Pediatric high-grade astrocytomas (pHGA) and diffuse intrinsic pontine gliomas 
(DIPG) are devastating malignancies for which no effective therapies exist. We 
investigated the therapeutic potential of PARP1 inhibition in preclinical models 
of pHGA and DIPG. PARP1 levels were characterized in pHGA and DIPG patient 
samples and tumor-derived cell lines. The effects of PARP inhibitors veliparib, 
olaparib, and niraparib as monotherapy or as radiosensitizers on cell viability, 
DNA damage, and PARP1 activity were evaluated in a panel of pHGA and DIPG cell 
lines. Survival benefit of niraparib was examined in an orthotopic xenograft 
model of pHGA. About 85% of pHGAs and 76% of DIPG tissue microarray samples 
expressed PARP1. Six of 8 primary cell lines highly expressed PARP1. 
Interestingly, across multiple cell lines, some PARP1 protein expression was 
required for response to PARP inhibition; however, there was no correlation 
between protein level or PARP1 activity and sensitivity to PARP inhibitors. 
Niraparib was the most effective at reducing cell viability and proliferation 
(MTT and Ki67). Niraparib induced DNA damage (γH2AX foci) and induced growth 
arrest. Pretreatment of pHGA cells with a sublethal dose of niraparib (1 μmol/L) 
before 2 Gy of ionizing radiation (IR) decreased the rate of DNA damage repair, 
colony growth, and relative cell number. Niraparib (50 mg/kg) inhibited PARP1 
activity in vivo and extended survival of mice with orthotopic pHGA xenografts, 
when administered before IR (20 Gy, fractionated), relative to control mice (40 
vs. 25 days). Our data provide in vitro and in vivo evidence that niraparib may 
be an effective radiosensitizer for pHGA and DIPG.