Poly-ADP-Ribose-Polymerase as a Therapeutic Target in Paediatric Diffuse Intrinsic Pontine Glioma and Paediatric High Grade Astrocytoma

Paediatric high-grade astrocytomas (pHGA) and diffuse-intrinsic-pontine-gliomas (DIPG) are devastating paediatric malignancies for which there are no effective therapies. Previous evidence found Poly-ADP-Ribose-Polymerase 1 (PARP1) over-expressed in DIPG and pHGA. Immunohistochemical and western-blot analysis was performed on pHGA and DIPG patient tumour samples and cell lines to establish PARP1 expression. Three PARP inhibitors, Veliparib, Olaparib, and Niraparib, were used to study PARP inhibition in multiple pHGA and DIPG cell lines and intracranial xenografts. PARP1 was expressed in the majority of pHGA and DIPG patient samples and cell lines and PARP inhibition in vitro resulted in growth arrest and/or apoptosis. Niraparib was the most effective monotherapeutic agent. Niraparib reduced the rate of DNA repair and sensitized cells in vitro to ionizing radiation (IR). In vivo, Niraparib when combined with IR, inhibited PARP1 and extended survival by 40%. Therefore, PARP1 may serve as a potential therapeutic target in pHGA and DIPG.M.Sc