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.
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.
authors.affiliation: University Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lemasson
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, MI, 48109 USA.
authors.forename: Hanxiao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, 48109 USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Galbán
authors.affiliation: Children's Research Institute, NW Washington, DC 20010, USA. Department of Radiation Oncology, Washington University, St. Louis, MO 63110, USA.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Li
authors.affiliation: Children's Research Institute, NW Washington, DC 20010, USA. Department of Radiation Oncology, Washington University, St. Louis, MO 63110, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, MI, 48109 USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Heist
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109 USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Tsein
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, MI, 48109 USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Chenevert
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109 USA.
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, MI, 48109 USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Galbán
authors.affiliation: Department of Neurological Surgery, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109 USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, MI, 48109 USA. Electronic address: bdross@umich.edu.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005818:Genetic Engineering; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage; D000077204:Temozolomide
chemical_list: D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D003606:Dacarbazine; D000077204:Temozolomide