WO2016201365A2 - Procédés pour le traitement de cancers - Google Patents

Procédés pour le traitement de cancers Download PDF

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Publication number
WO2016201365A2
WO2016201365A2 PCT/US2016/037078 US2016037078W WO2016201365A2 WO 2016201365 A2 WO2016201365 A2 WO 2016201365A2 US 2016037078 W US2016037078 W US 2016037078W WO 2016201365 A2 WO2016201365 A2 WO 2016201365A2
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Prior art keywords
cancer
expression profile
profile comprises
genes
expression
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PCT/US2016/037078
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English (en)
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WO2016201365A3 (fr
Inventor
Giuseppe VISANI
Pier Paolo PICCALUGA
Alessandro ISIDORI
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Visani Giuseppe
Piccaluga Pier Paolo
Isidori Alessandro
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Publication of WO2016201365A2 publication Critical patent/WO2016201365A2/fr
Publication of WO2016201365A3 publication Critical patent/WO2016201365A3/fr

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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • 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
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the methods described herein relate to treating cancer, such as hematological cancers, in a subject comprising administering of tosedostat either alone or in combination with another anti-cancer agent following the performance of gene expression profiling to determine appropriate treatment for the subject who has the cancer.
  • a drug may be combined with another anti-cancer therapy, which may be a small molecule compound, antibody or other biological molecule, or radiation, to improve patient outcomes.
  • methods for treating a cancer comprise requesting or obtaining a gene expression profile analysis of cancer cells contained in a biological sample (e.g., bone marrow or blood or a cell fraction thereof, or a tumor sample) and administering tosedostat when the gene expression profile indicates the likelihood of a clinical response to the treatment.
  • a biological sample e.g., bone marrow or blood or a cell fraction thereof, or a tumor sample
  • tosedostat is administered in combination with a second antineoplastic agent.
  • Embodiment 1 A method for treating a cancer in a subject comprising:
  • Embodiment 2 A method for treating a cancer in a subject comprising: (a) obtaining a biological sample comprising cancer cells from the subject; (b) performing gene expression profiling of the cancer cells, which comprises (i) preparing RNA transcripts, or expression products thereof, (ii) detecting expression level of the RNA transcripts, or expression products thereof, of the genes listed in Table 3 and
  • Table 4 in the cancer cells, (iii) classifying the expression level of the RNA transcripts, or expression products thereof, of the genes to provide a gene expression profile; and (c) administering tosedostat to the subject if the gene expression profile comprises differential expression of at least 3 genes selected from Table 3 and Table 4, wherein the genes listed in Table 1 are up-regulated and the genes listed in Table 2 are down- regulated in the cancer cells.
  • Embodiment 3 The method of Embodiment 1 or Embodiment 2 wherein the gene expression profile comprises differential expression of at least 3 genes selected from CD93, GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX.
  • Embodiment 4 The method of embodiment 3, wherein the 3 genes are CXCL16, CD93 and GRASP.
  • Embodiment 5 The method of Embodiment 1 or Embodiment 2 wherein the gene expression profile comprises differential expression of at least 10 genes selected from Table 3 and Table 4.
  • Embodiment 6 The method of Embodiment 1 or Embodiment 2 wherein the gene expression profile comprises differential expression of CD93, GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11- 428P16.2/ZNF532, SNN, TNFSF8, and VENTX.
  • Embodiment 7 The method of Embodiment 1 or Embodiment 2 wherein the gene expression profile comprises differential expression of at least 20 genes selected from Table 3 and Table 4.
  • Embodiment 8 The method of Embodiment 1 or Embodiment 2 wherein the gene expression profile comprises differential expression of at least 50 genes selected from Table 3 and Table 4.
  • Embodiment 9 The method of Embodiment 1 or Embodiment 2 wherein the gene expression profile comprises differential expression of at least 100 genes selected from Table 3 and Table 4.
  • Embodiment 10 The method of Embodiment 1 or Embodiment 2 wherein the gene expression profile comprises differential expression of at least 150 genes selected from Table 3 and Table 4.
  • Embodiment 11 The method of Embodiment 1 or Embodiment 2 wherein the gene expression profile comprises differential expression of the genes listed in Table 3 and Table 4.
  • Embodiment 12 A method for treating a cancer in a subject comprising: (a) obtaining a gene expression profile of cancer cells in a biological sample from the subject; and (b) administering tosedostat to the subject if the gene expression profile comprises differential expression of at least 3 genes selected from Table 1 and Table 2, wherein the genes listed in Table 1 are up-regulated and the genes listed in Table 2 are down-regulated in the cancer cells.
  • Embodiment 13 A method for treating a cancer in a subject comprising: (a) obtaining a biological sample comprising cancer cells from the subject; (b) performing gene expression profiling of the cancer cells, which comprises (i) preparing RNA transcripts, or expression products thereof, (ii) detecting expression level of the RNA transcripts, or expression products thereof, of the genes listed in Table 1 and Table 2 in the cancer cells, (iii) classifying the expression level of the RNA transcripts, or expression products thereof, of the genes to provide a gene expression profile; and (c) administering tosedostat to the subject if the gene expression profile comprises differential expression of at least 3 genes selected from Table 1 and Table 2, wherein the genes listed in Table 1 are up-regulated and the genes listed in Table 2 are down- regulated in the cancer cells.
  • Embodiment 14 The method of Embodiment 12 or Embodiment 13 wherein the gene expression profile comprises differential expression of at least 3 genes selected from ILIRAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXDl, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, PLOD2, FGF2, and ANPEP.
  • Embodiment 15 The method of Embodiment 12 or Embodiment 13 wherein the gene expression profile comprises differential expression of at least 10 genes selected from Table 1 and Table 2.
  • Embodiment 16 The method of Embodiment 12 or Embodiment 13 wherein the gene expression profile comprises differential expression of ILIRAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXDl, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, PLOD2, FGF2, and ANPEP.
  • Embodiment 17 The method of Embodiment 12 or Embodiment 13 wherein the gene expression profile comprises differential expression of at least 20 genes selected from Table 1 and Table 2.
  • Embodiment 18 The method of Embodiment 12 or Embodiment 13 wherein the gene expression profile comprises differential expression of at least 50 genes selected from Table 1 and Table 2.
  • Embodiment 19 The method of Embodiment 12 or Embodiment 13 wherein the gene expression profile comprises differential expression of at least 100 genes selected from Table 1 and Table 2.
  • Embodiment 20 The method of Embodiment 12 or Embodiment 13 wherein the gene expression profile comprises differential expression of at least 150 genes selected from Table 1 and Table 2.
  • Embodiment 21 The method of Embodiment 12 or Embodiment 13 wherein the gene expression profile comprises differential expression of the genes listed in Table 1 and Table 2.
  • Embodiment 22 The method of any one of Embodiments 1-21 wherein the method further comprises administering at least one additional antineoplastic therapy.
  • Embodiment 23 The method of Embodiment 22, wherein the at least one additional antineoplastic therapy is an alkylating agent, a taxane, a vinca alkaloid, an antimetabolite, an HDAC inhibitor, or a monoclonal antibody.
  • Embodiment 24 The method of Embodiment 23 wherein the at least one additional antineoplastic therapy is an antimetabolite selected from cytarabine, decitabine, capecitabine, 5-fluorouracil, methotrexate, azacytidine, 6-thioguanine, 6-mercaptopurine, arabinosylcytosine, clofarabine, dacarbazine, fludarabine, gemcitabine, and nelarabine.
  • Embodiment 25 The method of Embodiment 24 wherein the antimetabolite is selected from cytarabine, decitabine, and capecitabine.
  • Embodiment 26 The method of Embodiment 23 wherein the antimetabolite is cytarabine.
  • Embodiment 27 The method of Embodiment 23 wherein the at least one additional antineoplastic therapy is a histone deacetylase
  • Embodiment 28 The method of Embodiment 27 wherein the HDAC inhibitor is CHR-3996.
  • Embodiment 29 The method of any one of Embodiments 1-28, wherein the cancer is a hematological cancer.
  • Embodiment 30 The method of Embodiment 29 wherein the hematological cancer is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), multiple myeloma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), Hodgkin lymphoma, non-Hodgkin lymphoma, or hairy cell leukemia.
  • Embodiment 31 The method of Embodiment 29 wherein the hematological cancer is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
  • Embodiment 32 The method of any one of Embodiments 1-28 wherein the cancer is a solid tumor.
  • Embodiment 33 The method of Embodiment 32 wherein the solid tumor is melanoma, prostate cancer, testicular cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, ovarian cancer, Kaposi's sarcoma, skin cancer, squamous cell skin cancer, renal cancer, head cancer, neck cancer, throat cancer, squamous carcinoma that forms on moist mucosal linings, bladder cancer, osteosarcoma, cervical cancer, endometrial cancer, esophageal cancer, liver cancer, kidney cancer, an epithelial cell-derived cancer, and a mesenchymal cell-derived cancer.
  • Embodiment 34 The method of any one of Embodiments 1-33 wherein the biological sample is bone marrow or a cell fraction thereof, blood or a cell fraction thereof, or a tumor sample.
  • Embodiment 35 The method of any one of Embodiments 1- 31 wherein the cancer is a hematological cancer and the biological sample is bone marrow or a cell fraction thereof or blood or a cell fraction thereof.
  • Embodiment 36 An in vitro method for determining the likelihood of a subject who has a cancer responding to a treatment comprising tosedostat, said method comprising (a) detecting expression of genes in cancer cells obtained from the subject; (b) determining the level of expression of the genes in the cancer cells to provide a gene expression profile; and (c) categorizing the subject as a likely responder to the treatment if the gene expression profile comprises differential expression of at least 3 genes selected from Table 1 and Table 2, wherein the genes listed in Table 1 are up-regulated and the genes listed in Table 2 are down-regulated in the cancer cells.
  • Embodiment 37 The method of Embodiment 36, wherein the gene expression profile comprises differential expression of at least 3 genes selected from IL1RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, PLOD2, FGF2, and ANPEP.
  • Embodiment 38 The method of Embodiment 36, wherein the gene expression profile comprises differential expression of at least 10 genes selected from Table 1 and Table 2.
  • Embodiment 39 The method of Embodiment 36, wherein the gene expression profile comprises differential expression oilLlRAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, PLOD2, FGF2, and ANPEP.
  • Embodiment 40 The method of Embodiment 36, wherein the gene expression profile comprises differential expression of at least 20 genes selected from Table 1 and Table 2.
  • Embodiment 41 The method of Embodiment 36, wherein the gene expression profile comprises differential expression of at least 50 genes selected from Table 1 and Table 2.
  • Embodiment 42 The method of Embodiment 36, wherein the gene expression profile comprises differential expression of at least 100 genes selected from Table 1 and Table 2.
