- Document Number:
20240245643
- Appl. No:
18/473061
- Application Filed:
September 22, 2023
- نبذة مختصرة :
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.
- Claim:
1. A method of determining whether an individual having a cancer condition will respond to PARP inhibitor treatment comprising; providing a sample of cancer cells obtained from an individual having a cancer condition, and identifying one or more cancer cells in the sample as deficient in HR dependent DNA DSB repair relative to normal cells, wherein the presence of one or more cancer cells deficient in HR dependent DNA DSB repair indicates that the individual will respond to said treatment.
- Claim:
2. A method according to claim 1 comprising providing a PARP inhibitor suitable for administration to said individual.
- Claim:
3. A method according to claim 1 comprising administering a PARP inhibitor to said individual.
- Claim:
4. A method according to claim 1 wherein said cancer cells are identified as deficient in a HR dependent DNA DSB repair pathway by determining the HR dependent DNA DSB repair activity of said cancer cells.
- Claim:
5. A method according to claim 4 wherein the HR dependent DNA DSB repair activity of said cancer cells is determined by measuring the formation of foci containing Rad51 in the nucleus of the cancer cells in response to DNA damaging agents or PARP inhibitors
- Claim:
6. A method according to claim 1 wherein said cancer cells are identified as deficient in a HR dependent DNA DSB repair pathway by determining the presence of one or more mutations or polymorphisms in a nucleic acid sequence encoding a component of HR dependent DNA DSB repair in the cancer cells.
- Claim:
7. A method according to claim 6 wherein a portion of the nucleic acid sequence encoding a component of HR dependent DNA DSB repair suspected of containing mutations or polymorphisms is amplified using an amplification reaction and the amplified nucleic acid is then tested to determine the presence or absence of one or more mutations or polymorphisms which reduces or abrogates the expression or activity of the HR dependent DNA DSB repair pathway component.
- Claim:
8. A method according to claim 6 wherein the presence of one or more mutations or polymorphisms in a nucleic acid sequence encoding a component of HR dependent DNA DSB repair in the cancer cells is determined at the protein level by detecting the presence of a variant polypeptide which polypeptide is a component of HR dependent DNA DSB repair.
- Claim:
9. A method according to claim 8 wherein the variant polypeptide is detected by contacting a cancer cell sample with a binding member directed against the variant polypeptide.
- Claim:
10. A method according to claim 9 wherein the binding member is an antibody molecule.
- Claim:
11. A method according to claim 6 wherein said component of HR dependent DNA DSB repair is selected from the group consisting of: ataxia telangiectasia mutated (ATM), RAD51 homolog (RecA homolog, E. coli) (S. cerevisiae) (RAD51), RAD51 homolog B (S. cerevisiae) (RAD51L1), RAD51 homolog C (S. cerevisiae) (RAD51C), RAD51 homolog D (S. cerevisiae) (RAD51L3), DMC1 dosage suppressor of mck1 homolog, meiosis-specific homologous recombination (yeast) (DMC1), X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2), X-ray repair complementing defective repair in Chinese hamster cells 3 (XRCC3), RAD52 homolog (S. cerevisiae) (RAD52), RAD54-like (S. cerevisiae) (RAD54L), RAD54 homolog B (S. cerevisiae) (RAD54B), breast cancer 1 (BRCA1), breast cancer 2 (BRCA2), RAD50 homolog (S. cerevisiae) (RAD50), MRE11 meiotic recombination 11 homolog A (S cerevisae) (MRE11A) and nibrin (NBS1).
- Claim:
12. A method according to claim 11 wherein said cancer cells are identified as homozygous for a mutation in ATM, RAD51, RAD51L1, RAD51C, RAD51L3, DMC1, XRCC2, XRCC3, RAD52, RAD54L, RAD54B, BRCA1, BRCA2, RAD50, MRE11A, or NBS1.
- Claim:
13. A method according to claim 11 wherein said cancer cells are identified as heterozygous for a mutation in ATM, RAD51, RAD51L1, RAD51C, RAD51L3, DMC1, XRCC2, XRCC3, RAD52, RAD54L, RAD54B, BRCA1, BRCA2, RAD50, MRE11A, or NBS1.
- Claim:
14. A method according to claim 1 wherein said cancer cells are breast, ovary, pancreas or prostate cancer cells.
- Claim:
15. A method according to claim 1 wherein said PARP inhibitor is a PARP-1 inhibitor.
- Claim:
16. A method according to claim 1 wherein said PARP inhibitor is a nicotinamide, a benzamide, an isoquinolinone, a dihydroisoquinolinone, a benzimidazole, an indole, a phthalazinone, a quinazolinone, an isoindolinone, a phenanthridine, a phenanthridinone, a benzopyrone, an unsaturated hydroximic acid derivative or a pyridazine.
- Claim:
17. A method according to claim 16 wherein said PARP inhibitor is a phthalazin-1(2H)-one.
- Claim:
18. A method according to claim 1 wherein the method comprises obtaining said sample of cancer cells from the individual.
- Claim:
19. A method of determining whether an individual having a cancer condition will respond to PARP inhibitor treatment comprising; contacting a PARP inhibitor with a sample of cancer cells obtained from the individual having the cancer condition, and; determining the amount of cell death in said sample, wherein the presence of cell death in said sample indicates that the individual will respond to said treatment and the absence of cell death in said sample indicates that the individual will not respond to said treatment.
- Current International Class:
61; 61; 61; 61; 61; 61; 61; 61; 61; 61
- الرقم المعرف:
edspap.20240245643
Processing Request
No Comments.