Use of RNAI Inhibiting PARP Activity for the Manufacture of a Medicament for the Treatment of Cancer

Abstract

The present invention relates to the use of an agent that inhibits the activity of an enzyme that mediates repair of a DNA strand break in the manufacture of a medicament for the treatment of diseases caused by a defect in a gene that mediates homologous recombination.

1 . Use of an agent that inhibits the activity of an enzyme that mediates repair of a DNA strand break in the manufacture of a medicament for the treatment of diseases caused by a defect in a gene that mediates homologous recombination. 
     
     
         2 . The use as claimed in  claim 1  wherein the enzyme is poly(ADP-ribose) polymerase (PARP). 
     
     
         3 . The use as claimed in  claim 2  wherein the agent is a PARP inhibitor. 
     
     
         4 . The use as claimed in  claim 3  wherein the PARP inhibitor is selected from the group consisting of PARP-1, PARP-2, PARP-3, PARP-4, tankyrase 1 and tankyrase 2. 
     
     
         5 . The use as claimed in  claim 4  wherein the PARP is PARP-1. 
     
     
         6 . The use as claimed in  claim 1  or  claim 2  wherein the agent is an RNAi molecule specific to a PARP gene. 
     
     
         7 . The use as claimed in  claim 6  wherein the RNAi molecule is derived from a nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of:
 a) a nucleic acid sequence as represented by the sequence in  FIG. 9 ,  10 ,  11 ,  12 ,  13  or  14 , or a fragment thereof; 
 b) a nucleic acid sequence which hybridises to the nucleic acid sequences of  FIG. 9 ,  10 ,  11 ,  12 ,  13  or  14 , and encodes a gene for PARP; or 
 c) a nucleic acid sequence which comprises sequences which are degenerate as a result of the genetic code to the nucleic acid sequences defined in (a) and (b). 
 
     
     
         8 . The use as claimed in  claim 6  or  7  wherein the RNAi molecule comprises the nucleic acid sequence aaa agc cau ggu gga gua uga. 
     
     
         9 . The use as claimed in  claim 6  or  7  wherein the RNAi molecule consists of the nucleic acid sequence aag acc aau cuc ucc agu uca ac. 
     
     
         10 . The use as claimed in  claim 6  or  7  wherein the RNAi molecule consists of the nucleic acid sequence aag acc aac auc gag aac aac. 
     
     
         11 . The use as claimed in any preceding claim wherein the defect is a mutation in a gene encoding a protein involved in HR. 
     
     
         12 . The use as claimed in any of  claims 1  to  10  wherein the defect is the absence of a gene encoding a protein involved in HR. 
     
     
         13 . The use as claimed in any of  claims 1  to  10  wherein the defect is in the expression of a gene encoding a protein involved in HR. 
     
     
         14 . The use as claimed in any preceding claim wherein the gene that mediates HR is selected from the group consisting of XRCC1, ADPRT (PARP-1), ADPRTL2 (PARP-2), CTPS, RPA, RPA1, RPA2, RPA3, XPD, ERCC1, XPF, MMS19, RAD51, RAD51B, RAD51C, RAD51D, DMC1, XRCC2, XRCC3, BRCA1, BRCA2, RAD52, RAD54, RAD50, MRE11, NBS1, WRN, BLM, Ku70, Ku80, ATM, ATR, chk1, chk2, FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, RAD1, RAD9, FEN-1, Mus81, Eme1, DDS1 and BARD. 
     
     
         15 . The use as claimed in any preceding claim in the treatment of cancer. 
     
     
         16 . The use as claimed in  claim 15  wherein the cancer is selected from the group consisting of lung, colon, pancreatic, gastric, ovarian, cervical, breast and prostate cancer. 
     
     
         17 . The use as claimed in  claim 15  or  16  wherein the cancer is in a human. 
     
     
         18 . The use as claimed in any of  claims 15  to  17  wherein the cancer is gene-linked hereditary cancer. 
     
     
         19 . The use as claimed in  claim 18  wherein the cancer is breast cancer. 
     
     
         20 . The use as claimed in any of  claims 15  to  19  wherein the cancer cells to be treated are defective in BRCA1 expression. 
     
     
         21 . The use as claimed in any of  claims 15  to  19  wherein the cancer cells to be treated are defective in BRCA2 expression. 
     
     
         22 . The use as claimed in  claim 20  or  21  wherein the cancer cells are partially deficient in BRCA1 and/or BRCA2 expression. 
     
     
         23 . The use as claimed in  claim 20  or  21  wherein the cancer cells are totally deficient in BRCA1 and/or BRCA2 expression. 
     
     
         24 . The use as claimed in any preceding claim wherein the gene that mediates HR is a tumour suppressor gene. 
     
     
         25 . The use as claimed in  claim 24  wherein the tumour suppressor gene is BRCA1. 
     
     
         26 . The use as claimed in  claim 24  wherein the tumour suppressor gene is BRCA2 
     
     
         27 . Use of a PARP inhibitor in the manufacture of a medicament for inducing apoptosis in HR defective cells. 
     
     
         28 . The use as claimed in  claim 27  wherein the HR defective cells are cancer cells. 
     
     
         29 . The use as claimed in  claim 28  wherein the cancer cells defective in HR are partially deficient in HR. 
     
     
         30 . The use as claimed in  claim 28  wherein the cancer cells defective in HR are totally deficient in HR. 
     
     
         31 . A method of treatment of a disease or condition in a mammal, including human, which is caused by a genetic defect in a gene that mediates homologous recombination, which method comprises administering to the mammal a therapeutically effective amount of an agent that inhibits the activity of an enzyme that mediates repair of DNA strand breaks. 
     
     
         32 . A method of inducing apoptosis in HR defective cells in a mammal which method comprises administering to the mammal a therapeutically effective amount of a PARP inhibitor.