  • Embodiment 43 The method of Embodiment 36, wherein the gene expression profile comprises differential expression of at least 150 genes selected from Table 1 and Table 2; or the gene expression profile comprises differential expression of genes listed in Table 1 and Table 2.
  • Embodiment 44 An in vitro method for determining the likelihood of a subject who has a cancer responding to a treatment comprising tosedostat, said method comprising (a) detecting expression of genes in cancer cells obtained from the subject; (b) determining the level of expression of the genes in the cancer cells to provide a gene expression profile; and (c) categorizing the subject as a likely responder to the treatment if the gene expression profile comprises differential expression of at least 3 genes selected from Table 3 and Table 4, wherein the genes listed in Table 3 are up-regulated and the genes listed in Table 4 are down-regulated in the cancer cells.
  • Embodiment 45 The method of Embodiment 44, wherein the gene expression profile comprises differential expression of at least 3 genes selected from CD93, GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX:
  • Embodiment 46 The method of Embodiment 45, wherein the 3 genes are CXCL16, CD93 and GRASP.
  • Embodiment 47 The method of Embodiment 44, wherein the gene expression profile comprises differential expression of at least 10 genes selected from Table 3 and Table 4.
  • Embodiment 48 The method of Embodiment 44, wherein the gene expression profile comprises differential expression of CD93, CD93, GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX.
  • Embodiment 49 The method of Embodiment 44, wherein the gene expression profile comprises differential expression of at least 20 genes selected from Table 3 and Table 4.
  • Embodiment 50 The method of Embodiment 44, wherein the gene expression profile comprises differential expression of at least 50 genes selected from Table 3 and Table 4.
  • Embodiment 51 The method of Embodiment 44, wherein the gene expression profile comprises differential expression of at least 100 genes selected from Table 3 and Table 4.
  • Embodiment 52 The method of Embodiment 44, wherein the gene expression profile comprises differential expression of at least 150 genes selected from Table 3 and Table 4; or the gene expression profile comprises differential expression of genes listed in Table 3 and Table 4.
  • Embodiment 53 The method of any one of Embodiments 36-52 wherein the cancer is a hematological cancer.
  • Embodiment 54 The method of Embodiment 53 wherein the hematological cancer is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), multiple myeloma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), Hodgkin lymphoma, non-Hodgkin lymphoma, or hairy cell leukemia.
  • Embodiment 55 The method of Embodiment 53 wherein the hematological cancer is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
  • Embodiment 56 The method of any one of Embodiments 36-52 wherein the cancer is a solid tumor.
  • Embodiment 57 The method of Embodiment 56 wherein the solid tumor is melanoma, prostate cancer, testicular cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, ovarian cancer, Kaposi's sarcoma, skin cancer, squamous cell skin cancer, renal cancer, head cancer, neck cancer, throat cancer, squamous carcinoma that forms on moist mucosal linings, bladder cancer, osteosarcoma, cervical cancer, endometrial cancer, esophageal cancer, liver cancer, kidney cancer, an epithelial cell-derived cancer, and a mesenchymal cell-derived cancer.
  • Embodiment 58 The method of any one of Embodiments 36-57 wherein the biological sample is bone marrow or a cell fraction thereof, blood or a cell fraction thereof, or a tumor sample.
  • Embodiment 59 The method of any one of Embodiments 36-55 wherein the cancer is a hematological cancer and the biological sample is bone marrow or a cell fraction thereof.
  • Embodiment 60 A method for typing acute myelogenous leukemia (AML) cells, said method comprising determining a gene expression profile of cancer cells obtained from the blood or bone marrow of a subject with AML by detecting expression of at least three genes selected from Table 1 and Table 2.
  • Embodiment 61 The method of Embodiment 60, wherein the gene expression profile comprises detecting expression of at least 10 genes selected from Table 1 and Table 2.
  • Embodiment 62 The method of Embodiment 60, wherein the gene expression profile comprises detecting expression of at least 20, at least 50, at least 100, or at least 150 genes selected from Table 1 and Table 2, or the gene expression profile comprises detecting expression of all genes listed in Table 1 and Table 2.
  • Embodiment 63 The method of Embodiment 60, wherein the gene expression profile comprises detecting expression of the genes, IL1RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, PLOD2, FGF2, and ANPEP.
  • Embodiment 64 A method for typing acute myelogenous leukemia (AML) cells, said method comprising determining a gene expression profile of cancer cells obtained from the blood or bone marrow of a subject with AML by detecting expression of at least three genes selected from Table 3 and Table 4.
  • Embodiment 65 The method of Embodiment 64, wherein the gene expression profile comprises detecting expression of at least 10 genes selected from Table 3 and Table 4.
  • Embodiment 66 The method of Embodiment 64, wherein the gene expression profile comprises detecting expression of at least 20, at least 50, at least 100, or at least 150 genes selected from Table 3 and Table 4, or the gene expression profile comprises detecting expression of all genes listed in Table 3 and Table 4.
  • Embodiment 67 The method of Embodiment 64, wherein the gene expression profile comprises detecting expression of the genes, CD93, GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11- 428P16.2/ZNF532, SNN, TNFSF8, and VENTX.
  • Embodiment 68 The method of Embodiment 64, wherein the gene expression profile comprises detecting expression of the genes CXCL16, CD93 and GRASP.
  • Embodiment 69 A method for treating a cancer in a subject comprising: (a) obtaining a protein expression profile of cancer cells in a biological sample from the subject; and (b) administering tosedostat to the subject if the protein expression profile comprises differential expression of at least 3 proteins, which proteins are encoded by genes selected from Table 1 and Table 2, wherein the genes listed in Table 1 are up- regulated and the genes listed in Table 2 are down-regulated in the cancer cells of the subject who receives tosedostat.
  • Embodiment 70 A method for treating a cancer in a subject comprising: (a) obtaining a biological sample comprising cancer cells from the subject; (b) performing protein expression profiling of the cancer cells, which comprises (i) detecting the expression level of at least 3 proteins in the cancer cells, which proteins are encoded by genes selected from Table 1 and Table 2, and (ii) classifying the expression level of the proteins to provide a protein expression profile; and (c) administering tosedostat to the subject if the protein expression profile comprises differential expression of at least 3 proteins encoded by genes selected from Table 1 and Table 2, wherein the genes listed in Table 1 are up-regulated and the genes listed in Table 2 are down-regulated in the cancer cells.
  • Embodiment 71 The method of Embodiment 69 or Embodiment 70 wherein the protein expression profile comprises differential expression of at least 3 proteins encoded by genes selected from IL1RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A,
  • Embodiment 72 The method of Embodiment 69 or Embodiment 70 wherein the protein expression profile comprises differential expression of at least 10 proteins encoded by genes selected from Table 1 and Table 2.
  • Embodiment 73 The method of Embodiment 69 or Embodiment 70 wherein the protein expression profile comprises differential expression of the proteins encoded by IL1RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, PLOD2, FGF2, and ANPEP.
  • Embodiment 74 The method of Embodiment 69 or Embodiment 70 wherein (a) the protein expression profile comprises differential expression of at least 20 proteins encoded by genes selected from Table 1 and Table 2; (b) the protein expression profile comprises differential expression of at least 50 proteins encoded by genes selected from Table 1 and Table 2; (c) the protein expression profile comprises differential expression of at least 100 proteins encoded by genes selected from Table 1 and Table 2; (d) the protein expression profile comprises differential expression of at least 150 proteins encoded by genes selected from Table 1 and Table 2; or (e) the protein expression profile comprises differential expression of proteins encoded by genes listed in Table 1 and Table 2.
  • Embodiment 75 A method for treating a cancer in a subject comprising: (a) obtaining a protein expression profile of cancer cells in a biological sample from the subject; and (b) administering tosedostat to the subject if the protein expression profile comprises differential expression of at least 3 proteins, which proteins are encoded by genes selected from Table 3 and Table 4, wherein the genes listed in Table 3 are up- regulated and the genes listed in Table 4 are down-regulated in the cancer cells of the subj ect who receives tosedostat.
  • Embodiment 76 A method for treating a cancer in a subject comprising: (a) obtaining a biological sample comprising cancer cells from the subject; (b) performing protein expression profiling of the cancer cells, which comprises (i) detecting the expression level of at least 3 proteins in the cancer cells, which proteins are encoded by genes selected from Table 3 and Table 4, and (ii) classifying the expression level of the proteins to provide a protein expression profile; and (c) administering tosedostat to the subject if the protein expression profile comprises differential expression of at least 3 proteins encoded by genes selected from Table 3 and Table 4, wherein the genes listed in Table 3 are up-regulated and the genes listed in Table 4 are down-regulated in the cancer cells.
  • Embodiment 77 The method of Embodiment 75 or Embodiment 76 wherein the protein expression profile comprises differential expression of at least 3 proteins encoded by genes selected from CD93, GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ZNF532, SNN, TNFSF8, and VENTX.
  • Embodiment 78 The method of Embodiment 77, wherein the genes are selected from CXCL16, CD93 and GRASP.
  • Embodiment 79 The method of Embodiment 75 or Embodiment 76 wherein the protein expression profile comprises differential expression of at least 10 proteins encoded by genes selected from Table 3 and Table 4.
  • Embodiment 80 The method of Embodiment 75 or Embodiment 76 wherein the protein expression profile comprises differential expression of the proteins encoded by CD93, GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX.
  • Embodiment 81 The method of Embodiment 75 or Embodiment 76 wherein (a) the protein expression profile comprises differential expression of at least 20 proteins encoded by genes selected from Table 3 and Table 4; (b) the protein expression profile comprises differential expression of at least 50 proteins encoded by genes selected from Table 3 and Table 4; (c) the protein expression profile comprises differential expression of at least 100 proteins encoded by genes selected from Table 3 and Table 4; (d) the protein expression profile comprises differential expression of at least 150 proteins encoded by genes selected from Table 3 and Table 4; or (e) the protein expression profile comprises differential expression of proteins encoded by genes listed in Table 3 and Table 4.
  • Embodiment 82 The method of any one of Embodiments 69-81 wherein the method further comprises administering at least one additional antineoplastic therapy.
  • Embodiment 83 The method of Embodiment 82, wherein the at least one additional antineoplastic therapy is an alkylating agent, a taxane, a vinca alkaloid, an antimetabolite, an HDAC inhibitor, or a monoclonal antibody.
  • Embodiment 84 The method of Embodiment 83 wherein the at least one additional antineoplastic therapy is an antimetabolite selected from cytarabine, decitabine, capecitabine, 5-fluorouracil, methotrexate, azacytidine, 6-thioguanine, 6-mercaptopurine, arabinosylcytosine, clofarabine, dacarbazine, fludarabine, gemcitabine, and nelarabine.
  • Embodiment 85 The method of Embodiment 83 wherein the antimetabolite is selected from cytarabine, decitabine, and capecitabine.
  • Embodiment 86 method of Embodiment 83 wherein the antimetabolite is cytarabine.
