PARP inhibitors for cancer therapy

Abstract

Poly (ADP-ribose) polymerases (PARPs) can transfer their first ADP-ribose moiety from nicotinamide adenine dinucleotide (NAD+) to an acceptor protein. PARPs play a major role in a wide range of biologic processes through poly (ADP-ribosyl) ation, including the maintenance of genomic stability, transcriptional regulation, energy metabolism, and cell death. Recent findings have thrust (PARPs) into the limelight as potential chemotherapeutic targets, and PARP inhibitors (poly (ADP-ribose) polymerase inhibitors) are currently undergoing clinical evaluation for use as new anti-cancer drugs. PARPs promote the repair of single-strand breaks (SSB) by base excision repair (BER), and the inhibition of PARPs leads to the conversion from single-strand breaks (SSB) to double-strand breaks (DSB). Because BRCA1- or BRCA2-deficient cells are unable to complete homologous recombination efficiently, PARP inhibition in these cells causes a high degree of genomic instability and eventual cell death termed "synthetic lethality." This synthetic lethal approach has been validated in studies that show a striking single-agent activity of PARP inhibitors in preclinical models of BRCA1 and BRCA2 inactivation. Consistent with these results, the PARP inhibitor olaparib (previously known as AZD2281) has shown promising single-agent activity against it in early clinical testing. In additional studies, the PARP inhibitor has shown remarkable activity in BRCA1- or BRCA2-mutant tumors when used in combination with gemcitabine and carboplatin. Phase I and Phase II trials of several PARP inhibitors in combination with DNA-damaging agents are ongoing.