Combination therapy in a xenograft model of glioblastoma

Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist

Haiyan Wang, Shanbao Cai, Barbara J. Bailey, M. Reza Saadatzadeh, Jixin Ding, Eva Tonsing-Carter, Taxiarchis M. Georgiadis, T. Zachary Gunter, Eric C. Long, Robert E. Minto, Kevin R. Gordon, Stephanie E. Sen, Wenjing Cai, Jacob A. Eitel, David Waning, Lauren R. Bringman, Clark D. Wells, Mary E. Murray, Jann N. Sarkaria, Lawrence M. Gelbert & 5 others David R. Jones, Aaron A. Cohen-Gadol, Lindsey D. Mayo, Harlan E. Shannon, Karen E. Pollok

Research output: Contribution to journalArticle

8 Citations (Scopus)

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’ 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.

Original languageEnglish (US)
Pages (from-to)446-459
Number of pages14
JournalJournal of neurosurgery
Volume126
Issue number2
DOIs
StatePublished - Feb 1 2017

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temozolomide
Glioblastoma
Heterografts
Therapeutics
Growth
DNA Repair
Proto-Oncogene Proteins c-mdm2
Nuts
DNA Damage

All Science Journal Classification (ASJC) codes

  • Surgery
  • Clinical Neurology

Cite this

Wang, H., Cai, S., Bailey, B. J., Saadatzadeh, M. R., Ding, J., Tonsing-Carter, E., ... Pollok, K. E. (2017). Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist. Journal of neurosurgery, 126(2), 446-459. https://doi.org/10.3171/2016.1.JNS152513
Wang, Haiyan ; Cai, Shanbao ; Bailey, Barbara J. ; Saadatzadeh, M. Reza ; Ding, Jixin ; Tonsing-Carter, Eva ; Georgiadis, Taxiarchis M. ; Gunter, T. Zachary ; Long, Eric C. ; Minto, Robert E. ; Gordon, Kevin R. ; Sen, Stephanie E. ; Cai, Wenjing ; Eitel, Jacob A. ; Waning, David ; Bringman, Lauren R. ; Wells, Clark D. ; Murray, Mary E. ; Sarkaria, Jann N. ; Gelbert, Lawrence M. ; Jones, David R. ; Cohen-Gadol, Aaron A. ; Mayo, Lindsey D. ; Shannon, Harlan E. ; Pollok, Karen E. / Combination therapy in a xenograft model of glioblastoma : Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist. In: Journal of neurosurgery. 2017 ; Vol. 126, No. 2. pp. 446-459.
@article{9b4e94a6027e4ee084cd34030a91715e,
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’ 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.",
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 David Waning 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.}",
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language = "English (US)",
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pages = "446--459",
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issn = "0022-3085",
publisher = "American Association of Neurological Surgeons",
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Wang, H, Cai, S, Bailey, BJ, Saadatzadeh, MR, Ding, J, Tonsing-Carter, E, Georgiadis, TM, Gunter, TZ, Long, EC, Minto, RE, Gordon, KR, Sen, SE, Cai, W, Eitel, JA, Waning, D, Bringman, LR, Wells, CD, Murray, ME, Sarkaria, JN, Gelbert, LM, Jones, DR, Cohen-Gadol, AA, Mayo, LD, Shannon, HE & Pollok, KE 2017, 'Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist', Journal of neurosurgery, vol. 126, no. 2, pp. 446-459. https://doi.org/10.3171/2016.1.JNS152513

Combination therapy in a xenograft model of glioblastoma : Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist. / Wang, Haiyan; Cai, Shanbao; Bailey, Barbara J.; Saadatzadeh, M. Reza; Ding, Jixin; Tonsing-Carter, Eva; Georgiadis, Taxiarchis M.; Gunter, T. Zachary; Long, Eric C.; Minto, Robert E.; Gordon, Kevin R.; Sen, Stephanie E.; Cai, Wenjing; Eitel, Jacob A.; Waning, David; Bringman, Lauren R.; Wells, Clark D.; Murray, Mary E.; Sarkaria, Jann N.; Gelbert, Lawrence M.; Jones, David R.; Cohen-Gadol, Aaron A.; Mayo, Lindsey D.; Shannon, Harlan E.; Pollok, Karen E.

In: Journal of neurosurgery, Vol. 126, No. 2, 01.02.2017, p. 446-459.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Combination therapy in a xenograft model of glioblastoma

T2 - Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist

AU - Wang, Haiyan

AU - Cai, Shanbao

AU - Bailey, Barbara J.

AU - Saadatzadeh, M. Reza

AU - Ding, Jixin

AU - Tonsing-Carter, Eva

AU - Georgiadis, Taxiarchis M.

AU - Gunter, T. Zachary

AU - Long, Eric C.

AU - Minto, Robert E.

AU - Gordon, Kevin R.

AU - Sen, Stephanie E.

AU - Cai, Wenjing

AU - Eitel, Jacob A.

AU - Waning, David

AU - Bringman, Lauren R.

AU - Wells, Clark D.

AU - Murray, Mary E.

AU - Sarkaria, Jann N.

AU - Gelbert, Lawrence M.

AU - Jones, David R.

AU - Cohen-Gadol, Aaron A.

AU - Mayo, Lindsey D.

AU - Shannon, Harlan E.

AU - Pollok, Karen E.

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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’ 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.

AB - 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’ 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.

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