  • Embodiment 87 The method of Embodiment 83 wherein the at least one additional antineoplastic therapy is a histone deacetylase (HDAC) inhibitor.
  • Embodiment 88 The method of Embodiment 87 wherein the HDAC inhibitor is CHR-3996.
  • HDAC histone deacetylase
  • Embodiment 89 The method of any one of Embodiments 69-88, wherein the cancer is a hematological cancer.
  • Embodiment 90 The method of
  • Embodiment 89 wherein the hematological cancer is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), multiple myeloma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), Hodgkin lymphoma, non-Hodgkin lymphoma, or hairy cell leukemia.
  • Embodiment 91 The method of Embodiment 90 wherein the hematological cancer is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
  • Embodiment 92 The method of any one of Embodiments 69-88 wherein the cancer is a solid tumor.
  • Embodiment 93 The method of Embodiment 92 wherein the solid tumor is melanoma, prostate cancer, testicular cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, ovarian cancer, Kaposi's sarcoma, skin cancer, squamous cell skin cancer, renal cancer, head cancer, neck cancer, throat cancer, squamous carcinoma that forms on moist mucosal linings, bladder cancer,
  • osteosarcoma cervical cancer, endometrial cancer, esophageal cancer, liver cancer, kidney cancer, an epithelial cell-derived cancer, and a mesenchymal cell-derived cancer.
  • Embodiment 94 The method of any one of Embodiments 69-93 wherein the biological sample is bone marrow or a cell fraction thereof, blood or a cell fraction thereof, or a tumor sample.
  • Embodiment 95 The method of any one of Embodiments 69-91 wherein the cancer is a hematological cancer and the biological sample is bone marrow or a cell fraction thereof or blood or a cell fraction thereof.
  • Embodiment 96 An in vitro method for determining the likelihood of a subject who has a cancer responding to a treatment comprising tosedostat, said method comprising (a) detecting expression of proteins encoded by genes selected from Table 1 and Table 2 in cancer cells obtained from the subject; (b) determining the level of expression of the proteins in the cancer cells to provide a protein expression profile; and (c) categorizing the subject as a likely responder to the treatment if the protein expression profile comprises differential expression of at least 3 proteins encoded by genes selected from Table 1 and Table 2, wherein the genes listed in Table 1 are up- regulated and the genes listed in Table 2 are down-regulated in the cancer cells.
  • Embodiment 97 The method of Embodiment 96 wherein the protein expression profile comprises differential expression of at least 3 proteins encoded by genes selected from ILl RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, PLOD2, FGF2, and ANPEP.
  • Embodiment 98 The method of Embodiment 96 wherein the protein expression profile comprises differential expression of at least 10 proteins encoded by genes selected from Table 1 and Table 2.
  • Embodiment 99 The method of Embodiment 96 wherein the protein expression profile comprises differential expression of the proteins encoded by ILl RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, PLOD2, FGF2, and ANPEP.
  • Embodiment 100 The method of Embodiment 96 wherein (a) the protein expression profile comprises differential expression of at least 20 proteins encoded by genes selected from Table 1 and Table 2; (b) the protein expression profile comprises differential expression of at least 50 proteins encoded by genes selected from Table 1 and Table 2; (c) the protein expression profile comprises differential expression of at least 100 proteins encoded by genes selected from Table 1 and Table 2; (d) the protein expression profile comprises differential expression of at least 150 proteins encoded by genes selected from Table 1 and Table 2; or (e) the protein expression profile comprises differential expression of proteins encoded by genes listed in Table 1 and Table 2.
  • Embodiment 101 An in vitro method for determining the likelihood of a subject who has a cancer responding to a treatment comprising tosedostat, said method comprising (a) detecting expression of proteins encoded by genes selected from Table 3 and Table 4 in cancer cells obtained from the subject; (b) determining the level of expression of the proteins in the cancer cells to provide a protein expression profile; and (c) categorizing the subject as a likely responder to the treatment if the protein expression profile comprises differential expression of at least 3 proteins encoded by genes selected from Table 3 and Table 4, wherein the genes listed in Table 3 are up- regulated and the genes listed in Table 4 are down-regulated in the cancer cells.
  • Embodiment 102 The method of Embodiment 101 wherein the protein expression profile comprises differential expression of at least 3 proteins encoded by genes selected from CD93, GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11- 428P16.2/ZNF532, SNN, TNFSF8, and VENTX.
  • Embodiment 103 The method of Embodiment 97 wherein the protein expression profile comprises differential expression of at least 10 proteins encoded by genes selected from Table 3 and Table 4.
  • Embodiment 104 The method of Embodiment 101 wherein the protein expression profile comprises differential expression of the proteins encoded by CD93, GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX.
  • Embodiment 105 The method of Embodiment 101, wherein the protein expression profile comprises differential expression of proteins encoded by CXCL16, CD93 and GRASP.
  • Embodiment 106 The method of Embodiment 101 wherein (a) the protein expression profile comprises differential expression of at least 20 proteins encoded by genes selected from Table 3 and Table 4; (b) the protein expression profile comprises differential expression of at least 50 proteins encoded by genes selected from Table 3 and Table 4; (c) the protein expression profile comprises differential expression of at least 100 proteins encoded by genes selected from Table 3 and Table 4; (d) the protein expression profile comprises differential expression of at least 150 proteins encoded by genes selected from Table 3 and Table 4; or (e) the protein expression profile comprises differential expression of proteins encoded by genes listed in Table 3 and Table 4.
  • Embodiment 107 The method of any one of Embodiments 96-106 wherein the cancer is a hematological cancer selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), multiple myeloma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), Hodgkin lymphoma, non-Hodgkin lymphoma, or hairy cell leukemia.
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • Hodgkin lymphoma non-Hodgkin lymphoma
  • hairy cell leukemia a hematological cancer selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), multiple myeloma
  • Embodiment 108 The method of any one of Embodiments 96-106 wherein the cancer is a hematological cancer selected from acute myeloid leukemia (AML) and
  • Embodiment 109 The method of any one of Embodiments 96-106 wherein the cancer is a solid tumor selected from melanoma, prostate cancer, testicular cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, ovarian cancer, Kaposi's sarcoma, skin cancer, squamous cell skin cancer, renal cancer, head cancer, neck cancer, throat cancer, squamous carcinoma that forms on moist mucosal linings, bladder cancer, osteosarcoma, cervical cancer, endometrial cancer, esophageal cancer, liver cancer, kidney cancer, an epithelial cell-derived cancer, and a mesenchymal cell-derived cancer.
  • the cancer is a solid tumor selected from melanoma, prostate cancer, testicular cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, ovarian cancer, Kaposi's sarcoma, skin cancer, squamous cell skin
  • Embodiment 110 The method of any one of Embodiments 96-109 wherein the biological sample is bone marrow or a cell fraction thereof, blood or a cell fraction thereof, or a tumor sample.
  • Embodiment 111 The method of any one of
  • Embodiments 96-108 wherein the cancer is a hematological cancer and the biological sample is bone marrow or a cell fraction thereof or blood or a cell fraction thereof.
  • Embodiment 112 A method for typing acute myelogenous leukemia (AML) cells, said method comprising determining a protein expression profile of cancer cells obtained from the blood or bone marrow of a subject with AML by detecting expression of at least three proteins encoded by genes selected from Table 1 and Table 2.
  • Embodiment 113 The method of Embodiment 112, wherein the protein expression profile comprises at least 10 proteins encoded by genes selected from Table 1 and Table 2.
  • Embodiment 114 The method of Embodiment 112, wherein the protein expression profile comprises the proteins encoded by IL1RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A,
  • Embodiment 115 The method of Embodiment 112, wherein the protein expression profile comprises at least 20, at least 50, at least 100, or at least 150 proteins encoded by genes selected from Table 1 and Table 2, or the protein expression profile comprises all proteins encoded by the genes in Table 1 and Table 2.
  • Embodiment 116 A method for typing acute myelogenous leukemia (AML) cells, said method comprising determining a protein expression profile of cancer cells obtained from the blood or bone marrow of a subject with AML by detecting expression of at least three proteins encoded by genes selected from Table 3 and Table 4.
  • AML acute myelogenous leukemia
  • Embodiment 117 The method of Embodiment 116, wherein the protein expression profile comprises at least 10 proteins encoded by genes selected from Table 3 and Table 4.
  • Embodiment 118 The method of Embodiment 111, wherein the protein expression profile comprises the proteins encoded by CD93, GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX.
  • Embodiment 119 The method of Embodiment 116, wherein the protein expression profile comprises the proteins encoded by CXCL16, CD93 and GRASP.
  • Embodiment 120 The method of Embodiment 116, wherein the protein expression profile comprises at least 20, at least 50, at least 100, or at least 150 proteins encoded by genes selected from Table 3 and Table 4, or the protein expression profile comprises all proteins encoded by the genes in Table 3 and Table 4.
  • Embodiment 121 The method of any one of Embodiments 1-68, further comprising detecting the level of expression of a gene that encodes a target protein of tosedostat.
  • Embodiment 122 The method of Embodiment 121 wherein the gene is NPEPPS or LTA4H.
  • Embodiment 123 The method of any one of Embodiments 69-120, further comprising detecting the level of expression of a target protein of tosedostat.
  • Embodiment 124 The method of Embodiment 123 wherein the target protein is either puromycin-sensitive aminopeptidase or leukotriene A4 hydrolase.
  • a non-human animal may refer to one or more non-human animals, or a plurality of such animals
  • reference to "a cell” or “the cell” includes reference to one or more cells and equivalents thereof ⁇ e.g., a plurality of cells) known to those skilled in the art, and so forth.
  • Figure 1 provides a graphic illustrating gene expression analysis.
  • the graphic illustrates the different gene expression profiles of cancer cells from patients with complete remission) (CR) compared with patients who had no response (NR).
  • Figure 3 (A-C) presents a graphic of the 140 genes differentially expressed and classified according to relevant biological functions and pathways of GeneOntology database.
  • Figure 3 A response to other organism, defense response, inflammatory response, response to biotic stimulus, immune response, response to wounding, response to external stimulus, response to stress, signal transduction, cellular protein metabolic process); curated gene sets.
  • Figure 3B genes up-regulated in AML with PM1 mutated, genes down regulated in hematopoietic stem cell, genes modified in response to LPS with mechanical ventilation, genes up-regulated in myeloid cell development, dental caries up, genes up-regulated in circulating endotheliocytes in cancer, genes down-regulated in dental caries, target genes down regulated by
  • NUP98/HOXA9 fusion genes down-regulated in leukemic stem cell, genes down-regulated in response to HGF); and Figure 3C: oncogenic signatures related to RPS14, HOXA9, STK33, CAMP, RB/P107, AKT/MTOR, and ALK.
