Targeted Therapy for Brain Tumours: Role of PARP Inhibitors

C.      Leonetti; A.      Biroccio; G.      Graziani; L.      Tentori

Abstract

The prognosis of malignant glioma and metastatic brain tumours is still extremely poor, despite recent advances in therapeutic strategies with molecular-targeted agents. Poly(ADP-ribose) polymerase (PARP) inhibitors are a promising, novel class of anticancer drugs to be used either as single agents or in combination with chemotherapy and radiotherapy. 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, or ionizing radiations. Moreover, PARP inhibitors exert cytotoxic effects in monotherapy in BRCA mutated tumours, which are defective in the homologous recombination (HR) repair. Finally, recent studies have shown that inhibition of PARP function might also induce anti-angiogenic effects which might contribute to impair tumour growth.

Many clinical trials with PARP inhibitors are ongoing for the treatment of a variety of advanced solid tumours, including primary or secondary brain tumours. This review discusses the implications of targeting PARP on the design of new treatment regimens.

Keywords: Angiogenesis, chemoresistance, combination therapy, molecular-targeted therapy, poly(ADP-ribose) polymerase (PARP) inhibitors, telomere, temozolomide, topoisomerase I inhibitors, 6-Thioguanine, Base Excision Repair, DNA-dependent Protein Kinase, Homologous Recombination, Non Homologous DNA End Joining, Phosphate and Tension Homolog, Platelet-derived Growth Factor Receptor