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Ref Type Journal Article
PMID (26351319)
Authors Chornenkyy Y, Agnihotri S, Yu M, Buczkowicz P, Rakopoulos P, Golbourn B, Garzia L, Siddaway R, Leung S, Rutka JT, Taylor MD, Dirks PB, Hawkins C
Title Poly-ADP-Ribose Polymerase as a Therapeutic Target in Pediatric Diffuse Intrinsic Pontine Glioma and Pediatric High-Grade Astrocytoma.
Journal Molecular cancer therapeutics
Vol 14
Issue 11
Date 2015 Nov
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown astrocytoma not applicable Niraparib + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, a pediatric high grade astrocytoma cell line treated with a combination of ionizing radiation and Zejula (niraparib) demonstrated a greater reduction in cell survival in culture and a better survival benefit in xenograft models compared to either agent alone (PMID: 26351319). 26351319
Unknown unknown astrocytoma not applicable Niraparib Preclinical - Cell line xenograft Actionable In a preclinical study, pediatric high grade astrocytoma cell lines treated with Zejula (niraparib) demonstrated decreased cell viability and proliferation in culture, and a small survival benefit in xenograft models (PMID: 26351319). 26351319
Unknown unknown astrocytoma not applicable Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) resulted in decreased cell viability of some pediatric high grade astrocytoma cell lines in culture (PMID: 26351319). 26351319
Unknown unknown brain stem glioma not applicable Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) resulted in decreased cell viability of some diffuse intrinsic pontine glioma cell lines in culture (PMID: 26351319). 26351319
Unknown unknown brain stem glioma no benefit Veliparib Preclinical - Cell culture Actionable In a preclinical study, Veliparib (ABT-888) had a very limited effect on the cell viability of multiple cultured pediatric diffuse intrinsic pontine glioma cell lines (PMID: 26351319). 26351319
Unknown unknown brain stem glioma not applicable Niraparib + Radiotherapy Preclinical - Cell culture Actionable In a preclinical study, a diffuse intrinsic pontine glioma cell line treated with a combination of ionizing radiation and Zejula (niraparib) in culture demonstrated a greater reduction in cell survival compared to either agent alone (PMID: 26351319). 26351319
Unknown unknown astrocytoma no benefit Veliparib Preclinical - Cell culture Actionable In a preclinical study, Veliparib (ABT-888) had a very limited effect on the cell viability of multiple cultured pediatric high grade astrocytoma cell lines (PMID: 26351319). 26351319