia syndrome, multiple myeloma, and malignant lymphoma.
  • the cancer is hepatocellular carcinoma.
  • Angiogenesis inhibitors include VEGF (vascular endothelial growth factor) inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors (inhibitors of one or more of VEGFR-1, VEGFR-2, and VEGFR-3). ), soluble VEGFR, kinase inhibitors, fibroblast growth factor receptor (FGFR) inhibitors (including inhibitors of one or more of FGFR-1, FGFR-2, FGFR-3 and FGFR-4), mTOR ( mammalian target of rapamycin) inhibitors.
  • VEGF inhibitors include anti-VEGF antibodies (eg, bevacizumab, ranibizumab).
  • VEGFR inhibitors include fluquintinib, brivanib and anti-VEGFR antibodies (eg, ramucirumab). Soluble VEGFRs include aflibercept. Kinase inhibitors include lenvatinib, sorafenib, axitinib, sunitinib, pazopanib, regorafenib, cabozantinib. FGFR inhibitors include AZD4547, erdafitinib, pemigatinib, futivatinib, anti-FGFR antibodies (eg, bofatamab). mTOR inhibitors include sirolimus, everolimus, and temsirolimus.
  • the angiogenesis inhibitor is a kinase inhibitor, VEGFR inhibitor, or FGFR inhibitor.
  • the angiogenesis inhibitor is lenvatinib, sorafenib, fluquintinib, or AZD4547.
  • the name of each drug is used in the sense of including its pharmaceutically acceptable salts.
  • lenvatinib includes lenvatinib mesylate and sorafenib includes sorafenib tosylate.
  • the term antibody refers to a molecule comprising an immunoglobulin or a portion thereof that has the ability to bind to an antigen, and includes not only molecules in the form of naturally occurring immunoglobulins, but also chimeric antibodies, humanized antibodies, multispecific It is used in the sense of including molecules with various structures such as antibodies and antibody fragments.
  • the present invention provides biomarkers, including IGFBP-1, for predicting the prognosis of a subject with cancer after treatment with an angiogenesis inhibitor.
  • compositions and kits comprising IGFBP-1 detection reagents for predicting the prognosis of a subject with cancer after treatment with an angiogenesis inhibitor.
  • Compositions and kits can be used to practice the disclosed methods.
  • IGFBP-1 detection reagents include substances that specifically bind to IGFBP-1 (e.g., antibodies, aptamers (e.g., DNA, RNA, or peptide aptamers)), IGFBP-1-specific primers or probes. .
  • the IGFBP-1 detection reagent is an anti-IGFBP-1 antibody.
  • compositions and kits can be compositions and kits for measurements by immunological assays such as ELISA, EIA, RIA, western blot, dot blot, quantitative PCR, mass spectrometry and the like.
  • the kit may contain necessary reagents, controls, buffer solutions, containers, and the like depending on the measurement method.
  • the disclosure provides, in one aspect, combination therapy with an angiogenesis inhibitor and an IGFBP-1 inhibitor in the treatment of cancer.
  • an IGFBP-1 inhibitor means a substance that inhibits signal transduction from IGFBP-1, and can be a low-molecular-weight compound, protein, peptide, nucleic acid, or the like.
  • An IGFBP-1 inhibitor can be a substance that binds to IGFBP-1 or a substance that suppresses the expression of IGFBP-1.
  • the IGFBP-1 inhibitor can be a substance that inhibits the binding of IGFBP-1 to IGF or a substance that inhibits the binding of IGFBP-1 to integrin ⁇ 5/ ⁇ 1.
  • the IGFBP-1 inhibitor is an antibody or aptamer (eg, DNA, RNA, or peptide aptamer).
  • the IGFBP-1 inhibitor is an anti-IGFBP-1 antibody. In one embodiment, the IGFBP-1 inhibitor is an anti-IGFBP-1 antibody that inhibits binding of IGFBP-1 to integrin ⁇ 5/ ⁇ 1.
  • An anti-IGFBP-1 antibody can be appropriately produced by a person skilled in the art by a conventional method.
  • the IGFBP-1 inhibitor is a peptide comprising the amino acid sequence RGD (referred to as the RGD peptide) that inhibits binding to integrin ⁇ 5/ ⁇ 1 through the RGD domain.
