@article{1bb877f194514f41a8440174543eb523,
title = "Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist",
abstract = "obJective Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. methods The combination of TMZ with the MDM2 protein–protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. results In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nut-lin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. conclusions Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors{\textquoteright} knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein–protein interactions.",
keywords = "Combination therapy, DNA repair, Glioblastoma, MDM2, MDM2 inhibitor, Oncology, P53, Patient-derived xenograft, Temozolomide",
author = "Haiyan Wang and Shanbao Cai and Bailey, {Barbara J.} and Saadatzadeh, {M. Reza} and Jixin Ding and Eva Tonsing-Carter and Georgiadis, {Taxiarchis M.} and Gunter, {T. Zachary} and Long, {Eric C.} and Minto, {Robert E.} and Gordon, {Kevin R.} and Sen, {Stephanie E.} and Wenjing Cai and Eitel, {Jacob A.} and Waning, {David L.} and Bringman, {Lauren R.} and Wells, {Clark D.} and Murray, {Mary E.} and Sarkaria, {Jann N.} and Gelbert, {Lawrence M.} and Jones, {David R.} and Cohen-Gadol, {Aaron A.} and Mayo, {Lindsey D.} and Shannon, {Harlan E.} and Pollok, {Karen E.}",
note = "Funding Information: We thank Veronika Slivova and staff at the Methodist Research Institute Biorepository, Andi Masters (Clinical Pharmacology Analytical Core), Malgorzata M. Kamocka (Indiana Center for Biological Microscopy facility), Tony Sinn, and Tiaishia Spragins (In Vivo Therapeutics Core) for their expert assistance. We thank Drs. Melissa Fishel, Art Baluyut, and Mark Kelley for their critical reading of this manuscript. Research for this study was supported by the National Cancer Institute of the National Institutes of Health (award number R01CA138798 [H.W., B.B., E.T., L.M., and K.P.]), the DeVault Fellowship-IUSCC Cancer Biology Training Program (E.T.), the Indiana University Melvin and Bren Simon Cancer Center Translational Research Acceleration Collaboration program (K.P.), the Indiana Clinical and Translational Sciences Institute (K.P.), and the Indiana University-Purdue University Indianapolis Signature Center Initiative for the Cure of Glioblastoma. The In Vivo Therapeutics Core and the Clinical Pharmacology Analytical Core laboratory of the Indiana University Melvin and Bren Simon Cancer Center are both supported by the National Cancer Institute (P30 CA082709). We greatly appreciate the generous support of the Mary Ann and Gene Zink Family Glioblastoma Multiforme Research Fund, Team JOEY (a Heroes Foundation Program), the Riley Children{\textquoteright}s Foundation, and the Jeff Gordon Foundation (H.W. and K.P.). Publisher Copyright: {\textcopyright} AANS, 2017.",
year = "2017",
month = feb,
doi = "10.3171/2016.1.JNS152513",
language = "English (US)",
volume = "126",
pages = "446--459",
journal = "Journal of Neurosurgery",
issn = "0022-3085",
publisher = "American Association of Neurological Surgeons",
number = "2",
}