DNA damage repair inhibitors for treatment of cancer

• US 20060142231A1
• Filed: 10/06/2005
• Published: 06/29/2006
• Est. Priority Date: 12/01/2003
• Status: Active Grant

• Current Assignee: Kudos Pharmaceuticals Limited (Astrazeneca PLC), Institute of Cancer Research (University of London)
• Original Assignee: Kudos Pharmaceuticals Limited (Astrazeneca PLC)
• Inventors: O'Connor, Mark, Ashworth, Alan, Jackson, Stephen, Smith, Graeme, Martin, Niall
• Granted Patent: US 8,143,241 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/4706 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/502 ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

DNA Damage Repair Inhibitors for Treatment of Cancer 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.

Claims

1. A method of treatment of cancer in an individual comprising;

administering an inhibitor of a BER pathway to said individual,

wherein said cancer is deficient in a HR dependent DNA DSB repair pathway.

2. The method of claim 1 comprising the step of identifying the individual as having a cancer condition which is deficient in a HR dependent DNA DSB repair pathway.

3. The method of 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.

4. The method of claim 3 wherein said cancer cells have a BRCA1 or BRCA2 deficient phenotype.

5. The method of claim 4 wherein said cancer cells are deficient in BRCA1 or BRCA2.

6. The method of claim 5 wherein said cancer cells are homozygous for a mutation in BRCA1 or BRCA2.

7. The method of claim 3 wherein said cancer cells have phenotype selected from the group consisting of:

an ATM deficient phenotype, an ATR deficient phenotype, an CHK1 deficient phenotype, an CHK2 deficient phenotype, an Rad51 deficient phenotype, a DSS1 deficient phenotype, an RPA deficient phenotype and an XRCC3 deficient phenotype.

8. The method of claim 7 wherein said cancer cells are deficient in a gene selected from the group consisting of:

ATM, ATR, CHK1, CHK2, Rad51, DSS1, RPA and XRCC3.

9. The method of claim 8 wherein said cancer cells are homozygous for a mutation in a gene selected from the group consisting of:

ATM, ATR, CHK1, CHK2, Rad5l, DSS1, RPA and XRCC3.

10. The method of claim 1 wherein said cancer cells are deficient in a gene selected from the group consisting of:

FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG and FANCM.

11. The method of claim 10 wherein said cancer cells are homozygous for a mutation in a gene selected from the group consisting of:

FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG and FANCM.

12. The method of 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 relative to normal cells.

13. The method of 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.

14. The method of claim 1 wherein said cancer is breast, ovary, pancreas or prostate cancer.

15. The method of claim 1 wherein said individual is heterozygous for a mutation in a gene encoding a component of the HR dependent DNA DSB repair pathway.

16. The method of claim 15 wherein said individual is heterozygous for a mutation in ATM, ATR, CHK1, CHK2, Rad5l, DSS1, RPA, XRCC3, BRCA1 and/or BRCA2.

17. The method of claim 1 wherein the BER inhibitor is a peptide fragment of a component of the BER pathway.

18. The method of claim 1 wherein the BER inhibitor is a nucleic acid encoding all or part of the amino acid sequence of component of the BER pathway, or the complement thereof.

19. The method of claim 1 wherein the BER inhibitor inhibits PARP activity.

20. The method of claim 19 wherein said base excision repair 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, and analogues and derivatives thereof.

21. The method of claim 20 wherein said BER in inhibitor is a phthalazin-1(2H)-one or an analogue or derivative thereof.

22. The method of claim 19 wherein said inhibitor is a peptide fragment of PARP.

23. The method of claim 19 wherein the BER inhibitor is a nucleic acid encoding part or all of the PARP amino acid sequence, or the complement thereof.

24. A method of treating cancer comprising administering an inhibitor of HR dependent DNA DSB repair and an inhibitor of base excision repair to an individual in need thereof.

25. The method of claim 24 wherein the BER inhibitor inhibits PARP activity.

26. The method of claim 25 wherein the inhibitor of HR dependent DNA DSB repair inhibits ATM.