  • RGD peptides include GRGDNP (CAS: 114681-65-1) (SEQ ID NO: 1) and RGD (CAS: 99896-85-2).
  • angiogenesis inhibitor the angiogenesis inhibitors exemplified herein can be used.
  • a pharmaceutical composition can be formulated by a conventional method.
  • Pharmaceutical compositions contain, in addition to the active ingredient, pharmaceutically acceptable agents such as sterile water, saline, stabilizers, excipients, antioxidants, buffers, preservatives, surfactants, chelating agents, binders, and the like. carriers or additives used. Dosage forms include tablets, powders, granules, capsules, pills, liquids, syrups, suspensions, emulsions, suppositories, injections and the like.
  • the dosage, administration schedule and administration method of angiogenesis inhibitors and IGFBP-1 inhibitors can be appropriately determined by those skilled in the art based on factors such as the characteristics of the inhibitors, the target cancer type, age, body weight and condition. can.
  • the angiogenesis inhibitor is sorafenib, 200 to 400 mg once to several times a day (e.g., 1, 2, 3, or 4 times) for consecutive days, or for several days (2, 3, or every 4 days).
  • the angiogenesis inhibitor is lenvatinib, 4 to 24 mg (e.g., 8, 12, or 24 mg) once to several times a day (e.g., 1, 2, 3, or 4 times) on consecutive days , or every few days (2, 3, or 4 days).
  • IGFBP-1 inhibitor is an anti-IGFBP-1 antibody, 10 ⁇ g/kg to 100 mg/kg, 100 ⁇ g/kg to 10 mg/kg, or 1 mg/kg to 10 mg/kg daily , or every few days (2, 3, or 4 days).
  • Administration methods include oral administration and parenteral administration, and parenteral administration includes subcutaneous administration, intradermal administration, intramuscular administration, intravenous administration, and the like.
  • using an angiogenesis inhibitor and an IGFBP-1 inhibitor in combination means using them to treat the same subject at the same time.
  • the dosing schedules of the angiogenesis inhibitor and IGFBP-1 inhibitor may be the same or different.
  • the angiogenesis inhibitor and the IGFBP-1 inhibitor may be contained in the same composition or may be contained in different compositions, and the composition containing the angiogenesis inhibitor and the IGFBP-1 inhibitor are combined. may be provided as a kit in combination with the composition comprising.
  • the disclosure provides a method for treating cancer comprising administering an angiogenesis inhibitor and an IGFBP-1 inhibitor to a subject in need thereof.
  • the present disclosure provides an angiogenesis inhibitor for use in treating cancer, wherein the angiogenesis inhibitor is used in combination with an IGFBP-1 inhibitor; An IGFBP-1 inhibitor in combination with an angiogenesis inhibitor; and a combination of an angiogenesis inhibitor and an IGFBP-1 inhibitor for use in treating cancer.
  • the present disclosure is the use of an angiogenesis inhibitor for the manufacture of a medicament for use in treating cancer, wherein said angiogenesis inhibitor is combined with an IGFBP-1 inhibitor; use of an IGFBP-1 inhibitor for the manufacture of a medicament for use in the treatment of use of a combination of an angiogenesis inhibitor and an IGFBP-1 inhibitor for the manufacture of
  • a method for predicting the prognosis of a subject with cancer following treatment with an anti-angiogenic drug comprising measuring the amount of IGFBP-1 after treatment with an anti-angiogenic drug in a sample obtained from said subject. ,Method.
  • [2] 2. The method of 1, wherein the sample is a blood sample.
  • [3] 3. The method according to 2 above, wherein the blood sample is serum.
  • [4] 4. The method according to any one of 1 to 3 above, wherein the cancer is hepatocellular carcinoma.
  • the method of any one of 1 to 4 further comprising comparing said post-treatment IGFBP-1 amount to a reference value.
  • angiogenesis inhibitor is a VEGF inhibitor, VEGFR inhibitor, soluble VEGFR, kinase inhibitor, FGFR inhibitor, or mTOR inhibitor.
  • angiogenesis inhibitor is sorafenib, lenvatinib, fluquintinib, or AZD4547.
  • Biomarkers to predict prognosis after treatment with anti-angiogenic drugs in subjects with cancer including IGFBP-1.
