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.