Concurrent inhibition of neurosphere and monolayer cells of pediatric glioblastoma by aurora a inhibitor mln8237 predicted survival extension in pdox models

Mari Kogiso, Lin Qi, Frank K. Braun, Sarah G. Injac, Linna Zhang, Yuchen Du, Huiyuan Zhang, Frank Y. Lin, Sibo Zhao, Holly Lindsay, Jack M. Su, Patricia A. Baxter, Adekunle M. Adesina, Debra Liao, Mark G. Qian, Stacey Berg, Jodi A. Muscal, Xiao Nan Li*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Purpose: Pediatric glioblastoma multiforme (pGBM) is a highly aggressive tumor in need of novel therapies. Our objective was to demonstrate the therapeutic efficacy of MLN8237 (alisertib), an orally available selective inhibitor of Aurora A kinase (AURKA), and to evaluate which in vitro model system (monolayer or neurosphere) can predict therapeutic efficacy in vivo. Experimental Design: AURKA mRNA expressions were screened with qRT-PCR. In vitro antitumor effects were examined in three matching pairs of monolayer and neurosphere lines established from patient-derived orthotopic xenograft (PDOX) models of the untreated (IC-4687GBM), recurrent (IC-3752GBM), and terminal (IC-R0315GBM) tumors, and in vivo therapeutic efficacy through log rank analysis of survival times in two models (IC-4687GBM and IC-R0315GBM) following MLN8237 treatment (30 mg/kg/day, orally, 12 days). Drug concentrations in vivo and mechanism of action and resistance were also investigated. Results: AURKA mRNA overexpression was detected in 14 pGBM tumors, 10 PDOX models, and 6 cultured pGBM lines as compared with 11 low-grade gliomas and normal brains. MLN8237 penetrated into pGBM xenografts in mouse brains. Significant extension of survival times were achieved in IC-4687GBM of which both neurosphere and monolayer were inhibited in vitro, but not in IC-R0315GBM of which only neurosphere cells responded (similar to IC-3752GBM). Apoptosis-mediated MLN8237 induced cell death, and the presence of AURKA-negative and CD133 þ cells appears to have contributed to in vivo therapy resistance. Conclusions: MLN8237 successfully targeted AURKA in a subset of pGBMs. Our data suggest that combination therapy should aim at AURKA-negative and/or CD133 þ pGBM cells to prevent tumor recurrence.

Original languageEnglish (US)
Pages (from-to)2159-2170
Number of pages12
JournalClinical Cancer Research
Volume24
Issue number9
DOIs
StatePublished - May 1 2018

