Tumor treatment

Abstract

The invention concerns an improved method for treating tumor, including cancer, which combines the administration of a chemotherapeutic agent and an antagonist of a gene product the expression of which is upregulated by the chemotherapeutic agent. The invention further concerns methods and means for the diagnosis and classification of tumors, and for the prognosis of the outcome of tumor treatment, and patient response to a particular treatment modality.

1 . A method comprising administering to a subject diagnosed with a tumor an effective amount of a chemotherapeutic agent, and an antagonist of a gene product encoded by a gene the expression of which has been determined to be selectively upregulated in said tumor relative to corresponding normal cells by said chemotherapeutic agent. 
     
     
         2 . The method of  claim 1  wherein the tumor is cancer. 
     
     
         3 . The method of  claim 2  wherein said subject is human. 
     
     
         4 . The method of  claim 3  wherein said cancer is selected from the group consisting of breast cancer, colorectal cancer, lung cancer, prostate cancer, hepatocellular cancer, gastric cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, thyroid cancer, renal cancer, carcinoma, melanoma, brain cancer, and skin cancer. 
     
     
         5 . The method of  claim 4  wherein said cancer is lung cancer. 
     
     
         6 . The method of  claim 4  wherein said cancer is breast cancer. 
     
     
         7 . The method of  claim 4  wherein said cancer is colorectal cancer. 
     
     
         8 . The method of  claim 7  wherein said colorectal cancer is adenocarcinoma. 
     
     
         9 . The method of  claim 4  wherein said cancer is squamous cell carcinoma. 
     
     
         10 . The method of  claim 3  wherein said chemotherapeutic agent is selected from the group consisting of alkylating agents; alkyl sulfonates; aziridines; ethylenimines; methylamelamines; nitrogen mustards; nitrosureas; anti-metabolites; folic acid analogues; purine analogs; pyrimidine analogs, androgens; anti-adrenals; folic acid replenishers; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSKÒ; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11, irinotecan); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; anti-hormonal agents; and pharmaceutically acceptable salts, acids or derivatives thereof. 
     
     
         11 . The method of  claim 10  wherein the chemotherapeutic agent is CPT-11 or 5-FU. 
     
     
         12 . The method of  claim 11  wherein the chemotherapeutic agent is CPT-11. 
     
     
         13 . The method of  claim 12  wherein said cancer is colorectal cancer. 
     
     
         14 . The method of  claim 13  wherein said colon cancer is metastatic adenocarcinoma. 
     
     
         15 . The method of  claim 3  wherein the antagonist is selected from the group consisting of antibodies, antibody fragments, immunoconjugates, peptides, non-peptide small organic molecules, antisense molecules, and oligonucleotide decoys. 
     
     
         16 . The method of  claim 15  wherein the antagonist binds to said gene product. 
     
     
         17 . The method of  claim 16  wherein the antagonist is an antibody. 
     
     
         18 . The method of  claim 16  wherein the antibody is an antibody fragment. 
     
     
         19 . The method of  claim 14  wherein the antibody fragment is selected from the group consisting of Fab, Fab′, F(ab′)2, Fv fragments, diabodies, linear antibodies, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. 
     
     
         20 . The method of  claim 16  wherein the antagonist is an immunoconjugate. 
     
     
         21 . The method of  claim 20  wherein the antagonist is an immunoconjugate comprising a LY6D/E48 monoclonal antibody. 
     
     
         22 . The method of  claim 21  wherein the immunoclojugate is a LY6D/E48-MMAE immunoconjugate. 
     
     
         23 . The method of  claim 17  wherein the antibody is humanized. 
     
     
         24 . The method of  claim 17  wherein the antibody is human. 
     
     
         25 . The method of  claim 12  wherein the gene upregulated by CPT-11 is one or more of the genes listed in Table I. 
     
     
         26 . The method of  claim 25  wherein the gene upregulated by CPT-11 is selected from the group consisting of LY6D/E48/(Accession No. Y12642); galectin-7 (Accession No. AA010777); periplakin (Accession No. AF001691); antileukoproteinase (Accession No. X04470); aquaporin (Accession No. N74607); annexin 8 (Accession No. X16662); neuromedin U (Accession No. X76029); maspin (Accession No. U04313); aquaporin 3 (Accession No. AA630981); keratin 23 (Accession No. AI961431); est (Accession No. A1769930); SPRR3 (Accession No. AI278521); S100-type protein (Accession No. AI963434); and genes with expression patterns similar to galectin-7. 
     
     
         27 . The method of  claim 26  wherein the genes with similar expression patters to galectin-7 are selected from the group consisting of keratin 10; keratin 1; keritinocyte differentiation associated protein; GSPT2; plakophillin; loricrin; est GB AI739528; keratin 14; est GB W73855; profilaggrin; C4.4a; desmocollin 3; keratin 5; LY6D/E48; HNK-1 sulfotransferase; maspin; Unigene cluster Hs.201446; ataxia-telangiectasia group D associated protein; and annexin VIII. 
     
     
         28 . The method of  claim 27  wherein the gene upregulated by CPT-11 is selected from the group consisting of LY6D/E48 (Accession No. Y12642); galectin-7 (Accession No. AA010777); periplakin (Accession No. AF001691); maspin (Accession No. U04313); and aquaporin 3 (Accession No. AA630981). 
     
     
         29 . The method of  claim 28  wherein the gene upregulated by CPT-11 is LY6D/E48 (Accession No. Y12642) or galectin-7 (Accession No. AA010777). 
     
     
         30 . The method of  claim 29  wherein the gene upregulated by CPT-11 is LY6D/E48 and the antagonist is an anti-LY6D/E48 antibody, antibody fragment or immunoconjugate. 
     
     
         31 . A method for inhibiting the proliferation of tumor cells comprising:
 (a) confirming the presence of at least one gene that is selectively upregulated in said tumor cells relative to normal cells by a chemotherapeutic agent; and   (b) treating said tumor cells with said chemotherapeutic agent and an antagonist of at least one of said genes.   
     
     
         32 . The method of  claim 31  wherein said tumor cells are those of a solid tumor. 
     
     
         33 . The method of  claim 32  wherein said solid tumor is a cancer. 
     
     
         34 . The method of  claim 33  wherein said cancer is sleeted from the group consisting of breast cancer, colorectal cancer, lung cancer, prostate cancer, hepatocellular cancer, gastric cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, thyroid cancer, renal cancer, carcinoma, melanoma, and brain cancer. 
     
     
         35 . The method of  claim 24  wherein said antagonist is an antibody, antibody fragment or immunoconjugate. 
     
     
         36 . The method of  claim 35  wherein said treatment is concurrent. 
     
     
         37 . The method of  claim 35  wherein said treatment is consecutive. 
     
     
         38 . The method of  claim 35  wherein said cells are treated with the chemotherapeutic agents first, followed by treatment with said antibody, antibody fragment or immunoconjugate. 
     
     
         39 . The method of  claim 35  wherein treatment with said chemotherapeutic agent continues concurrently with the treatment with said antibody, antibody fragment or immunoconjugate. 
     
     
         40 . A therapeutic composition comprising an effective amount of a chemotherapeutic agent and an antagonist of a gene product encoded by a gene the expression of which is selectively upregulated in tumor cells relative to corresponding normal cells by said chemotherapeutic agent. 
     
     
         41 . The composition of  claim 40  wherein said chemotherapeutic agent is 5-FU or CPT-11. 
     
     
         42 . The composition of  claim 41  wherein the chemotherapeutic agent is CPT-11. 
     
     
         43 . The composition of  claim 42  wherein said tumor is colorectal cancer. 
     
     
         44 . The composition of  claim 43  wherein said tumor is colorectal adenocarcinoma. 
     
     
         45 . The composition of  claim 44  wherein said gene is selected from the group consisting of LY6D/E48 (Accession No. Y12642); galectin-7 (Accession No. AA010777); periplakin (Accession No. AF001691); maspin (Accession No. U04313); and aquaporin 3 (Accession No. AA630981). 
     
     
         46 . The composition of  claim 45  wherein said antagonist is an antibody, antibody fragment or immunoconjugate. 
     
     
         47 . The composition of  claim 45  wherein said antagonist is a non-peptide small molecule. 
     
     
         48 . A prognostic method, comprising:
 (a) determining the expression level of one or more genes selected from the group consisting of LY6D/E48 (Accession No. Y12642); galectin-7 (Accession No. AA010777); periplakin (Accession No. AF001691); maspin (Accession No. U04313); and aquaporin 3 (Accession No. AA630981), or its expression product, in tumor cells of a subject diagnosed with adenocarcinoma, before and following treatment with CPT-11, relative to corresponding normal cells; and   (b) identifying said patient as likely to respond well to combination treatment with CPT-11 and an antagonists of a gene, the expression of which has been selectively induced by CPT-11 treatment.