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Neoplasia. 2016 Feb;18(2):82-9. doi: 10.1016/j.neo.2015.11.014.

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.

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University Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble, France.
Department of Radiology, University of Michigan, Ann Arbor, MI, 48109 USA.
Department of Pathology, University of Michigan, Ann Arbor, MI, 48109 USA.
Children's Research Institute, NW Washington, DC 20010, USA. Department of Radiation Oncology, Washington University, St. Louis, MO 63110, USA.
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109 USA.
Department of Neurological Surgery, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109 USA.
Department of Radiology, University of Michigan, Ann Arbor, MI, 48109 USA. Electronic address:


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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