Methods for enhancing the efficacy of cancer therapy

Abstract

The invention concerns the identification of tumor antigens the expression of which is selectively upregulated by retinoid treatment. The invention further concerns improved methods of cancer treatment and, in particular, methods enhancing the efficacy of the treatment of cancers characterized by aberrant Wnt signaling by administration of retinoic acid or other retinoids.

What is claimed is:  
     
         1 . A method for the selective enhancement of the expression of a protein in a tumor cell characterized by aberrant Wnt signaling comprising treating said tumor cell with an effective amount of a retinoid.  
     
     
         2 . The method of  claim 1  wherein said protein is characterized by synergistic enhancement of its expression by a combination of Wnt-1 and said retinoid.  
     
     
         3 . The method of  claim 2  wherein said protein is a cell surface protein.  
     
     
         4 . The method of  claim 2  wherein said protein is over-expressed in tumor cells relative to corresponding normal cells.  
     
     
         5 . The method of  claim 2  wherein said protein is selected from the group consisting of 4-1BB ligand, ephrin b1, ISLR, autotaxin, and Stra6.  
     
     
         6 . The method of  claim 5  wherein said protein is selected from the group consisting of 4-1BB ligand, ephrin b1, ISLR, and Stra 6.  
     
     
         7 . The method of  claim 6  wherein said protein is selected from the group consisting of 4-1BB ligand, ephrin b1, and ISLR.  
     
     
         8 . The method of  claim 1  wherein said retinoid is a retinoic acid.  
     
     
         9 . The method of  claim 1  wherein said tumor is a human cancer.  
     
     
         10 . The method of  claim 9  wherein said human cancer is selected from the group consisting of ovarian cancer, endometrial cancer, Wilm's kidney tumor, colon cancer, breast cancer, prostate cancer, gastric cancer, lung cancer, hepatocellular cancer, and melanoma.  
     
     
         11 . A method for the treatment of a tumor characterized by aberrant Wnt signaling comprising treating said tumor with an effective amount of a combination of a retinoid and an anti-tumor agent, wherein said anti-tumor agent targets a protein in said tumor the expression of which is enhanced by retinoid treatment.  
     
     
         12 . The method of  claim 11  wherein the expression of said protein is synergistically enhanced by a combination of Wnt-1 and a retinoid.  
     
     
         13 . The method of  claim 11  wherein said protein is a cell surface protein.  
     
     
         14 . The method of  claim 11  wherein said protein is selected from the group consisting of 4-1BB ligand, ephrin b1, ISLR, autotaxin and Stra6.  
     
     
         15 . The method of  claim 14  wherein said protein is selected from the group consisting of 4-1BB ligand, ephrin b1, ISLR and Stra 6.  
     
     
         16 . The method of  claim 15  wherein said protein is selected from the group consisting of 4-1BB ligand, ephrin b1 and ISLR.  
     
     
         17 . The method of  claim 11  wherein said retinoid is administered prior to the administration of said anti-tumor agent.  
     
     
         18 . The method of  claim 11  wherein said retinoid is administered concurrently with the administration of said anti-tumor agent.  
     
     
         19 . The method of  claim 11  wherein said retinoid is administered following the administration of said anti-tumor agent.  
     
     
         20 . The method of  claim 11  wherein said anti-tumor agent is an antibody.  
     
     
         21 . The method of  claim 20  wherein said antibody is an antibody fragment.  
     
     
         22 . The method of  claim 21  wherein said antibody fragment is selected from the group consisting of Fab, Fab′, F(ab′) 2 , and Fv fragments, diabodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.  
     
     
         23 . The method of  claim 20  wherein said antibody is a chimeric antibody.  
     
     
         24 . The method of  claim 20  wherein said antibody is a humanized antibody.  
     
     
         25 . The method of  claim 20  wherein said antibody is a human antibody.  
     
     
         26 . The method of  claim 20  wherein said antibody is conjugated to a cytotoxic agent.  
     
     
         27 . The method of  claim 26  wherein said cytotoxic agent is a toxin.  
     
     
         28 . The method of  claim 27  wherein said toxin is a maytansinoid.  
     
     
         29 . The method of  claim 20  wherein said antibody is produced in CHO cells.  
     
     
         30 . The method of  claim 20  wherein said antibody is produced in bacteria.  
     
     
         31 . The method of  claim 20 , further comprising treatment with a chemotherapeutic agent.  
     
     
         32 . The method of  claim 20 , further comprising radiation treatment.  
     
     
         33 . The method of  claim 11  wherein said tumor is a human cancer.  
     
