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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.

Author information

1
University Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble, France.
2
Department of Radiology, University of Michigan, Ann Arbor, MI, 48109 USA.
3
Department of Pathology, University of Michigan, Ann Arbor, MI, 48109 USA.
4
Children's Research Institute, NW Washington, DC 20010, USA. Department of Radiation Oncology, Washington University, St. Louis, MO 63110, USA.
5
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109 USA.
6
Department of Neurological Surgery, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109 USA.
7
Department of Radiology, University of Michigan, Ann Arbor, MI, 48109 USA. Electronic address: bdross@umich.edu.

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.

PMID:
26936394
PMCID:
PMC5005260
DOI:
10.1016/j.neo.2015.11.014
[Indexed for MEDLINE]
Free PMC Article

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