  • a composition comprising an IGFBP-1 detection reagent for predicting the prognosis of a subject with cancer after treatment with an angiogenesis inhibitor.
  • the IGFBP-1 detection reagent is an antibody, aptamer, primer or probe.
  • the IGFBP-1 detection reagent is an anti-IGFBP-1 antibody.
  • a kit comprising an IGFBP-1 detection reagent for predicting the prognosis of a subject with cancer after treatment with an anti-angiogenic drug.
  • the IGFBP-1 detection reagent is an antibody, aptamer, primer or probe.
  • the IGFBP-1 detection reagent is an anti-IGFBP-1 antibody.
  • a pharmaceutical composition for treating cancer comprising: including angiogenesis inhibitors, combined with IGFBP-1 inhibitors, including an IGFBP-1 inhibitor combined with an angiogenesis inhibitor, or an angiogenesis inhibitor and an IGFBP-1 inhibitor; pharmaceutical composition.
  • the pharmaceutical composition according to 19 above which comprises an angiogenesis inhibitor and is used in combination with an IGFBP-1 inhibitor.
  • the pharmaceutical composition according to 19 above which comprises an IGFBP-1 inhibitor and is used in combination with an angiogenesis inhibitor.
  • the pharmaceutical composition according to any one of 19 to 22 above, wherein the angiogenesis inhibitor is a VEGF inhibitor, VEGFR inhibitor, soluble VEGFR, kinase inhibitor, FGFR inhibitor, or mTOR inhibitor.
  • the angiogenesis inhibitor is sorafenib, lenvatinib, fluquintinib, or AZD4547.
  • the IGFBP-1 inhibitor is a substance that inhibits the binding of IGFBP-1 to integrin ⁇ 5/ ⁇ 1.
  • the IGFBP-1 inhibitor is an anti-IGFBP-1 antibody.
  • the cancer is hepatocellular carcinoma.
  • kits for treating cancer comprising a composition comprising an angiogenesis inhibitor and a composition comprising an IGFBP-1 inhibitor.
  • a method for treating cancer comprising administering an angiogenesis inhibitor and an IGFBP-1 inhibitor to a subject in need thereof.
  • the angiogenesis inhibitor is a VEGF inhibitor, VEGFR inhibitor, soluble VEGFR, kinase inhibitor, FGFR inhibitor, or mTOR inhibitor.
  • the angiogenesis inhibitor is sorafenib, lenvatinib, fluquintinib, or AZD4547.
  • the IGFBP-1 inhibitor is a substance that inhibits the binding of IGFBP-1 to integrin ⁇ 5/ ⁇ 1.
  • the IGFBP-1 inhibitor is an anti-IGFBP-1 antibody.
  • 34 The method according to any one of 29 to 33 above, wherein the cancer is hepatocellular carcinoma.
  • case 31 had contrast-enhanced CT taken 1 month before and after treatment. Selected examples.
  • changes in 55 angiogenesis-related proteins were comprehensively searched using the Angiogenesis Assay Kit (R&D Systems). As a result, IGFBP-1 was identified as a protein with high expression intensity and a large rate of change before and after lenvatinib treatment.
  • the CT value of the tumor before and after treatment was obtained, and the rate of change in CT value was calculated as follows. CT values were average values of three different regions.
  • Pre-CT value a/b (Tumor/Aorta) a: CT value of tumor before treatment b: CT value of aorta before treatment
  • Post CT value c/d (Tumor/Aorta)
  • c CT value of tumor after treatment
  • d CT value of aorta after treatment
  • Rate of change in CT value post-CT value / pre-CT value
  • the survival times of the 31 cases were stratified by the serum IGFBP-1 level before lenvatinib treatment, the serum IGFBP-1 level after treatment, or the rate of change in IGFBP-1 before and after treatment. Both were divided into two groups by median value (before treatment: 22006 ng/mL, after treatment: 44081 ng/mL, rate of change: 2.05). It was found that cases with high IGFBP-1 levels after lenvatinib treatment and cases with large increases in IGFBP-1 levels after lenvatinib treatment had a worse prognosis (Fig. 3).