  • Figures 4A and 4B are tables showing the diagnostic accuracy evaluation of studies on 188 genes ⁇ i.e., the ability of the classifier to predict a given case as a potential "responder” or “non-responder”).
  • the catmaker software was used for all calculations, and the original output is plotted.
  • the classifier was based on a support vector machine algorithm. After classification of samples based on the expression of the gene signature, catmaker was used to properly calculate the accuracy.
  • Figures 5A-D present data showing the diagnostic accuracy of as few as 10 or 3 genes selected from the signatures.
  • Figure 5 A the ability of a reduced signature (3 genes, CXCL16, CD93 and GRASP) is presented.
  • Figure 5A hierarchical clustering shows a high accuracy (only 1 mismatch for each group).
  • Figure 5B diagnostic accuracy was evaluated with catmaker (see above). Again, the original output of the software is plotted.
  • Figures 5C and D the ability of a reduced signature (10 genes including the previous 3) was tested. At clustering (Figure 5C), only 2 mismatches were observed.
  • Figure 5D the diagnostic accuracy was properly calculated with catmaker.
  • a method for treating a cancer in a subject comprises requesting, obtaining or performing a gene expression profile analysis of cancer cells contained in a biological sample ⁇ e.g., bone marrow or blood or a cell fraction thereof, or a tumor sample) to determine the likelihood that the subject will have a clinical response, such as partial or complete remission, to treatment and administering tosedostat, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutical salt thereof if the gene expression profile analysis indicates that the cancer in the subject will likely respond to treatment with tosedostat .
  • the subject has a hematological cancer (e.g., acute myeloid leukemia (AML), myelodysplastic syndrome (MDS)).
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • the subject has a solid tumor cancer.
  • methods for treating hematological cancers and solid tumor cancers by administering tosedostat have a greater likelihood of success in subjects whose cancer cells exhibit differential expression of genes involved in any one or more of a ⁇ -catenin pathway, response to other organism pathway, an STK33/Stm pathway, a T F- ⁇ pathway via NF- ⁇ signaling, an Erb-B2 pathway, defense response, an inflammatory response pathway, immune response, response to stress, signal transduction, PM1 mutated AML, hematopoietic stem cell, myeloid cell development and an epithelial-mesenchymal transition pathway.
  • Subjects who have a cancer have a greater likelihood of achieving a clinical response, such as complete remission, to tosedostat if the cancer cells have differential expression of at least three (i.e., 3 or more) of the genes that are presented in Tables 1 and 3 (up-regulated genes) and Tables 2 and 4 (down-regulated genes) herein.
  • subjects who are likely to respond to treatment with tosedostat include those whose tumor cells have deregulated expression of at least 3 oilLlRAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, PLOD2, FGF2, and ANPEP genes or at least 3 of GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ZNF532, SNN, TNFSF8, and VENTX genes, for example CXCL16, CD93 and GRASP genes.
  • the genes listed in each of Table 1-4 and the proteins encoded by these genes may also be called biomarkers.
  • These in vitro methods comprise detecting expression of multiple different genes (e.g., by detecting mRNA or an expression product thereof (e.g., cRNA, cDNA) or the expressed protein, which is sometimes called proteomics analysis) in the cancer cells. Determining the level of expression of mRNA molecules transcribed from different genes provides a gene expression profile.
  • the methods comprise categorizing the subject as a likely responder to the treatment if the gene expression profile comprises differential expression of at least 3 (i.e., 3 or more) of the genes listed in Tables 1 and 2, including but not limited to the following genes: IL1RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, PLOD2, FGF2, and ANPEP, or the genes listed in Tables 3 and 4, including but not limited to or at least 3 of GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX genes, for example CXCL16, CD93 and GRASP genes.
  • the methods described herein comprise a step of requesting, receiving, providing, obtaining, analysing, or determining a gene expression profile of cancer cells from a subject being considered for treatment with tosedostat (which treatment may further comprise one or more additional antineoplastic agents).
  • Gene expression profiling is the determination of the pattern of genes expressed in a cell (for example, determining the relative expression of multiple mRNA transcripts), such as a cancer cell, by measuring the level of expression of tens, hundreds, or thousands of genes, or the entire genome.
  • the profiles obtained by the methods described herein are useful for predicting or determining whether a subject who has a cancer will have a clinical response to tosedostat, alone or in combination with one or more other antineoplastic therapy.
  • the gene expression profile of cancer cells treatable by tosedostat alone or in combination with at least one other antineoplastic therapy includes differential expression of genes. Differential expression means that expression of one or more genes is different in the test sample comprising cancer cells from the patient to be treated compared with expression of the one or more genes in a control sample.
  • Controls may be concurrently performed or the control could be a historic control.
  • the control could be cancer cells from subjects who have the same type of cancer and were treated with the same treatment regimen but whose cancer was not effectively treated by the regimen.
  • tests samples were obtained from patients with AML who had complete remission after treatment
  • Differential expression may comprise an increase in the level of expression of one or more genes or a decrease in the level of expression of one or more genes compared with a control. Differential expression may also include detectable expression of one or more genes of the cancer cells in the test sample, which one or more genes are not detectable in a control sample.
  • a clinical response to treatment may include descriptions of complete remission, partial remission, cure, or overall survival.
  • the clinical response or outcome could also be expressed, for example, in terms of Recurrence-Free Interval (RFI), Disease-Free Survival (DFS), or Distant Recurrence-Free Interval (DRFI).
  • RFID Recurrence-Free Interval
  • DFS Disease-Free Survival
  • DRFI Distant Recurrence-Free Interval
  • Gene expression profiling may be performed by using microarrays of nucleic acids (RNA or DNA) representing different genes. Such microarrays are prepared according to methods routinely practiced in the art and numerous arrays are commercially available. Methods for detecting genes expressed are routinely practiced and well known to persons skilled in the art. Cells, in this instance, cancer cells are obtained from a subject and then processed in a manner appropriate for the cells, followed by isolation and preparation of nucleic acids for gene expression analysis (or preparation of proteins if protein expression is measured).
  • RNA or DNA nucleic acids
  • Gene expression may be measured by hybridizing mRNA or expression products thereof, e.g., cRNA, cDNA from cancer cells to the representative nucleic acids of the microarray, which is detected with probes comprising a detectable label, such as a fluorophore or a radioactive label.
  • Gene expression profiling may also be performed by employing real-time PCR (e.g., OpenArray Technology; TaqMan® gene expression technologies (see Life
  • qPCR quantitative PCR
  • Additional methods that are used for gene expression profiling include serial analysis of gene expression (SAGETM).
  • Second generation sequencing methods also include SuperSAGETM and Ion TorrentTM Next Generation Sequencing.
  • SuperSAGE is used for determining expression of any gene transcribed in a cell.
  • Digital PCR may be used, which enables precise measurements and can resolve gene expression level changes of two-fold or less.
  • Digital PCR can also determine the absolute quantification of a transcript without the need for a reference gene (see, e.g., Life Technologies,
  • Data analysis tools are available in the art that transform raw data from the methods used for measuring the level of expression of transcribed genes.
  • Raw data from a microarray analysis or a sequencing method can be analysed (for example, using principal component analysis) by any one of a number of software packages and algorithms available in the art (e.g., GeneSpring GX12 (Agilent)).
  • Hierarchical clustering may be used to group similar objects into "clusters” (see, e.g., Hartigan, "Clustering Algorithms”; John Wiley & Sons, Inc., New York. 1975:351 pp.; Eisen et al, Proc. Natl. Acad. Sci. USA 1998;95:14863-68).
  • Hierarchical clustering can be used to produce a dendogram that shows the hierarchy of the clusters. This illustrates how the results from a microarray analysis, for example, group together based on similarity of features.
  • Hierarchical clustering is considered an unsupervised clustering method. Unsupervised clustering does not take into account any experimental variables such as treatment, phenotype, tissue, etc. when clustering. Supervised clustering does consider experimental variables when clustering (e.g., patient's response to treatment).
  • Additional analytical methods include assessing whether specific cell functions and biological processes, defined according to gene ontology, are associated with gene ontology.
  • stepwise discriminant analysis may be performed (e.g., by applying IBM Spss Statistics 20.0 (IBM, Armonk, USA).
  • classification may also be performed to classify whether a cell type correlates with a specific clinical outcome (e.g., achievement of complete remission).
  • Sample classification may be performed using a Support Vector Machine (SVM) algorithm and the leave-one-out method.
  • SVM Support Vector Machine
  • the classifier is a confidence measure scoring function based on the values of a set of genes (gene cluster), which are differentially expressed in two sets of cell types, and thus, can be used for cell type classification. The higher the score, the likelihood is greater that a cell type is related to the phenotype set.
  • GSEA Gene Set Enrichment Analysis
  • GO Gene Ontology
  • KEGG Oncogenic Signatures
  • GSEA MsigDB GSEA MsigDB
  • a gene in a cell or population of cells for example, cancer cells from a patient who has a beneficial clinical response to treatment with tosedostat (alone or in combination with a second antineoplastic agent), at levels higher than the expression of that gene in a second cell or population of cancer cells, for example, cancer cells from a patient who had no clinical response to treatment with tosedostat (alone or in combination with a second antineoplastic agent).
  • Reagents that may be used to detect the expression of one or more genes
  • nucleic acid probes capable of specifically hybridizing to the gene of interest
  • aptamers capable of specifically amplifying the gene of interest
  • antibodies or other ligands e.g., enzyme substrates, signaling molecules and the like
  • the gene expression profiling methods described herein may also be used in combination with detection of protein expression, such as by
  • FISH fluorescence in situ hybridization
  • chromatography e.g., mass spectrometry
  • spectrometry e.g., mass spectrometry
  • the methods described herein may also be used in combination with detection of additional genes, miRNAs, and proteins, such as proteins that are targets of a particular antineoplastic agent.
  • methods comprising gene expression profiling using the genes described in Tables 1 and 2 may further comprise detecting the presence or expression of a target protein of tosedostat (e.g., puromycin-sensitive aminopeptidase and leukotriene A4 hydrolase) encoded by a gene that is not included in Tables 1 and 2 or detecting expression of the gene encoding a target protein (e.g., NPEPPS and LTA4H, encoding puromycin-sensitive aminopeptidase and leukotriene A4 hydrolase, respectively).
  • a target protein of tosedostat e.g., puromycin-sensitive aminopeptidase and leukotriene A4 hydrolase
  • CD 13 aminopeptidase N
  • Biological samples containing cancer cells may be obtained from a subject, preferably in a manner as nonintrusive and comfortable as possible.
  • a biological sample comprising cancer cells may be blood, serum, plasma or a blood cell fraction , a biopsy specimen (e.g., tumor specimen), body fluids (e.g., lung lavage, ascites, mucosal washings, synovial fluid), bone marrow or a cell fraction thereof, lymph nodes, tissue explant, organ culture, or any other tissue or cell preparation from the subject.
