Dna damage repair inhibitors for treatment of cancer

Abstract

The present invention relates to the recognition that inhibition of the base excision repair pathway is selectively lethal in cells which are deficient in HR dependent DNA DSB repair. Methods and means relating to the treatment of cancers which are deficient in HR dependent DNA DSB repair using inhibitors which target base excision repair components, such as PARP, is provided herein.

1 .- 19 . (canceled) 
     
     
         20 . A method of treatment of a cancer deficient in the homologous recombination (HR) dependent deoxyribonucleic acid (DNA) double strand break (DSB) repair pathway in an individual in need thereof comprising;
 administering a poly (ADP-ribose) polymerase (PARP) inhibitor to said individual.   
     
     
         21 . A method according to  claim 20  wherein the cancer is deficient in breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2). 
     
     
         22 . A method according to  claim 20  wherein said PARP inhibitor is selected from the group consisting of nicotinamides, benzamides, isoquinolinones, dihydroisoquinolinones, benzimidazoles, indoles, phthalazin-1(2H)-ones, quinazolinones, isoindolinones, phenanthridines, benzopyrones, unsaturated hydroximic acid derivatives, caffeine, theophylline, and thymidine. 
     
     
         23 . A method according to  claim 22  wherein said PARP inhibitor is a phthalazin-1(2H)-one. 
     
     
         24 . A method according to  claim 20  further comprising administering a DNA damaging chemotherapeutic agent to said individual wherein the DNA damaging chemotherapeutic agent is selected from the group consisting of camptothecin, irinotecan, topotecan, rubitecan, temozolomide, DTIC (dacarbazine), cisplatin, cisplatin-doxorubicincyclophosphamide, carboplatin, and carboplatin-paclitaxel, doxorubicin-cyclophosphamide, capecitabine, cyclophosphamide-methotrexate-5-fluorouracil, docetaxel, 5-flouracil-epirubicincyclophosphamide, paclitaxel, vinorelbine, etoposide, and pegylated liposomal doxorubicin. 
     
     
         25 . A method of treatment of cancer in an individual in need thereof comprising;
 identifying a cell obtained from the individual as having one or more mutations or polymorphisms in a nucleic acid sequence encoding a component of the HR dependent DNA DSB repair pathway; and   administering a poly (ADP-ribose) polymerase (PARP) inhibitor to said individual.   
     
     
         26 . A method according to  claim 25  wherein said component of the HR dependent DNA DSB repair pathway is breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2). 
     
     
         27 . A method according to  claim 25  wherein the cell is identified as heterozygous for said one or more mutations or polymorphisms. 
     
     
         28 . A method according to  claim 25  wherein the cell is identified as heterozygous for a mutation or polymorphism in BRCA1 and/or BRCA2. 
     
     
         29 . A method according to  claim 25  wherein said PARP inhibitor is selected from the group consisting of nicotinamides, benzamides, isoquinolinones, dihydroisoquinolinones, benzimidazoles, indoles, phthalazin-1(2H)-ones, quinazolinones, isoindolinones, phenanthridines, benzopyrones, unsaturated hydroximic acid derivatives, caffeine, theophylline, and thymidine. 
     
     
         30 . A method according to  claim 29  wherein said PARP inhibitor is a phthalazin-1(2H)-one 
     
     
         31 . A method according to  claim 25  further comprising administering a DNA damaging chemotherapeutic agent to said individual wherein the DNA damaging chemotherapeutic agent is selected from the group consisting of camptothecin, irinotecan, topotecan, rubitecan, temozolomide, DTIC (dacarbazine), cisplatin, cisplatin-doxorubicincyclophosphamide, carboplatin, and carboplatin-paclitaxel, doxorubicin-cyclophosphamide, capecitabine, cyclophosphamide-methotrexate-5-fluorouracil, docetaxel, 5-flouracil-epirubicincyclophosphamide, paclitaxel, vinorelbine, etoposide, and pegylated liposomal doxorubicin. 
     
     
         32 . A method according to  claim 25  wherein the cancer is deficient in the HR dependent DNA DSB repair pathway. 
     
     
         33 . A method of treatment of cancer in an individual in need thereof comprising;
 administering a poly (ADP-ribose) polymerase (PARP) inhibitor to said individual,   wherein a cell obtained from the individual has been previously identified as having one or more mutations or polymorphisms in a nucleic acid sequence encoding a component of the HR dependent DNA DSB repair pathway.   
     
     
         34 . A method according to  claim 33  wherein the component of the HR dependent DNA DSB repair pathway is breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2). 
     
     
         35 . A method according to  claim 33  wherein the cell is identified as heterozygous for said one or more mutations or polymorphisms. 
     
     
         36 . A method according to  claim 33  wherein the cell is identified as heterozygous for a mutation or polymorphism in BRCA1 and/or BRCA2, 
     
     
         37 . A method according to  claim 33  wherein said PARP inhibitor is selected from the group consisting of nicotinamides, benzamides, isoquinolinones, dihydroisoquinolinones, benzimidazoles, indoles, phthalazin-1(2H)-ones, quinazolinones, isoindolinones, phenanthridines, benzopyrones, unsaturated hydroximic acid derivatives, caffeine, theophylline, and thymidine. 
     
     
         38 . A method according to  claim 37  wherein said PARP inhibitor is a phthalazin-1(2H)-one. 
     
     
         39 . A method according to  claim 33  further comprising administering a DNA damaging chemotherapeutic agent to said individual wherein the DNA damaging chemotherapeutic agent is selected from the group consisting of camptothecin, irinotecan, topotecan, rubitecan, temozolomide, DTIC (dacarbazine), cisplatin, cisplatin-doxorubicincyclophosphamide, carboplatin, and carboplatin-paclitaxel, doxorubicin-cyclophosphamide, capecitabine, cyclophosphamide-methotrexate-5-fluorouracil, docetaxel, 5-flouracil-epirubicincyclophosphamide, paclitaxel, vinorelbine, etoposide, and pegylated liposomal doxorubicin. 
     
     
         40 . A method according to  claim 33  wherein the cancer is deficient in the HR dependent DNA DSB repair pathway.