  • hepatocellular carcinoma cell line (Hep-55.1C) (5 ⁇ 10 6 cells) was subcutaneously inoculated into the dorsal side of C57BL/6 mice to prepare hepatocellular carcinoma model mice. After administering lenvatinib (10 mg/kg/day) or sorafenib (30 mg/kg/day) to this model mouse for 14 days, tumors were excised and measured. Serum IGFBP-1 was assessed by ELISA, and IGFBP-1 mRNA and protein expression in tumors by qPCR and Western blotting, respectively.
  • lenvatinib and sorafenib reduced tumor volume and weight and inhibited tumor growth (Fig. 4). It was also shown that administration of lenvatinib and sorafenib increased serum IGFBP-1, and furthermore, IGFBP-1 expression in tumors was increased at the gene and protein levels (Fig. 5).
  • IGFBP-1 is an angiogenic marker
  • CA9 is a hypoxic marker for hepatocellular carcinoma.
  • Administration of lenvatinib or sorafenib decreased the expression of CD31 and increased the expression of CA9, indicating that the administration of lenvatinib decreased blood vessels in the tumor and created a hypoxic environment (Fig. 6).
  • the liver which is the main production site of IGFBP-1, no increase in IGFBP-1 was observed after administration of lenvatinib (Fig. 7). It was suggested that IGFBP-1, which is elevated by intratumoral hypoxia, may be involved in resistance to lenvatinib or sorafenib.
  • Hep-55.1C cells were cultured for 24 hours in the presence of lenvatinib (0-10 ⁇ M) (normal oxygen). Expression of IGFBP-1 was then assessed by qPCR. Expression of mRNA was normalized by expression of GAPDH. No increase in IGFBP-1 was observed in Hep-55.1C cells due to lenvatinib administration (Fig. 8).
  • Hep-55.1C cells were cultured under normoxic (20% O 2 ) or hypoxic (2% O 2 ) conditions for 24 hours and the expression of IGFBP-1 was assessed by qPCR and Western blotting. mRNA and protein expression were normalized by expression of ⁇ -actin (ATCB) or GAPDH. Hypoxic stimulation increased the expression of IGFBP-1 at the gene and protein levels in Hep-55.1C cells (Fig. 9).
  • IGFBP-1 (0, 250, 500 ng/ml ) for 48 h and the growth rate was assessed. Cell proliferation was assessed using the MTT assay. Direct application of IGFBP-1 to cancer cells did not increase cell proliferation (Fig. 10).
  • human vascular endothelial cells 1 ⁇ 10 3 cells were cultured in the presence of IGFBP-1 (0, 100, 250 ng/ml) for 48 hours and then proliferated. Evaluated speed. In the presence of IGFBP-1 (0, 100, 250 ng/ml), tube formation ability of HUVEC was similarly evaluated using tube formation assay.
  • IGFBP-1 was shown to enhance vascular endothelial cell proliferation and tube formation (Fig. 11). In addition, IGFBP-1 was shown to enhance vascular endothelial cell proliferation and tube formation even in the presence of lenvatinib (Fig. 12).
  • IGFBP-1 vascular endothelial cell proliferation and tube formation in the presence of angiogenesis inhibitors other than lenvatinib. selected from lenvatinib (3 ⁇ M), sorafenib (3 ⁇ M), VEGFR-1,2,3 inhibitor (fluquintinib) (1 ⁇ M), and FGFR-1,2,3 inhibitor (AZD4547) (1 ⁇ M)
  • angiogenesis inhibitors other than lenvatinib. selected from lenvatinib (3 ⁇ M), sorafenib (3 ⁇ M), VEGFR-1,2,3 inhibitor (fluquintinib) (1 ⁇ M), and FGFR-1,2,3 inhibitor (AZD4547) (1 ⁇ M)
  • Tube formation assays were performed as described above in the presence of angiogenesis inhibitors and IGFBP-1 (250 ng/ml). IGFBP-1 was shown to enhance angiogenesis in the presence of any angiogenesis inhibitor (Fig. 13).
  • IGFBP-1 The expression of IGFBP-1 was increased by hypoxic stimulation, and this increase was suppressed by the addition of YC-1 (Figs. 14-16). This suggests that the expression of IGFBP-1 is increased by hypoxic stimuli, particularly by signaling pathways mediated by HIF-1 ⁇ and HIF-2 ⁇ .
