DNA damage repair inhibitors for the treatment of cancer
View Patent ↗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. A method of treatment of cancer in an individual comprising;
identifying a cancer cell obtained from the individual as deficient in homologous recombination (HR) dependent deoxyribonucleic acid (DNA) double strand break (DSB) repair relative to normal cells; and
administering a poly(ADP-ribose)polymerase (PARP) inhibitor to said individual.
2. A method according to claim 1 wherein said cancer is identified as a HR dependent DNA DSB repair deficient cancer by determining the HR dependent DNA DSB repair activity of cancer cells from the individual.
3. A method according to claim 1 wherein the activity of the HR dependent DNA DSB repair pathway is determined in the cancer cells by measuring the formation of foci containing Rad51 in the nucleus in response to DNA damage or PARP inhibitors.
4. A method according to claim 1 wherein said cancer is identified as an HR dependent DSB repair deficient cancer by determining the presence in cancer cells from the individual of one or more mutations or polymorphisms in a nucleic acid sequence encoding a component of the HR dependent DNA DSB repair pathway.
5. A method according claim 1 wherein said cancer comprises one or more cancer cells having a reduced or abrogated ability to repair DNA DSB by HR relative to normal cells.
6. A method according to claim 5 wherein said cancer cells are deficient in breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2).
7. A method according to claim 6 wherein said cancer cells are homozygous for a mutation in BRCA1 or BRCA2.
8. A method according to claim 6 wherein said cancer cells are heterozygous for a mutation in BRCA1 and/or BRCA2.
9. A method according to claim 1 wherein said PARP inhibitor is a phthalazin-1(2H)-one.
10. A method according to claim 2 wherein the HR dependent DNA DSB repair activity of cancer cells from the individual is determined relative to normal cells.
11. A method according to claim 2 where the cancer cell obtained from the individual is deficient in a HR dependent DNA DSB repair pathway relative to normal cells.