PARP inhibitors for cancer treatment: an update on current clinical trials.

Poly(ADP-ribose) polymerase (PARP) inhibitors are a promising class of anticancer agents to be used either alone or in combination with chemotherapy (e.g., the methylating compound temozolomide, topoisomerase I poisons) and radiotherapy. Moreover, PARP inhibitors exert cytotoxic effects as single agents in BRCA mutated tumours, which are defective in the homologous recombination (HR) repair of DNA double strand breaks (DSBs). Germline mutations in one allele of the tumour suppressor BRCA1 or BRCA2 genes predispose to the development of several cancers, such as breast and ovarian cancers which arise after inactivation of the remaining BRCA allele. In normal or heterozygous cells, treatment with PARP inhibitor as single agent does not cause cytotoxic effects, since the DSBs, generated after collision with the replication fork of single strand breaks deriving from PARP inhibition, are repaired by HR. PARP inhibitors, instead, selectively kill tumour cells carrying mutations in both alleles of BRCA genes, as DSBs can no longer be repaired. Therefore, the use of PARP inhibitors in BRCA deficient tumours provides the basis for a novel “synthetic lethal” approach to cancer treatment. Many phase I, II and III clinical studies with PARP inhibitors have been recently completed or are currently recruiting patients for the treatment of a variety of advanced solid tumours, including ovarian cancer, triple-negative (i.e., estrogen receptor-negative, progesterone receptor-negative and HER2-negative) breast cancer, melanoma, glioblastoma, colorectal cancer, and haematological malignancies.