     
         34 . The method of  claim 33  wherein said human cancer is selected from the group consisting of ovarian cancer, endometrial cancer, Wilm's kidney tumor, colon cancer, breast cancer, prostate cancer, gastric cancer, lung cancer, hepatocellular cancer, and melanoma.  
     
     
         35 . A method for identifying a gene target for tumor treatment comprising: 
 (a) contacting a cell expressing a Wnt proto-oncogene with a retinoid;    (b) determining the gene expression profile of said cell; and    (c) identifying a gene the expression of which is enhanced by said retinoid treatment relative to its expression in a corresponding untreated cell, as a target for tumor treatment.    
     
     
         36 . The method of  claim 35  wherein said cell is engineered to conditionally express said Wnt proto-oncogen.  
     
     
         37 . The method of  claim 36  wherein said proto-oncogen is Wnt-1.  
     
     
         38 . The method of  claim 36  further comprising the step of inducing the expression of said Wnt-1 and identifying a gene the expression of which is synergistically enhanced by said tumor treatment and Wnt-1 signaling, as a target for tumor treatment.  
     
     
         39 . The method of  claim 35  wherein said cell is a tumor cell.  
     
     
         40 . The method of  claim 35  comprising identifying a gene the expression of which is selectively enhanced by said retinoid treatment relative to a normal cell treated with said retinoid, as a target for tumor treatment.  
     
     
         41 . The method of  claim 39  wherein said tumor cell is from a frozen tumor sample.  
     
     
         42 . The method of  claim 41  wherein said tumor cell is from a paraffin-embedded, formalin-fixed tumor sample.  
     
     
         43 . The method of  claim 35  wherein the gene expression profile is determined by reverse transcriptase-PCR (RT-PCR) analysis.  
     
     
         44 . The method of  claim 35  wherein the gene expression profile is determined by in situ hybridization.  
     
     
         45 . The method of  claim 35  wherein the gene expression profile is determined by northern blotting.  
     
     
         46 . A method for the treatment of a tumor in a mammalian subject comprising the steps of: 
 (a) incubating a sample of said tumor with a retinoid;    (b) determining the gene expression profile of said sample prior to and following said incubation;    (c) identifying a gene the expression of which is enhanced by said retionid; and    (d) treating said patient with a combination of a retinoid and an anti-tumor agent targeting said gene.    
     
     
         47 . The method of  claim 46  wherein said sample is additionally incubated with Wnt-1.  
     
     
         48 . The method of  claim 47  comprising identifying, in step (c) a gene the expression of which is synergistically enhanced by a combination of said retinoid and Wnt-1.  
     
     
         49 . The method of  claim 46  wherein said anti-tumor agent is an antibody.  
     
     
         50 . The method of  claim 49  wherein said antibody is an antibody fragment.  
     
     
         51 . The method of  claim 50  wherein said antibody fragment is selected from the group consisting of Fab, Fab′, F(ab′) 2 , and Fv fragments, diabodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.  
     
     
         52 . The method of  claim 49  wherein said antibody is a chimeric antibody.  
     
     
         53 . The method of  claim 49  wherein said antibody is a humanized antibody.  
     
     
         54 . The method of  claim 49  wherein said antibody is a human antibody.  
     
     
         55 . The method of  claim 49  wherein said antibody is conjugated to a cytotoxic agent.  
     
     
         56 . The method of  claim 55  wherein said cytotoxic agent is a toxin.  
     
     
         57 . The method of  claim 56  wherein said toxin is a maytansinoid.  
     
     
         58 . The method of  claim 49  wherein said antibody is produced in CHO cells.  
     
     
         59 . The method of  claim 50  wherein said antibody is produced in bacteria.  
     
     
         60 . The method of  claim 46  further comprising treatment with a chemotherapeutic agent.  
     
     
         61 . The method of  claim 46  further comprising radiation treatment.  
     
     
         62 . A method for diagnosing a cancer characterized by aberrant Wnt signaling in a mammalian subject comprising 
 (a) contacting a biological sample obtained from said patient with retinoic acid;    (b) detecting the gene expression profile is said biological sample; and    (c) detecting a tumor antigen the expression of which is enhanced by said retinoid treatment.    
     
     
         63 . The method of  claim 62  wherein said tumor antigen is selected from the group consisting of 4-1BB ligand, ephrin b1, ESLR, autotaxin, and Stra6.  
     
     
         64 . An article of manufacture comprising: a container; 
 an anti-tumor agent within said container; and    instructions to administer said anti-tumor agent in combination with a retinoid.    
     
     
         65 . The article of manufacture of  claim 64  further comprising a retinoid.  
     
     
         66 . The article of manufacture of  claim 65  wherein said retinoid is a retinoic acid.