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

Authors

Benjamin Lemasson, Universite Grenoble Alpes
Hanxiao Wang, University of Michigan, Ann Arbor
Stefanie Galbán, University of Michigan, Ann Arbor
Yinghua Li, Children's Research Institute, Children's National Medical Center
Yuan Zhu, Children's Research Institute, Children's National Medical Center
Kevin A. Heist, University of Michigan, Ann Arbor
Christina Tsein, University of Michigan, Ann Arbor
Thomas L. Chenevert, University of Michigan, Ann Arbor
Alnawaz Rehemtulla, University of Michigan, Ann Arbor
Craig J. Galbán, University of Michigan, Ann Arbor
Eric C. Holland, University of Washington
Brian D. Ross, University of Michigan, Ann Arbor

Document Type

Journal Article

Publication Date

1-1-2016

Journal

Neoplasia (United States)

Volume

18

Issue

2

DOI

10.1016/j.neo.2015.11.014

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.

APA Citation

Lemasson, B., Wang, H., Galbán, S., Li, Y., Zhu, Y., Heist, K., Tsein, C., Chenevert, T., Rehemtulla, A., Galbán, C., Holland, E., & Ross, B. (2016). 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. Neoplasia (United States), 18 (2). http://dx.doi.org/10.1016/j.neo.2015.11.014