  • a sample may further refer to a tissue or cell preparation in which the morphological integrity or physical state has been disrupted, for example, by dissection, dissociation, solubilization, fractionation, homogenization, biochemical or chemical extraction, pulverization, lyophilization, sonication, or any other means for processing a sample derived from a subject.
  • a biological sample used in the methods described herein may comprise a primary cell culture (e.g., cancer or tumor cells), or culture adapted cell line, including but not limited to, genetically engineered cell lines that may contain chromosomally integrated or episomal recombinant nucleic acid sequences, immortalized or immortalizable cell lines, somatic cell hybrid cell lines, differentiated or differentiatable cell lines, transformed cell lines, and the like.
  • a primary cell culture e.g., cancer or tumor cells
  • culture adapted cell line including but not limited to, genetically engineered cell lines that may contain chromosomally integrated or episomal recombinant nucleic acid sequences, immortalized or immortalizable cell lines, somatic cell hybrid cell lines, differentiated or differentiatable cell lines, transformed cell lines, and the like.
  • the gene expression profile obtained for use in the methods described herein for treating a subject who has cancer with tosedostat (alone or in combination with at least one additional antineoplastic therapy), comprises differential expression of one or more genes in each of the following cell pathways: ⁇ - catenin pathway, response to other organism pathway, an STK33 pathway, a TNF-a pathway via F- ⁇ signaling, an ErbB2 pathway, defense response, an inflammatory response pathway, immune response, response to stress, signal transduction, PM1 mutated AML, hematopoietic stem cell, myeloid cell development and an epithelial- mesenchymal transition pathway.
  • differential expression of at least three of the genes provided in Table 1 and Table 2 is determined, including but not limited to at least three oilLlRAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1,
  • PLOD2, FGF2, and ANPEP genes or at least three of the genes provided in Table 3 and Table 4, including but not limited to at least three of of GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX genes, for example CXCL16, CD93 and GRASP genes.
  • methods are provided for obtaining, requesting, receiving, determining, or analyzing the expression of a protein expressed by a differentially expressed gene.
  • proteins can be determined using any one of numerous methods routinely practiced in the art, including but not limited to, immunofluorescence, immunohistochemistry, immunoblotting, ELISAs, flow cytometry (including FISH), chromatography, and spectrometry (e.g., mass
  • Protein detection methods may comprise use of reagents, such as antibodies (monoclonal or polyclonal), protein ligands, or other binding moieties that are linked in some manner to a detectable moiety (e.g., a fluorophore, a radionuclide, an enzyme, and biotin).
  • reagents such as antibodies (monoclonal or polyclonal), protein ligands, or other binding moieties that are linked in some manner to a detectable moiety (e.g., a fluorophore, a radionuclide, an enzyme, and biotin).
  • a protein expression profile obtained for use in the methods described herein for treating a subject who has cancer with tosedostat (alone or in combination with at least one additional antineoplastic therapy), comprises obtaining a protein expression profile comprising differential expression of one or more proteins that is involved or is a component in each of the following cell pathways: ⁇ - catenin pathway, response to other organism pathway, an STK33 pathway, a TNF-a pathway via F- ⁇ signaling, an ErbB2 pathway, defense response, an inflammatory response, immune response, response to stress, signal transduction, PM1 mutated AML, hematopoietic stem cell, myeloid cell development and an epithelial- mesenchymal transition pathway.
  • the methods comprise obtaining a protein expression profile comprising differential expression of at least 3 proteins, which proteins are each encoded by genes selected from the genes listed in Table 1 and Table 2, including but not limited to IL1RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, PLOD2, FGF2, and ANPEP; or proteins encoded by genes selected from the genes listed in Table 3 and Table 4, including but not limited to be GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX genes, for example CXCL16, CD93 and GRASP genes.
  • Antineoplastic Agents include IL1RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE,
  • the aminopeptidase-inhibitor tosedostat (CHR-2797) is described as a matrix metalloproteinase inhibitor or an aminopeptidase inhibitor.
  • Tosedostat (2S-[2R- (S-Hydroxy-hydroxycarbamoyl-methyl)-4-methylpentanoylamino]-2-phenylethanoic acid cyclopentyl ester; CAS Registry Number 238750-77-1) inhibits members of the Ml and Ml 7 classes of aminopeptidases.
  • Tosedostat is an orally bioavailable agent, which has been investigated in clinical trials for treatment of patients with leukemia (e.g., relapsed/refractory acute myeloid leukemia (AML)) and cancers that are solid tumors.
  • leukemia e.g., relapsed/refractory acute myeloid leukemia (AML)
  • AML acute myeloid leukemia
  • Tosedostat is converted intracellularly into a poorly membrane- permeable active metabolite (CHR-79888) that inhibits the Ml family of
  • aminopeptidases particularly puromycin-sensitive aminopeptidase (PuSA), and leukotriene A4 (LTA4) hydrolase (see, e.g., Krige et al, Cancer Res.
  • aminopeptidase N which is a Zn2+ dependent membrane-bound ectopeptidase that preferentially degrades proteins and peptides with a N-terminal neutral amino acid (see, e.g., Wickstrom etal., Cancer Sci. 2011; 102: 501-508). Inhibition of these aminopeptidase N
  • Noxa is a member of the BH3 (Bcl-2 homology 3)-only subgroup of the proapoptotic Bcl-2 (B-cell
  • the methods described herein for treating a cancer comprise administering tosedostat in combination with at least one other (i.e., one or more) antineoplastic therapy (also called anti-cancer therapy).
  • the at least one other antineoplastic therapy is at least one additional antineoplastic agent (which may be referred to herein as a second antineoplastic agent) is a compound classified as an antimetabolite.
  • exemplary antimetabolites include nucleosides antagonists, such as purines (for example, azathioprine, mercaptopurine) and pyrimidines.
  • Antimetabolite agents that may be used in combination with tosedostat include cytarabine, decitabine, and capecitabine.
  • antimetabolites include, without limitation, 5-fluorouracil, methotrexate, azacytidine, 6- thioguanine, 6-mercaptopurine, arabinosylcytosine, clofarabine, dacarbazine, fludarabine, gemcitabine, and nelarabine.
  • the antimetabolite also called Ara-C or AraC
  • Ara-C also called AraC
  • AraC AraC
  • CAS# 147-94-4 a pynmidine nucleoside analog that inhibits the synthesis of DNA. Its actions are specific for the S phase of the cell cycle.
  • Cytarabine has been used in the treatment of leukemias such as acute non- lymphoblastic leukemia.
  • the antimetabolite is capecitabine (CAS# 154361-50-9), which is a fluoropyrimidine carbamate.
  • capecitabine is selectively activated by tumor cells to its cytotoxic moiety, 5- fluorouracil (5-FU). Subsequently, in tumor cells and in normal cells, 5-FU is metabolized to two active metabolites: 5-fluoro-2-deoxyuridine monophosphate
  • FdUMP 5-fluorouridine triphosphate
  • FUTP 5-fluorouridine triphosphate
  • the antimetabolite is decitabine
  • tosedostat may be administered in combination with a histone deacetylase (HDAC) inhibitor such as CHR-3996
  • HDAC histone deacetylase
  • HDAC inhibitors may be categorized into four main structural classes: short-chain fatty acids ⁇ e.g., butyrate and valproic acid); hydroxamates (e.g., trichostatin A, saha (sub-eroylanilide hydroxamic acid or vorinostat), LBH589 (panobinostat), PXD101 (belinostat), oxamflatin, and tubacin); benzamides (e.g., S DX275 (MS275) and MGCD0103); and cyclic tetrapeptides (e.g., FK228 (romidepsin), trapoxin A, and apicidin).
  • CHR-3996 is a second generation hydroxamate and may upregulate HSP70 and downregulate anti-apoptotic Bcl-2 proteins more substantially than some first-generation HDAC inhibitors.
  • HDAC inhibitors for the various HDAC molecules varies. Hydroxamates are pan-HDAC inhibitors and target all classical HDAcs. Butyrate, vpa, and trapoxin A target class 1 and 2a HDACs. S DX275 inhibits class 1 HDACs (but not HDAC8); romidepsin preferentially targets HDACl and HDAC2; and tubacin selectively inhibits HDAC6.
  • the at least one other antineoplastic therapy may comprise any one or more of an alkylating agent; an anthracycline, a plant alkaloid, taxane, and a topoisomerase inhibitor.
  • Alkylating agents include by way of example, cisplatin, carboplatin, oxalaplatin, cyclophosphamide, mechlorethamine, chlorambucil, and ifosfamide.
  • Vinca alkaloids include for example, vincristine, vinblastine, vinorelbine, vindesine.
  • Taxanes include, for example, paclitaxel, docetaxel, and cabazitaxel, and inhibit microtubule function.
  • Podophyllotoxin inhibits microtubule assembly and DNA topoisomerase II.
  • Exemplary topoisomerase inhibitors are type I topoisomerase inhibitors such as the camptothecins, for example, irinotecan and topotecan.
  • Other topoisomerase inhibitors are type II topoisomerase inhibitors, for example, amascrine, etoposide, etoposide phosphate, and teniposide, which are semisynthetic derivatives of eipoodophyllotoxins.
  • Cytotoxic antibiotics that are chemotherapeutic agents include without limitation doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, and mitomycin.
  • cancer or tumor are clinically descriptive terms that encompass diseases typically characterized by cells that exhibit abnormal cellular proliferation.
  • the term cancer is generally used to describe a malignant tumor or the disease state arising from the tumor.
  • an abnormal growth may be referred to in the art as a neoplasm.
  • the term tumor such as in reference to a tissue, generally refers to any abnormal tissue growth that is characterized, at least in part, by excessive and abnormal cellular proliferation.
  • a tumor may be metastatic and capable of spreading beyond its anatomical site of origin and initial colonization to other areas throughout the body of the subject.
  • a cancer may be characterized as a solid tumor or liquid tumor (e.g., a leukemia).
  • hematological cancers also called blood cell tumors or liquid tumors
  • lymphomas e.g., Hodgkin
  • Leukemias include for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), and hairy cell leukemia.
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • MDS myelodysplastic syndrome
  • hairy cell leukemia In elderly patients, a myelodysplasia, which is a clonal disorder, could anticipate the development of AML of few months or years.
  • Cancers that are solid tumors and occur in greater frequency in humans and that may be treatable by the methods described herein include, for example, melanoma, prostate cancer, testicular cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, ovarian cancer, Kaposi's sarcoma, skin cancer (including squamous cell skin cancer), renal cancer, head and neck cancers, throat cancer, squamous carcinomas that form on the moist mucosal linings of the nose, mouth, throat, etc.), bladder cancer, osteosarcoma (bone cancer), cervical cancer, endometrial cancer, esophageal cancer, liver cancer, and kidney cancer, and an epithelial cell-derived cancer, and a mesenchymal cell-derived cancer.
