Compositions and Methods for the Diagnosis and Therapy of BCL2-Associated Cancers

Abstract

Provided are methods and compositions for the treatment of cancers associated with overexpression of a BCL2 gene and/or gene product in a subject, and methods and compositions for the improvement of anti-cancer therapy, such as chemotherapy and radiation therapy. Also provided are methods for determining the efficacy of a cancer therapy in a subject, methods for diagnosing cancer, methods for assessing patient prognosis, and methods for inducing apoptosis of a cell.

What is claimed is: 
     
         1 . A method of diagnosing or prognosticating a BCL2-associated cancer in a subject, comprising:
 measuring a level of at least one miR gene product in a sample from the subject;   comparing the level of the at least one miR gene product in the sample to a control; and diagnosing the subject as having a BCL2-associated cancer if the level of the at least one miR gene product in the test sample from the subject is low relative to that of the control, wherein the at least one miR gene product comprises a nucleotide sequence that is complementary to a nucleotide sequence in a BCL2 gene transcript.   
     
     
         2 . The method of  claim 1 , wherein the at least one miR gene product is miR-15a or miR-16-1. 
     
     
         3 . The method of  claim 1 , wherein the at least one miR gene product is selected from the group consisting of: miR-182, miR-181, miR-30, miR-15a, miR-16-1, miR-15b, miR-16-2, miR-195, miR-34, miR-153, miR-21, miR-217, miR-205, miR-204, miR-211, miR-143, miR-96, miR-103, miR-107, miR-129, miR-9, miR-137, miR-217, miR-186, and combinations thereof. 
     
     
         4 . The method of  claim 1 , wherein the at least one miR gene product is selected from the group consisting of: miR-182, miR-181, miR-30, miR-15a, miR-16-1, miR-15b, miR-16-2, miR-195, and combinations thereof. 
     
     
         5 . The method of  claim 1 , wherein the at least one miR gene product comprises a nucleotide sequence that is complementary to nucleotides 3741-3749 of SEQ ID NO: 55. 
     
     
         6 . The method of  claim 1 , wherein the control is the level of the at least one miR gene product from a subject that does not have a BCL2-associated cancer. 
     
     
         7 . The method of  claim 1 , wherein the control is the level of the at least one miR gene product from a non-cancerous sample of the subject. 
     
     
         8 . The method of  claim 1 , wherein the cancer is selected from the group consisting of: CLL, lung cancer, and lymphoma. 
     
     
         9 . The method of  claim 1 , wherein the cancer is a lymphoma selected from the group consisting of: a follicular lymphoma cell, a small cell lymphoma cell, a large cell lymphoma cell, and a non-Hodgkin's lymphoma cell. 
     
     
         10 . The method of  claim 1 , wherein the cancer is lung cancer. 
     
     
         11 . The method of  claim 10 , wherein the lung cancer is a non-small cell lung carcinoma cell. 
     
     
         12 . The method of  claim 1 , wherein the cancer is a cancer selected from the group consisting of: acute myeloid leukemia, multiple myeloma, melanoma, a hematologic malignancy, a solid tumor, colorectal cancer, brain carcinoma, breast carcinoma, prostate carcinoma, Epstein-Barr virus-associated lymphoproliferative disease, renal carcinoma, hepatocellular carcinoma and gastric carcinoma. 
     
     
         13 . The method of  claim 1 , wherein the sample is derived from tumor tissue. 
     
     
         14 . The method of  claim 1 , wherein the sample is derived from blood. 
     
     
         15 . The method of  claim 1 , wherein the at least one miR gene product is measured by hybridization assay. 
     
     
         16 . A method of diagnosing a subject having a BCL2-associated cancer, comprising:
 reverse transcribing at least one miR gene product from a nucleic acid-containing test sample from tissue of the subject to provide at least one corresponding miR gene product target oligonucleotide;   hybridizing the at least one corresponding miR gene product target oligodeoxynucleotide to a microarray comprising miRNA-specific probe oligonucleotides that includes at least one probe specific for at least one miR gene product comprising a nucleotide sequence complementary to a nucleotide sequence in a BCL2 gene transcript, to provide a hybridization profile for the test sample;   comparing the test sample hybridization profile to at least one control hybridization profile of non-cancerous tissue; and   diagnosing the subject as having the BCL2-associated cancer if the level of at least one miR gene product in the test sample is low relative to the control level of corresponding miR gene product.   
     
     
         17 . The method of  claim 16  further comprising measuring Bcl2 protein expression. 
     
     
         18 . The method of  claim 16  wherein the BCL2-associated cancer is selected from the group consisting of: CLL, lung cancer, prostate cancer, and colorectal cancer. 
     
     
         19 . The method of  claim 16 , wherein the miR gene product is miR-15a and/or miR-16-1. 
     
     
         20 . A method for determining the efficacy of a cancer therapy in a subject, comprising administering at least one therapeutic agent to the subject and subsequently measuring the expression of at least one miR gene product in a sample from the subject, wherein the miR gene product comprises a nucleotide sequence that is complementary to a nucleotide sequence in a BCL2 gene transcript. 
     
     
         21 . The method of  claim 20 , wherein the subject has CLL. 
     
     
         22 . The method of  claim 20 , wherein the subject has a cancer associated with overexpression of Bcl2 protein. 
     
     
         23 . The method of  claim 20 , wherein the miR gene product is miR-15a, miR-16-1, miR-15b, miR-16-2 or a combination thereof. 
     
     
         24 . The method of  claim 20 , wherein an increase in the expression of the miR gene product relative to a suitable control is indicative of successful treatment. 
     
     
         25 . A pharmaceutical composition for treating a Bcl2-associated cancer, comprising at least one anti-cancer agent and at least one miR gene product, wherein the at least one miR gene product comprises a nucleotide sequence that is complementary to nucleotides 3741-3749 of SEQ ID NO: 55.