PARP inhibitors and familial breast cancer (#86)
The poly(ADP-ribose) polymerase family (PARPs) is a set of molecules involved in the repair of DNA damage and in many other cellular processes. One of the most highly studied processes is that involved with DNA base excision repair (BER). This has led to one of the first examples of a “synthetic lethal” approach to cancer therapy when inhibition of PARP activity in BER in the setting of a cancer arising because of an inherited defect in DNA homologous repair (HR) results in cancer cell death. Elegant pre-clinical studies have illustrated this approach in BRCA mutant tumours and initial clinical studies of single agent PARP inhibitors in BRCA mutation carriers with breast or ovarian cancer have confirmed their clinical activity. The challenges for the future include
· Understanding mechanisms of resistance to PARP inhibitors
· Combining PARP inhibitors with other therapies to maximise clinical efficacy
· Moving PARP inhibitors into the adjuvant therapy and cancer prevention settings
· Expanding the use of PARP inhibitors to other cancers with inherited or acquired compromise of their DNA-repairing machineries.