  • melanoma prostate cancer
  • testicular cancer breast cancer
  • brain cancer pancreatic cancer
  • colon cancer thyroid cancer
  • stomach cancer lung cancer
  • lung cancer ovarian cancer
  • a method for treating a cancer in a subject comprising requesting, receiving, providing, obtaining, analysing, or determining a gene expression profile of cancer cells from the subject.
  • Such a subject may be considered for treatment with tosedostat, which in certain embodiments may be used in combination with at least one other antineoplastic therapy (e.g., an antimetabolite).
  • the method comprises administering tosedostat if the gene expression profile comprises differential expression of at least 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 155, or all genes listed in Tables 1-4.
  • genes listed in Table 1 or Table 3 is increased in cancer cells from patients who had a complete response to treatment compared to cancer cells from patients who had no response to treatment.
  • the expression of genes listed in Table 2 or Table 4 is decreased in cancer cells from patients who had a complete response to treatment compared to cancer cells from patients who had no response to treatment.
  • the method further comprises administering tosedostat if the gene expression profile comprises differential expression of at least 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of the following genes: IL1RAP, TAFID, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXDl, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, PLOD2, FGF2, and ANPEP; or at least 3, 5, 6, 7, 8 or 9 of the following genes:
  • GRASP CXCL16, HNMT, LILRAl, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX genes, for example CXCL16, CD93 and GRASP genes.
  • Subjects likely to respond to treatment have increased expression of PLOD2 and FGF2 and decreased expression oflLlRAP, TAFID, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXDl, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, and ANPEP; or increased expression of GRASP, CXCL16, HNMT, LILRAl, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX genes, for example CXCL16, CD93 and GRASP genes.
  • the gene expression profile of a subject may be compared with the gene expression profile obtained historically of subjects who have been treated with tosedostat but who
  • a method for treating a cancer in a subject comprising: (a) obtaining a biological sample comprising cancer cells from the subject; (b) performing gene expression profiling of the cancer cells, which comprises (i) preparing RNA transcripts, or expression products thereof (e.g., cRNA, cDNA), (ii) detecting the expression level in the cancer cells of the RNA transcripts, or expression products thereof, of the genes listed in Tables 1-4 (or a subset thereof); (ii) classifying the expression level of the RNA transcripts, or expression products thereof, of the genes to provide a gene expression profile; and (c) administering tosedostat to the subject if the gene expression profile comprises differential expression of at least 3 of the genes listed in Tables 1-4, wherein the genes listed in Table 1 or Table 3 are up-regulated and the genes listed in Table 2 or Table 4 are down-regulated in the cancer cells.
  • gene expression profiling of the cancer cells which comprises (i) preparing RNA transcripts, or expression products thereof (e.g., cRNA
  • RNA transcripts or expression products thereof can be performed by any number of techniques described herein and routinely practiced in the art.
  • the RNA transcripts or expression products may be permitted to bind to or hybridize to a microarray of genes of interest (e.g., the genes listed in Tables 1-4 or a subset thereof) and then detecting the hybridized molecules, typically by using reagents with detectable labels (e.g., a fluorophore).
  • detectable labels e.g., a fluorophore
  • Other techniques include, but are not limited to, qPCR, real-time PCR, Digital PCR, serial analysis (e.g., SAGE), and sequencing methods (e.g., second generation sequencing methods).
  • a method for treating a cancer in a subject comprising: (a) obtaining a biological sample comprising cancer cells from the subject; (b) performing protein expression profiling of the cancer cells comprising detecting the expression level of at least 3 proteins in the cancer cells, which proteins are encoded by genes listed in Tables 1-4. Proteins may be isolated from cancer cells or cell lysates comprising proteins may be prepared by methods routinely practiced in the art. After determining the level of expression of proteins encoded by genes listed in Tables 1-4, the expression level of the proteins encoded by these genes is classified, by methods described herein, to provide a protein expression profile.
  • tosedostat (alone or in combination with at least one additional antineoplastic agent) is administered to the subject.
  • a subject who has a cancer e.g., AML or MDS
  • the genes listed in Tables 1 and 3 exhibit increased expression in cancer cells from patients who had a complete response to treatment compared to cancer cells from patients who had no response to treatment.
  • the genes listed in Tables 2 and 4 exhibit decreased expression in cancer cells from patients who had a complete response to treatment compared to cancer cells from patients who had no response to treatment.
  • the cancer cells obtained from the subject exhibit increased expression of one or more genes provided in Tables 1 or 3 and/or decreased expression of one or more genes listed in Tables 2 or 4.
  • Subjects who are more likely to be treatable with tosedostat have cancer cells that show increased expression of at least 2, 5, 10, 20, 30, 40, 50, 60, 70, or all of the genes listed in Tables 1 or 3 and show decreased expressed in at least 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, or all of the genes listed in Tables 2 or 4.
  • Increased expression of a gene in Tables 1 or 3 may be 1.5, 2, 4, 5, 7.5, 10, or more times greater than the expression of the respective gene in a subject who has cancer and that has no response to tosedostat.
  • Decreased expression of a gene in Tables 2 or 4 may be 1.5, 2, 4, 5, 7.5, 10, or more times less than the expression of the respective gene in a subject who has cancer and whose cancer has no response to tosedostat.
  • a method for treating a cancer in a subject comprising requesting, receiving, providing, obtaining, analysing, or determining a protein expression profile of cancer cells from the subject.
  • a subject may be considered for treatment with tosedostat, which in certain embodiments may be used in combination with at least one other antineoplastic therapy (e.g., an antimetabolite).
  • the method comprises administering tosedostat if the protein expression profile comprises differential expression of at least 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 155 or all proteins that are encoded by the genes listed in Tables 1-4.
  • the method further comprises administering tosedostat if the protein expression profile comprises differential expression of at least 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 proteins encoded by the following genes:
  • IL1RAP TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SATl, FAM129A, ATP2B1, HIFIA, RNF144B, CCNLl, PLOD2, FGF2, and ANPEP or at least 3, 5, 6, 7, 8 or 9 of GRASP, CXCL16, HNMT, LILRAl, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX genes, for example CXCL16, CD93 and GRASP genes.
  • Subjects likely to respond to treatment have increased expression of proteins encoded by PLOD2 and FGF2 and decreased expression of proteins encoded by IL1RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SATl, FAM129A, ATP2B1, HIFIA, RNF144B, CCNLl, and ANPEP or increased expression of proteins encoded by GRASP, CXCL16, HNMT, LILRAl, PADI4, RP11- 428P16.2/ZNF532, SNN, TNFSF8, and VENTX.
  • the protein expression profile of a subject may be compared with the protein expression profile obtained historically of subjects who have been treated with tosedostat but who did not have a beneficial clinical response to treatment (for example, using the data described herein and summarized in Tables 1-6).
  • the methods described herein that comprise determining, requesting, providing, analyzing or obtaining a gene expression profile or a protein expression profile may further comprise detection of additional genes ⁇ i.e. those not listed in Tables 1-4), miRNAs, and proteins ⁇ i.e., those not encoded by genes listed in Tables 1- 4), such as proteins that are targets of a particular antineoplastic agent.
  • methods described herein that comprise gene expression profiling or protein expression profiling (which may also be called proteomics) related to expression of the genes described in Tables 1 and 2 may further comprise detecting the presence or expression of a target proteins of tosedostat (e.g., puromycin-sensitive aminopeptidase or leukotriene A4 hydrolase) that is not included in Tables 1-4 or detecting expression of the gene that encodes a target protein (e.g., NPEPPS and LTA4H encoding puromycin-sensitive aminopeptidase and leukotriene A4 hydrolase, respectively).
  • a target proteins of tosedostat e.g., puromycin-sensitive aminopeptidase or leukotriene A4 hydrolase
  • Another protein reported to be a target of tosedostat, CD 13 is encoded by the gene ANPEP, which is included in Table 2.
  • the method further comprising obtaining a biological sample that contains tumor cells (also called cancer cells herein), which may be processed and prepared by methods routinely practiced in the art for use in gene or protein expression profiling techniques and procedures.
  • tumor cells also called cancer cells herein
  • the subject has a hematological cancer (e.g., AML, MDS, multiple myeloma, ALL, CLL, CML, non-Hodgkin lymphoma, Hodgkin lymphoma, or hairy cell leukemia; see, e.g., description herein).
  • the cancer is a solid tumor.
  • the solid tumor may be any one of the cancers described herein, including but not limited to melanoma, prostate cancer, testicular cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, ovarian cancer, Kaposi's sarcoma, skin cancer, squamous cell skin cancer, renal cancer, head cancer, neck cancer, throat cancer, squamous carcinoma that forms on moist mucosal linings, bladder cancer, osteosarcoma, cervical cancer, endometrial cancer, esophageal cancer, liver cancer, kidney cancer, an epithelial cell-derived cancer, and a mesenchymal cell- derived cancer.
  • the methods further comprise administering one or more additional antineoplastic therapies in combination with tosedostat.
  • the additional antineoplastic therapy may be any one of several types of small molecule antineoplastic agents, including but not limited to an antimetabolite, a HDAC inhibitor, an alkylating agent, an anthracycline, a plant alkaloid, a taxane, and a topoisomerase inhibitor, which are described in greater detail herein and which are familiar to a person skilled in the oncology art.
  • the additional antineoplastic agent is an antimetabolite.
  • the antimetabolite is selected from cytarabine, decitabine, capecitabine, 5-fluorouracil, methotrexate, azacytidine, 6- thioguanine, 6-mercaptopurine, arabinosylcytosine, clofarabine, dacarbazine, fludarabine, gemcitabine, and nelarabine.
  • the antimetabolite is cytarabine, decitabine, or capecitabine.
  • the antimetabolite is cytarabine.
  • the second antineoplastic agent is an HDAC inhibitor, such as CHR-3996.
  • the one or more antineoplastic therapies administered in combination with tosedostat may be an antibody, such as a monoclonal antibody (which may be conjugated to a cytotoxic moiety or targeting moiety) or other biological molecule, or radiation.
  • an antibody such as a monoclonal antibody (which may be conjugated to a cytotoxic moiety or targeting moiety) or other biological molecule, or radiation.
  • Tosedostat and, in certain embodiments, at least one other antineoplastic agent are administered to the subject via a route and at a dose and frequency as appropriate for the particular agent.
  • Each of tosedostat and the at least one additional antineoplastic agent may be administered by any one of several different routes that effectively delivers an effective amount of the compound.
  • the routes may be the same or different.
  • Such administrative routes include, for example, oral, intravenous, subcutaneous, enteral, rectal, intranasal, buccal, sublingual, intramuscular, topical intradermal, subdermal, and transdermal.
  • An appropriate dose and a suitable duration and frequency of administration for tosedostat and the particular additional route include, for example, oral, intravenous, subcutaneous, enteral, rectal, intranasal, buccal, sublingual, intramuscular, topical intradermal, subdermal, and transdermal.
