PARP inhibitors for cancer treatment

Poly(ADP-ribose) polymerase (PARP) inhibitors are a promising, novel class of anticancer agents to be used either alone or in combination with chemotherapy and radiotherapy. PARP defines a family of enzymes that catalyse the synthesis of linear or branched biopolymers of ADP-ribose using NAD+ as substrate. Poly(ADP-ribosyl)ation of proteins is regarded as an ubiquitous post-translational modification that modulates a number of cellular processes, including DNA repair. PARP-1 is the founding member of the family and is responsible for most of the cellular poly(ADP-ribose) generated in response to genotoxic stress. Among the eighteen PARP family members identified so far, PARP-1 and PARP-2 are the only PARP proteins that bind to DNA single strand breaks (SSBs), facilitating the repair process by the base excision repair. For this reason, PARPs have been extensively investigated as targets of novel drugs that may be used to enhance the antitumour activity of SSBs inducing agents, such as the methylating compound temozolomide, which is the drug of choice for glioblastoma multiforme, or ionizing radiations. 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 SSBs 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. Synthetic lethality occurs when there is a lethal synergy between two otherwise non-lethal events: PARP inhibition induces a DNA lesion which is lethal only when combined with tumour-associated defects in the HR pathway. Finally, recent studies have shown that inhibition of PARP function might also induce anti-angiogenic effects which might contribute to impair tumour growth. During the last decade several classes of PARP inhibitors, that compete with the substrate NAD+ and interfere with its binding to PARP active site, have been developed and a number of them entered the stage of clinical trials. Many phase I, II and III clinical studies with PARP inhibitors are currently recruiting patients or have been recently completed 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, malignant glioma, colorectal cancer, and leukaemia.