Abstract |
Despite the use of ionizing radiation (IR) and temozolomide (TMZ), outcome for glioblastoma (GBM) patients remains dismal. Poly (ADP-ribose) polymerase (PARP) is important in repair pathways for IR-induced DNA damage and TMZ-induced alkylation at N7-methylguanine and N3-methyldenine. However, optimized protocols for administration of PARP inhibitors have not been delineated. In this study, the PARP inhibitor ABT-888 was evaluated in combination with and compared to current standard-of-care in a genetically engineered mouse GBM model. Results demonstrated that concomitant TMZ/IR/ ABT-888 with adjuvant TMZ/ ABT-888 was more effective in inducing apoptosis and reducing proliferation with significant tumor growth delay and improved overall survival over concomitant TMZ/IR with adjuvant TMZ. Diffusion-weighted MRI, an early translatable response biomarker detected changes in tumors reflecting response at 1 day post TMZ/IR/ ABT-888 treatment. This study provides strong scientific rationale for the development of an optimized dosing regimen for a PARP inhibitor with TMZ/IR for upfront treatment of GBM.
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Authors | Benjamin Lemasson, Hanxiao Wang, Stefanie Galbán, Yinghua Li, Yuan Zhu, Kevin A Heist, Christina Tsein, Thomas L Chenevert, Alnawaz Rehemtulla, Craig J Galbán, Eric C Holland, Brian D Ross |
Journal | Neoplasia (New York, N.Y.)
(Neoplasia)
Vol. 18
Issue 2
Pg. 82-9
(Feb 2016)
ISSN: 1476-5586 [Electronic] United States |
PMID | 26936394
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Benzimidazoles
- Poly(ADP-ribose) Polymerase Inhibitors
- veliparib
- Dacarbazine
- Temozolomide
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Topics |
- Animals
- Apoptosis
(drug effects)
- Benzimidazoles
(administration & dosage)
- Cell Line, Tumor
- Chemoradiotherapy
- Dacarbazine
(administration & dosage, analogs & derivatives)
- Disease Models, Animal
- Drug Resistance, Neoplasm
(drug effects, genetics)
- Genetic Engineering
- Glioblastoma
(drug therapy, genetics, pathology, radiotherapy)
- Humans
- Magnetic Resonance Imaging
- Mice
- Poly(ADP-ribose) Polymerase Inhibitors
(administration & dosage)
- Temozolomide
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