  • antineoplastic agent(s) may be determined by such factors as the subject's condition, such as, stage of the cancer, severity of symptoms caused by the cancer, general health status, as well as age, gender, and weight, the particular form of the active
  • antineoplastic agent and the method of administration.
  • Optimal doses of an agent may generally be determined using experimental models and/or clinical trials if not already established in the relevant art. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for an agent (including when administered for prophylactic benefit) described herein are well within the skill of a person skilled in the relevant art.
  • an amount of an antineoplastic agent may be between 0.01 mg/kg and 1000 mg/kg (e.g., about 0.1 to 1 mg/kg, about 1 to 10 mg/kg, about 10- 50 mg/kg, about 50-100 mg/kg, about 100-500 mg/kg, or about 500-1000 mg/kg) body weight.
  • tosedostat may be administered orally.
  • exemplary doses that may be delivered daily to the subject include doses of 60 or 120 mg/day.
  • the dose may be adjusted higher or lower by a person skilled in the clinical art depending on any one or more of general health status, age, gender, weight, type of cancer, stage of disease, prognosis of disease, and ability to tolerate side effects of the agent.
  • the dose of tosedostat may therefore be between 20-480 mg/day (e.g., 20, 40, 60, 80, 100, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 280, 300, 320, 340, 350, 360, 380, 400, 420, 440, 450, 460, 480 mg/day).
  • methods of treating a subject who has a leukemia e.g., AML
  • each of tosedostat and the at least one additional agent may be administered with the same frequency or may be administered with different frequencies.
  • the at least one additional agent may be administered in cycles, which include a treatment period and non-treatment period.
  • the administration of the two or more agents may overlap.
  • tosedostat may be administered daily for between about 1-4 weeks, between about 1-6 months, between about 1-8 months (e.g., between about 30-240 days), between about 1-10 months, or between about 1-12 months (i.e., from between about 1 month to 1 year) and the additional neoplastic agent may be administered in cycles, which may be any number of days between 1-7 days, between 1-10 days, between 1-14 days, between 1-21 days, or between 1-30 days.
  • a subject (or patient) to be treated may be a mammal, including a human or non-human animal.
  • Non-human animals that may be treated include mammals, for example, non-human primates (e.g., monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, rabbits), lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline, bovine, and other domestic, farm, and zoo animals.
  • non-human primates e.g., monkey, chimpanzee, gorilla, and the like
  • rodents e.g., rats, mice, gerbils, hamsters, ferrets, rabbits
  • lagomorphs e.g., pig, miniature pig
  • swine e.g., pig, miniature pig
  • equine canine
  • in vitro methods for determining the likelihood that a subject who has a cancer will respond to a treatment comprising tosedostat.
  • Such methods comprise detecting expression of genes or the encoded proteins in cancer cells obtained from the subject, for example, by any one of the methods and techniques described herein for obtaining a gene expression profile or protein expression profile.
  • the level of expression which may be an increase or decrease compared to a control sample, of the genes in the cancer cells is determined to provide a gene expression profile.
  • the level of expression of a protein which may be an increase or decrease compared to a control sample, in the cancer cells is determined to provide a protein expression profile.
  • the genes and the encoded protein products for which expression is determined may be preselected according the knowledge in the art for a particular cancer or may include all genes that may be expressed in the cancer cell.
  • the subject may be categorized (classified) as a likely responder to the treatment if the gene expression profile comprises differential expression of 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 155, or all genes listed in Tables 1-4.
  • the subject may be categorized (classified) as a likely responder to the treatment if the gene expression profile comprises differential expression of at least 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of the following genes: IL1RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, PLOD2, FGF2, and ANPEP; or at least 3, 5, 6, 7, 8 or 9 of GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX genes, for example CXCL16, CD93 and GRASP genes.
  • the cancer cells may have an increased expression of PLOD2 and FGF2 and decreased expression oilLlRAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SAT1, FAM129A, ATP2B1, HIF1A, RNF144B, CCNL1, and ANPEP; or increased expression of GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ZNF532, SNN, TNFSF8, and VENTX genes, for example CXCL16, CD93 and GRASP genes.
  • the method may comprise comparison with a control sample, which may be a sample run concurrently, or the control sample may be an historical sample for which data have previously been obtained (e.g., the data described herein and summarized in Tables 1-6).
  • the subject may be categorized (classified) as a likely responder to the treatment if the protein expression profile comprises differential expression of the proteins encoded by 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 155, or all prone sets listed in Tables 1-4.
  • the subject may be categorized (classified) as a likely responder to the treatment if the protein expression profile comprises differential expression of the proteins encoded by at least 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of the following genes: IL1RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXDl, PTPRE, SATl, FAM129A, ATP2B1, HIFIA, RNF144B, CCNL1, PLOD2, FGF2, and ANPEP; or at least 3, 5, 6, 7, 8 or 9 of GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ZNF532, SNN, TNFSF8, and VENTX genes, for example CXCL16, CD93 and GRASP genes.
  • the cancer cells may have an increased expression of the proteins encoded by each of PLOD2 and FGF2 and decreased expression of proteins encoded by each of IL
  • the method may comprise comparison with a control sample, which may be a sample run concurrently, or the control sample may be an historical sample for which data have previously been obtained (e.g., the data described herein and summarized in Tables 1-6).
  • the methods for categorizing or classifying a subject as a likely responder to treatment may further comprise detection of additional genes (i.e. those not listed in Tables 1-4), miRNAs, and proteins (i.e., those not encoded by genes listed in Tables 1-4), such as proteins that are targets of a particular antineoplastic agent.
  • these methods may further comprise detecting the presence or expression of a target protein of tosedostat (e.g., puromycin-sensitive aminopeptidase and leukotriene A4 hydrolase) that is not included in Tables 1-4 or detecting expression of the gene encoding a target protein (e.g., NPEPPS and LTA4H, encoding puromycin- sensitive aminopeptidase and leukotriene A4 hydrolase, respectively).
  • a target protein of tosedostat e.g., puromycin-sensitive aminopeptidase and leukotriene A4 hydrolase
  • NPEPPS and LTA4H encoding puromycin- sensitive aminopeptidase and leukotriene A4 hydrolase
  • the biological sample comprising the cancer cells may be blood, serum, plasma, or a blood cell fraction or bone marrow, or a cell fraction thereof.
  • the biological sample when the subject has a hematological cancer (see description herein), is blood, serum, or plasma or a blood cell fraction or bone marrow, or a cell fraction thereof.
  • the biological sample may be a biopsy of a solid tumor (i.e., tumor sample) obtained from an organ where the tumor originated or from an organ to which the cancer has metastasized.
  • the solid tumor may be obtained from any one of the cancers described herein, including but not limited to pancreatic cancer, melanoma, colon cancer, breast cancer, lung cancer, liver cancer, ovarian cancer, or prostate cancer.
  • methods for typing acute myelogenous leukemia (AML) cells. These methods comprise determining a protein expression profile for cancer cells obtained from the blood or bone marrow of a subject with AML. Any one of the methods and techniques described herein for obtaining a gene expression profile may be performed. The method comprises determining the level of expression, which may be an increase or decrease compared to a control sample, of genes in the cancer cells is determined to provide a gene expression profile. The genes for which expression is determined may be preselected according the knowledge in the art or may include all genes that may be expressed in an AML cell.
  • the method comprises determining differential expression of 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160 or all genes listed in Tables 1-4 .
  • the cancer cells are determined to be AML cells if the gene expression profile comprises differential expression of at least 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of the following genes: IL1RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SATl, FAM129A, ATP2B1, HIFIA, RNF144B, CCNLl, PLOD2, FGF2, and ANPEP; or at least 3, 5, 6, 7, 8 or 9 of GRASP, CXCL16, HNMT, LILRAl, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX genes, for example CXCL16, CD93 and GRASP genes.
  • the cancer cells are typed as AML cells if the cells may have an increased expression of PLOD2 and FGF2 and decreased expression oilLlRAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SATl, F AMI 29 A, ATP2B1, HIFIA,
  • control sample may be including with the typing method or may be an historical sample for which data have previously been obtained (e.g., the data described herein and summarized in Tables 1-6).
  • methods for treating a cancer in a subject comprising obtaining a protein expression profile of cancer cells from the subject; and administering tosedostat to the subject if the protein expression profile comprises expression of at least 3 polypeptides encoded by genes selected from Tables 1-4 (e.g., but not limited to IL1RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SATl, FAM129A, ATP2B1, HIFIA, RNF144B, CCNLl, PLOD2, FGF2, and ANPEP; or GRASP, CXCL16, HNMT, LILRAl, PADI4, RP11-428P16.2/ZNF532, SNN, TNFSF8, and VENTX genes, for example CXCL16, CD93 and GRASP genes).
  • genes selected from Tables 1-4 e.g., but not limited to IL1RAP, TAF1D, ANKRD28, TBC1D8,
  • in vitro methods for determining the likelihood that a subject who has a cancer will respond to a treatment comprising tosedostat, which method comprises obtaining cancer cells from the subject and determining a protein expression profile of cancer cells from the subject.
  • the protein expression profile comprises expression of at least 3 polypeptides encoded by genes selected from Tables 1 and 2 (e.g., but not limited to IL1RAP, TAF1D, ANKRD28, TBC1D8, C5AR1, NAMPT, FGD4, MXD1, PTPRE, SATl, FAM129A, ATP2B1, HIFIA, RNF144B, CCNLl, PLOD2, FGF2, and ANPEP; or GRASP, CXCL16, HNMT, LILRA1, PADI4, RP11-428P16.2/ ZNF532, SNN, TNFSF8, and VENTX genes, for example CXCL16, CD93 and GRASP genes), the subject has a likelihood of having a clinical response to treatment with tosedostat.
  • AML cells may be typed by protein expression profiling, which may also be called proteomics.
  • compositions that comprise tosedostat and pharmaceutical compositions that comprise any one or more the additional antineoplastic agents described herein.
  • a pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, which
  • an effective amount or therapeutically effective amount refers to an amount of an agent or a composition comprising one or more agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • compositions described herein may be formulated as a lyophilizate, or the agent may be encapsulated within liposomes using technology known in the art.
  • Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.
  • antineoplastic agent described herein may be formulated for sustained or slow release.
  • Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site.
  • Sustained-release formulations may contain the active ingredient dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active ingredient release. The amount of active agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition to be treated or prevented.
  • a pharmaceutical composition comprising an antineoplastic agent described herein for use in combination with tosedostat may be called a second pharmaceutical composition. If one or more additional antineoplastic agents are used in combination with tosedostat, the
  • pharmaceutical composition comprising tosedostat may be called a first pharmaceutical composition
  • a pharmaceutical composition comprising a second other antineoplastic agent may be called a second pharmaceutical composition
  • pharmaceutical preparation may refer to the combination of a pharmaceutical composition comprising tosedostat (which may also be called a first pharmaceutical composition) and a second pharmaceutical composition comprising the at least one additional antineoplastic agent.
