PARP inhibition: targeting the Achilles' heel of DNA repair to treat germline and sporadic ovarian cancers.
OBJECTIVE
Ovarian cancer remains the gynaecological malignancy with the highest mortality in the Western world. The strategy of identifying biologically distinct subgroups of ovarian cancer by means of clinical characteristics, histology and molecular profiling is an exciting prospect in personalizing and improving therapy for ovarian cancer.


RESULTS
Preclinical recognition that BRCA1 and BRCA2-associated tumours are very sensitive to inhibition of poly-ADP ribose polymerase (PARP), a key molecule in DNA repair, led to ovarian cancer patients with germline BRCA1 and BRCA2 mutations being treated with the PARP inhibitor olaparib (AZD2281, KU-0059436; KuDOS/Astra-Zeneca). The initial trials of olaparib in this patient population demonstrated an impressive rate of clinical benefit. Furthermore, tumours from patients with sporadic ovarian cancer have been found to commonly have somatic BRCA1 and BRCA2 mutations or other defects in DNA repair, with the implication that PARP inhibition may also have a role in treating these patients.


CONCLUSIONS
In this review, we discuss DNA repair mechanisms and strategies used to target them in oncology, our current experience with PARP inhibition in BRCA1 and BRCA2-mutation associated and sporadic ovarian cancer, as well as current issues in the clinical development of these agents.
Carden
Craig P
CP
The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, UK.
Yap
Timothy A
TA
Kaye
Stan B
SB
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004260:DNA Repair / Q000187:drug effects*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics
D000970:Antineoplastic Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases