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

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

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, optimi...

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Main 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
Format: Article
Language:English
Published: Elsevier 2016-02-01
Series:Neoplasia: An International Journal for Oncology Research
Online Access:http://www.sciencedirect.com/science/article/pii/S1476558615001694
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spelling doaj-5bcaf691955f4d099f872a7ed4c119f02020-11-25T00:47:10ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022016-02-01182828910.1016/j.neo.2015.11.014Evaluation of Concurrent Radiation, Temozolomide and ABT-888 Treatment Followed by Maintenance Therapy with Temozolomide and ABT-888 in a Genetically Engineered Glioblastoma Mouse ModelBenjamin Lemasson0Hanxiao Wang1Stefanie Galbán2Yinghua Li3Yuan Zhu4Kevin A. Heist5Christina Tsein6Thomas L. Chenevert7Alnawaz Rehemtulla8Craig J. Galbán9Eric C. Holland10Brian D. Ross11University Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble, FranceDepartment of Radiology, University of Michigan, Ann Arbor, MI, 48109 USADepartment of Pathology, University of Michigan, Ann Arbor, MI, 48109 USAChildren’s Research Institute, NW Washington, DC 20010, USA. Department of Radiation Oncology, Washington University, St. Louis, MO 63110, USAChildren’s Research Institute, NW Washington, DC 20010, USA. Department of Radiation Oncology, Washington University, St. Louis, MO 63110, USADepartment of Radiology, University of Michigan, Ann Arbor, MI, 48109 USADepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109 USADepartment of Radiology, University of Michigan, Ann Arbor, MI, 48109 USADepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109 USADepartment of Radiology, University of Michigan, Ann Arbor, MI, 48109 USADepartment of Neurological Surgery, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109 USADepartment of Radiology, University of Michigan, Ann Arbor, MI, 48109 USADespite 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.http://www.sciencedirect.com/science/article/pii/S1476558615001694
collection DOAJ
language English
format Article
sources DOAJ
author 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
spellingShingle 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
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: An International Journal for Oncology Research
author_facet 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
author_sort Benjamin Lemasson
title 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
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
publisher Elsevier
series Neoplasia: An International Journal for Oncology Research
issn 1476-5586
1522-8002
publishDate 2016-02-01
description 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.
url http://www.sciencedirect.com/science/article/pii/S1476558615001694
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