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Evaluation of Concurrent Radiation, Temozolomide and ABT-888 Treatment Followed by Maintenance Therapy with Temozolomide and ABT-888 in a Genetically Engineered Glioblastoma Mouse Model.

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.
AuthorsBenjamin 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
JournalNeoplasia (New York, N.Y.) (Neoplasia) Vol. 18 Issue 2 Pg. 82-9 (Feb 2016) ISSN: 1476-5586 [Electronic] United States
PMID26936394 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Benzimidazoles
  • Poly(ADP-ribose) Polymerase Inhibitors
  • veliparib
  • Dacarbazine
  • Temozolomide
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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