Method of Treating Cancer by Inhibition of DNA Repair Proteins

Abstract

Methods of treating cancer using antisense oligonucleotides directed against DNA double-strand break repair proteins such as BRCA2 or RAD51 are provided. The antisense oligonucleotides can he used alone, in tandem or in combination with other cancer therapies, in particular with therapies that lead to DNA damage, inhibition of DNA repair or inhibition of DNA synthesis, such as radiation, platinum drugs, alkylating agents, PARP inhibitors, or inhibitors of thymidylate synthase.

1 - 47 . (canceled) 
     
     
         48 . A method of treating cancer in a subject comprising administering to the subject an effective amount of an antisense oligonucleotide comprising a sequence complementary to an mRNA encoding a DNA double strand break repair protein, wherein the antisense oligonucleotide has a length between 7 and 100 nucleotides in length, between about 12 and about 50 nucleotides, between about 12 and 35 nucleotides or between about 12 and 30 nucleotides. 
     
     
         49 . The method according to  claim 48 , wherein the mRNA encodes BRCA2 or RAD51. 
     
     
         50 . The method according to  claim 48 , wherein the antisense oligonucleotide comprises (a) at least 7 consecutive nucleotides of the sequence as set forth in any one of SEQ ID NOs: 1, 2, 3, 13, 14 or 15; (b) at least 10 consecutive nucleotides of the sequence as set forth in any one of SEQ ID NOs: 1, 2, 3, 13, 14 or 15; or (c) the sequence as set forth in any one of SEQ ID NOs: 1, 2, 3, 13, 14 or 15. 
     
     
         51 . The method according to  claim 48 , wherein the antisense oligonucleotide comprises (a) one or more phosphorothioate bonds; (b) one or more 2′-O-methyl modified nucleotides; (c) one or more 2′-O-methoxyethyl (2′-MOE) modified nucleotides; or (d) both RNA and DNA nucleotides. 
     
     
         52 . The method according to  claim 48 , wherein the antisense oligonucleotide is a gapmer antisense oligonucleotide. 
     
     
         53 . The method according to  claim 48 , wherein the cancer is a solid tumour. 
     
     
         54 . The method according to  claim 53 , wherein the cancer is lung cancer, colorectal cancer, gastric cancer, esophageal cancer, breast cancer, ovarian cancer, head and neck cancer or prostate cancer. 
     
     
         55 . The method according to  claim 48 , wherein the antisense oligonucleotide is administered in combination with a second antisense oligonucleotide of between 7 and 100 nucleotides in length comprising a sequence complementary to an mRNA encoding a DNA double strand break repair protein. 
     
     
         56 . The method according to  claim 55 , wherein (a) each antisense oligonucleotide comprises a sequence complementary to a mRNA encoding BRCA2; (b) the first antisense oligonucleotide comprises a sequence complementary to a mRNA encoding BRCA2 and the second antisense oligonucleotide comprises a sequence complementary to an mRNA encoding a different DNA double strand break repair protein in the homologous recombination repair pathway; or (c) the first antisense oligonucleotide comprises a sequence complementary to a mRNA encoding BRCA2 and the second antisense oligonucleotide comprises a sequence complementary to a mRNA encoding a DNA double strand break repair protein in the non-homologous end joining repair pathway. 
     
     
         57 . The method according to  claim 48 , wherein the antisense oligonucleotide is administered in combination with another cancer therapy. 
     
     
         58 . The method according to  claim 57 , wherein the cancer therapy results in DNA damage, inhibition of a DNA repair pathway or inhibition of DNA synthesis. 
     
     
         59 . The method according to  claim 57 , wherein the cancer therapy comprises
 (a) radiation therapy, treatment with a chemotherapeutic drug and/or treatment with an antisense oligonucleotide;   (b) treatment with an alkylating agent;   (c) treatment with a platinum-based chemotherapeutic;   (d) radiation therapy;   (e) treatment with a PARP inhibitor;   (f) treatment with an inhibitor of thymidylate synthase; wherein optionally the inhibitor of thymidylate synthase is (a) an antisense oligonucleotide targeted to thymidylate synthase mRNA; or (b) a chemotherapeutic drug, wherein optionally the chemotherapeutic drug is 5-FU, 5-FUdR, capecitabine, raltitrexed, methotrexate or pemetrexed.   
     
     
         60 . An antisense oligonucleotide of between 7 and 100 nucleotides in length comprising at least 7 consecutive nucleotides of the sequence as set forth in any one of SEQ ID NOs: 2, 3, 14, 15, 30, 31, 32, 33, 34, 35 or 36. 
     
     
         61 . The antisense oligonucleotide according to  claim 60 , wherein the antisense oligonucleotide comprises the sequence as set forth in any one of SEQ ID NOs: 2, 3, 14, 15, 30, 31, 32, 33, 34, 35 or 36. 
     
     
         62 . The antisense oligonucleotide according to  claim 60 , comprising
 (a) one or more phosphorothioate bonds;   (b) one or more 2′-O-methyl modified nucleotides;   (c) one or more 2′-O-methoxyethyl (2′-MOE) modified nucleotides; or   (d) both RNA and DNA nucleotides.   
     
     
         63 . The antisense oligonucleotides according to  claim 60 , wherein the antisense oligonucleotide is a gapmer antisense oligonucleotide. 
     
     
         64 . A pharmaceutical composition comprising one or more of the antisense oligonucleotides according to  claim 60 .