  • IGFBP-1 insulin-like protein-1
  • vascular endothelial cell proliferation and tube formation After serum-free culture of HUVEC (1 ⁇ 10 5 cells) for 12 hours, IGFBP-1 (250 ng/ml) was added, and phosphorylation of FAK and ERK-1/2 was evaluated after 5 and 15 minutes. did. Expression of each protein was normalized by expression of GAPDH.
  • HUVEC (5 ⁇ 10 3 cells) were treated with integrin ⁇ 5/ ⁇ 1 inhibitor (ATN-161) at various concentrations (0, 1, 3, 10 ⁇ M) in the presence of IGFBP-1 (250 ng/ml) ( CAS No: 262438-43-7) or FAK inhibitor 14 (CAS No: 4506-66-5), cultured for 48 hours in the presence or absence, and performed a proliferation assay using the MTT assay. did.
  • HUVEC (1 ⁇ 10 3 cells) were cultured in the presence of IGFBP-1 (250 ng/ml) and integrin ⁇ 5/ ⁇ 1 inhibitor (3 ⁇ M) or FAK inhibitor (10 ⁇ M) to promote tube formation. An assay was performed.
  • IGFBP-1 enhanced the phosphorylation of FAK and ERK-1/2 (Fig. 17).
  • integrin ⁇ 5 ⁇ 1 inhibitors and FAK inhibitors suppressed IGFBP-1-induced enhancement of vascular endothelial cell proliferation and tube formation (FIGS. 18 and 19).
  • IGFBP-1 was suggested to promote vascular endothelial cell proliferation and angiogenesis through signaling through integrin ⁇ 5/ ⁇ 1 - FAK - ERK.
  • IGFBP-1 was deficient in HuH7 cells or HepG2 cells, and these IGFBP-1 deficient cells (5 ⁇ 10 6 cells) or GFP-expressing cells as a control were subcutaneously inoculated into the dorsal side of Balb/c mice to form a hepatocellular carcinoma model. I made a mouse. Tumors were excised and measured after 14 days of administration of lenvatinib (10 mg/kg/day).
  • IGFBP-1-deficient tumors showed stronger growth suppression by lenvatinib than control tumors (Figs. 20 and 21). Deletion of IGFBP-1 expression was shown to increase sensitivity to lenvatinib.
  • HepG2 cells were transplanted into Balb/c mice as described above, and lenvatinib (10 mg/kg/day) alone, anti-IGFBP-1 antibody (IGFBP1 Monoclonal Antibody; ThermoFisher Catalog # MA5-23727) (0.03 mg/ kg/day) alone or in combination for 14 days, tumors were excised and measured.
  • lenvatinib 10 mg/kg/day
  • anti-IGFBP-1 antibody IGFBP1 Monoclonal Antibody; ThermoFisher Catalog # MA5-23727
  • lenvatinib or anti-IGFBP-1 antibody alone did not significantly suppress tumor growth, but when used in combination, tumor growth was significantly suppressed (Fig. 22). It was shown that the combined use of lenvatinib and anti-IGFBP-1 antibody enhanced the antitumor effect.
  • lenvatinib or integrin ⁇ 5/ ⁇ 1 inhibitor alone did not significantly suppress tumor growth, but their combined use significantly suppressed tumor growth (Fig. 23).
  • Combined use of lenvatinib and an integrin ⁇ 5/ ⁇ 1 inhibitor was shown to enhance the antitumor effect.

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Abstract

La présente invention comprend : un biomarqueur servant à prédire le pronostic d'un patient atteint d'un cancer contenant IGFBP-1 après traitement du patient avec un inhibiteur d'angiogenèse ; un procédé de prédiction du pronostic d'un patient atteint d'un cancer après traitement du patient avec un inhibiteur d'angiogenèse, le procédé comprenant la mesure de la quantité d'IGFBP-1 dans un échantillon provenant du patient après le traitement avec l'inhibiteur d'angiogenèse ; une composition et un kit, chacun contenant un réactif de détection d'IGFBP-1 et étant utilisé pour la prédiction du pronostic d'un patient atteint d'un cancer après un traitement du patient avec un inhibiteur d'angiogenèse ; une composition pharmaceutique, un kit et un procédé, chacun étant utilisé pour le traitement d'un cancer, et dans chacun desquels un inhibiteur d'angiogenèse et un inhibiteur d'IGFBP-1 sont utilisés en combinaison ; et d'autres caractéristiques.
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