  • first and second pharmaceutical compositions of the pharmaceutical preparation maybe administered at different frequencies and routes.
  • Kits with unit doses of either tosedostat, or with unit doses of an at least one additional neoplastic agent described herein, or both, usually in oral or injectable doses are provided.
  • Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating the cancer, and optionally an appliance or device for delivery of the
  • kits comprising a pharmaceutical preparation wherein the pharmaceutical preparation comprises a pharmaceutical composition comprising tosedostat (which may also be called a first pharmaceutical composition) and a second pharmaceutical composition comprising a second antineoplastic agent.
  • the second antineoplastic agent may be any one of such agents described herein.
  • CYTARABINE A Phase II prospective, multicenter clinical study designed according to
  • Patients were evaluated with bone marrow aspiration for morphologic, immunophenotypic, and cytogenetic (FISH) examination during screening, after the second course of therapy, and every 3 months thereafter to assess treatment efficacy.
  • FISH cytogenetic
  • the response criteria were as defined by International Working Group (IWG) criteria (see, e.g., Cheson et al, J. Clin. Oncol. 21: 4642-4649 (2003)).
  • CR Complete remission
  • ANC absolute neutrophil count
  • ANC absolute neutrophil count
  • platelet count >100,000/mm 3 .
  • CRp Complete Remission with Incomplete Platelet Recovery
  • PD Any one of the following: (1) >50% increase in bone marrow blast percentage from the best value to a value of at least 25%; (2) >50% increase in circulating (peripheral) blasts (with rising trend); (3) new appearance of circulating (peripheral) blasts (with rising trend on at least 2 consecutive occasions); or (4) development of extramedullary leukemia.
  • Stable Disease Any disease category other than CR, CRp, MLFS, or PD.
  • SPSS version 20 SPSS version 20 (SPSS, Chicago, USA).
  • OS and EFS were estimated according to Kaplan- Mayer method.
  • the complete response rate was 45.4% (15/33); overall response rate was 54.4%) (15 CR, 3 PR); and no response was observed in 7/33 patients who had progressive disease (PD) and 4/33 patients who had stable disease (SD).
  • AML blasts were collected from patients' peripheral blood or bone marrow at diagnosis before treatment initiation.
  • PBMC peripheral blood or bone marrow were isolated and stored as cellular pellets in liquid nitrogen.
  • Total RNA was then extracted using the TRIzol® reagent (Invitrogen and Life Technologies), purified using the RNeasy Kit (QIAGEN) as previously described (see, e.g., Piccaluga et a/., J. Clin. Invest. 2007;117:823-834; Piccaluga et al. , Cancer Res. 67:10703-10, 2007; Piccaluga et a/., Blood 117:3596-608, 2011; Visani et a/., Leukemia 2014
  • Affymetrix microarray Human Gene 1.0. Raw data were then imported in GeneSpring GX12 (Agilent, USA) and analysed as previously reported (see, e.g., Piccaluga etal, J. Clin. Invest. 2007;117:823-834; Piccaluga etal, Cancer Res. 67:10703-10, 2007;
  • PCA Principal component analysis
  • GeneSpring GX 12.0 (Agilent, USA) as previously described (see, e.g., Piccaluga et al, 2011, supra).
  • Unsupervised clustering was generated using a hierarchical algorithm based on the average-linkage method (see, e.g., Hartigan, "Clustering Algorithms”; John Wiley & Sons, Inc., New York. 1975:351 pp.; Eisen etal, Proc. Natl. Acad. Sci. USA 1998;95:14863-68). Only genes displaying a two-fold average change in the expression level across the whole panel were chosen to generate the hierarchical clustering. The expression value of each selected gene is normalized to have a zero mean value and unit standard deviation. The distance between two individual samples was calculated by Pearson distance with the normalized expression values. To perform the supervised gene expression analysis, GeneSpring GX12.0 was used, and
  • each column represents a sample and each row represents a gene.
  • the color scale bar shows the relative gene expression changes normalized by the standard deviation (0 is the mean expression level of a given gene).
  • EASE software was applied in order to establish whether specific cell functions and biological processes, defined according to gene ontology (see, e.g., Jenssen etal., Nat. Genet. 2001;28:21-28; Hosack et a/., Genome Biol. 2003;4:R70), were significantly represented among the deregulated genes ⁇ see, e.g., Dennis et al, Genome Biol. 2003;4:P3; Huang etal, Nat. Protoc. 2009;4:44-57).
  • MCS minimal gene sets
  • stepwise discriminant analysis was performed using IBM Spss Statistics 20.0 (IBM, Armonk, USA) ⁇ see, e.g., Piccaluga etal, 2013, supra).
  • a Support Vector Machine (SVM) algorithm and the leave-one-out method were used to classify cell type correlating with a specific clinical outcome ⁇ i.e., achievement or not of complete remission, CR) ⁇ see, e.g., Piccaluga et al., Cancer Res. 67: 10703-10, 2007; Piccaluga et al, Blood 2011, supra; Piccaluga et al, Haematologica 2008, supra; Piccaluga et al, 2013, supra).
  • the classifier is a confidence measure scoring function based on the values of a set of genes (gene cluster), which are differentially expressed in two sets of cell types, and thus, can be used for cell type classification. The higher the score, the more likely that a cell type is related to the phenotype set. Samples with confidence measure score lower than 0.05 would not be assigned to a particular phenotype and flagged as unclassified.
  • GSEA Gene Set Enrichment Analysis
  • GO Gene Ontology
  • KEGG Oncogenic Signatures and Kyoto Encyclopedia of Genes and Genomes
  • GSEA MsigDB ⁇ see, e.g., Internet site, broadinstitute[dot]org/gsea/msigdb) web-based analysis tool ⁇ see, e.g., Mootha etal, Proc. Natl. Acad. Sci. USA 100, 605-10 (2003); Subramanian etal, Proc. Natl. Acad. Sci. USA 102, 15545-50 (2005)), setting the options to the default (displaying top 10 gene sets with FDR q-value below 0.05).
  • Diagnostic accuracy evaluation A diagnostic accuracy analysis was then designed in order to test the ability of the developed molecular classifier (in particular of the 5-genes based support vector machine classifier) to discriminate AML patients likely to obtain a CR when treated with tosedostat and AraC. Calculations of sensitivity (ST), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), positive and negative likelihood ratio (LR), and odd ratio were made by CATmaker software (Centre for Evidence Based Medicine, Oxford University, at Internet web site cebm[dot]net). The study was conducted according to the REMARK guidelines for biomarker testing ⁇ see, e.g., McShane, et al, J. Natl. Cancer Inst.
  • Table 1 Presented in Table 1 are genes that were upregulated in cells from patients who had complete remission compared with cells from patients who had no response.
  • Table 2 provides genes that were down-regulated in cells from patients who had complete remission compared with cells from patients who had no response.
  • Table 3 provides additional genes that were upregulated in cells from patients who had complete remission compared with cells from patients who had no response, and Table 4 provides further genes that were down-regulated in cells from patients who had complete remission compared with cells from patients who had no response.
  • the 188 genes differentially expressed were significantly associated with six relevant biological functions and pathways: defense response, inflammatory response, immune response, response to stress, signal transduction, PM1 mutated AML, hematopoietic stem cell, and myeloid cell development Information pertinent to these pathway gene sets is provided in Table 5.
  • Table 6 provides information relevant to other pathway gene sets.
  • Figure 3 illustrates the proportion of differentially expressed genes in each of the six pathway related gene sets.
  • ADAM8 ADAM metallopeptidase
  • CD300LF CD300 molecule-like
  • HCP5 HLA complex P5, HCP5,
  • IDII isopentenyl-diphosphate delta
  • IGF2R insulin-like growth factor 2
  • KYNU kynureninase
  • LILRAl leukocyte
  • glycoprotein 1 glycoprotein 1
  • MMD monocyte to macrophage
  • MNDA myeloid cell nuclear
  • MX2 myxovirus (influenza virus)
  • NAMPT phosphoribosyltransferase
  • NCF1B neutrophil cytosolic factor
  • TNFRSFIB tumor necrosis factor
  • TNFSF13B tumor necrosis factor
  • TNFSF8 tumor necrosis factor
  • AKT3 v-akt murine thymoma viral oncogene homolog 3

Abstract

La présente invention concerne des procédés pour le traitement d'un cancer, tel qu'un cancer hématologique ou une tumeur solide, comprenant l'exécution d'une analyse du profil d'expression génique d'un échantillon biologique (par exemple, un échantillon de moelle osseuse, de sang ou d'une tumeur) et l'administration de tosedostat lorsque le profil d'expression génique indique la probabilité d'une réponse clinique pour le traitement.<i /> Dans certains modes de réalisation, le tosedostat est administré en combinaison avec un ou plusieurs agents antinéoplasiques supplémentaires.
PCT/US2016/037078 2015-06-12 2016-06-10 Procédés pour le traitement de cancers WO2016201365A2 (fr)

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CN110923319A (zh) * 2019-12-20 2020-03-27 华中科技大学同济医学院附属同济医院 Ptpre作为靶标在制备或筛选抗肝癌药物中的用途及其相关药物
CN112280865A (zh) * 2020-11-17 2021-01-29 圣湘生物科技股份有限公司 一种用于检测肝癌的试剂组合，试剂盒及其用途
US20220031668A1 (en) * 2020-07-29 2022-02-03 University Of Kentucky Research Foundation Methods of inhibiting procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2
JP7392083B2 (ja) 2017-06-22 2023-12-05 キャンブリッジ ライフ サイエンシーズ リミテッド 抗ｅｒｂｂ３抗体治療に対する食道癌の応答を予測する方法およびキット

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WO2010110346A1 (fr) * 2009-03-24 2010-09-30 独立行政法人理化学研究所 Marqueurs de cellules souches leucémiques
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JP7392083B2 (ja) 2017-06-22 2023-12-05 キャンブリッジ ライフ サイエンシーズ リミテッド 抗ｅｒｂｂ３抗体治療に対する食道癌の応答を予測する方法およびキット
WO2019134946A1 (fr) * 2018-01-04 2019-07-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pour le traitement d'un mélanome résistant
CN110923319A (zh) * 2019-12-20 2020-03-27 华中科技大学同济医学院附属同济医院 Ptpre作为靶标在制备或筛选抗肝癌药物中的用途及其相关药物
CN110923319B (zh) * 2019-12-20 2023-09-12 华中科技大学同济医学院附属同济医院 Ptpre作为靶标在制备或筛选抗肝癌药物中的用途及其相关药物
US20220031668A1 (en) * 2020-07-29 2022-02-03 University Of Kentucky Research Foundation Methods of inhibiting procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2
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