Fingerprint

Aurora Kinase A
Glioblastoma
Pediatrics
Survival
Heterografts
Therapeutics
Neoplasms
Messenger RNA
Brain
Survival Analysis
MLN 8237
Glioma
Cell Death
Research Design
Apoptosis
Recurrence
Polymerase Chain Reaction
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kogiso, Mari ; Qi, Lin ; Braun, Frank K. ; Injac, Sarah G. ; Zhang, Linna ; Du, Yuchen ; Zhang, Huiyuan ; Lin, Frank Y. ; Zhao, Sibo ; Lindsay, Holly ; Su, Jack M. ; Baxter, Patricia A. ; Adesina, Adekunle M. ; Liao, Debra ; Qian, Mark G. ; Berg, Stacey ; Muscal, Jodi A. ; Li, Xiao Nan. / Concurrent inhibition of neurosphere and monolayer cells of pediatric glioblastoma by aurora a inhibitor mln8237 predicted survival extension in pdox models. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 9. pp. 2159-2170.
@article{e853b8a2a2ef45758734ff81459e7986,
title = "Concurrent inhibition of neurosphere and monolayer cells of pediatric glioblastoma by aurora a inhibitor mln8237 predicted survival extension in pdox models",
abstract = "Purpose: Pediatric glioblastoma multiforme (pGBM) is a highly aggressive tumor in need of novel therapies. Our objective was to demonstrate the therapeutic efficacy of MLN8237 (alisertib), an orally available selective inhibitor of Aurora A kinase (AURKA), and to evaluate which in vitro model system (monolayer or neurosphere) can predict therapeutic efficacy in vivo. Experimental Design: AURKA mRNA expressions were screened with qRT-PCR. In vitro antitumor effects were examined in three matching pairs of monolayer and neurosphere lines established from patient-derived orthotopic xenograft (PDOX) models of the untreated (IC-4687GBM), recurrent (IC-3752GBM), and terminal (IC-R0315GBM) tumors, and in vivo therapeutic efficacy through log rank analysis of survival times in two models (IC-4687GBM and IC-R0315GBM) following MLN8237 treatment (30 mg/kg/day, orally, 12 days). Drug concentrations in vivo and mechanism of action and resistance were also investigated. Results: AURKA mRNA overexpression was detected in 14 pGBM tumors, 10 PDOX models, and 6 cultured pGBM lines as compared with 11 low-grade gliomas and normal brains. MLN8237 penetrated into pGBM xenografts in mouse brains. Significant extension of survival times were achieved in IC-4687GBM of which both neurosphere and monolayer were inhibited in vitro, but not in IC-R0315GBM of which only neurosphere cells responded (similar to IC-3752GBM). Apoptosis-mediated MLN8237 induced cell death, and the presence of AURKA-negative and CD133 {\th} cells appears to have contributed to in vivo therapy resistance. Conclusions: MLN8237 successfully targeted AURKA in a subset of pGBMs. Our data suggest that combination therapy should aim at AURKA-negative and/or CD133 {\th} pGBM cells to prevent tumor recurrence.",
author = "Mari Kogiso and Lin Qi and Braun, {Frank K.} and Injac, {Sarah G.} and Linna Zhang and Yuchen Du and Huiyuan Zhang and Lin, {Frank Y.} and Sibo Zhao and Holly Lindsay and Su, {Jack M.} and Baxter, {Patricia A.} and Adesina, {Adekunle M.} and Debra Liao and Qian, {Mark G.} and Stacey Berg and Muscal, {Jodi A.} and Li, {Xiao Nan}",
year = "2018",
month = "5",
day = "1",
doi = "10.1158/1078-0432.CCR-17-2256",
language = "English (US)",
volume = "24",
pages = "2159--2170",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
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Kogiso, M, Qi, L, Braun, FK, Injac, SG, Zhang, L, Du, Y, Zhang, H, Lin, FY, Zhao, S, Lindsay, H, Su, JM, Baxter, PA, Adesina, AM, Liao, D, Qian, MG, Berg, S, Muscal, JA & Li, XN 2018, 'Concurrent inhibition of neurosphere and monolayer cells of pediatric glioblastoma by aurora a inhibitor mln8237 predicted survival extension in pdox models', Clinical Cancer Research, vol. 24, no. 9, pp. 2159-2170. https://doi.org/10.1158/1078-0432.CCR-17-2256

Concurrent inhibition of neurosphere and monolayer cells of pediatric glioblastoma by aurora a inhibitor mln8237 predicted survival extension in pdox models. / Kogiso, Mari; Qi, Lin; Braun, Frank K.; Injac, Sarah G.; Zhang, Linna; Du, Yuchen; Zhang, Huiyuan; Lin, Frank Y.; Zhao, Sibo; Lindsay, Holly; Su, Jack M.; Baxter, Patricia A.; Adesina, Adekunle M.; Liao, Debra; Qian, Mark G.; Berg, Stacey; Muscal, Jodi A.; Li, Xiao Nan.

In: Clinical Cancer Research, Vol. 24, No. 9, 01.05.2018, p. 2159-2170.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Concurrent inhibition of neurosphere and monolayer cells of pediatric glioblastoma by aurora a inhibitor mln8237 predicted survival extension in pdox models

AU - Kogiso, Mari

AU - Qi, Lin

AU - Braun, Frank K.

AU - Injac, Sarah G.

AU - Zhang, Linna

AU - Du, Yuchen

AU - Zhang, Huiyuan

AU - Lin, Frank Y.

AU - Zhao, Sibo

AU - Lindsay, Holly

AU - Su, Jack M.

AU - Baxter, Patricia A.

AU - Adesina, Adekunle M.

AU - Liao, Debra

AU - Qian, Mark G.

AU - Berg, Stacey

AU - Muscal, Jodi A.

AU - Li, Xiao Nan

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Purpose: Pediatric glioblastoma multiforme (pGBM) is a highly aggressive tumor in need of novel therapies. Our objective was to demonstrate the therapeutic efficacy of MLN8237 (alisertib), an orally available selective inhibitor of Aurora A kinase (AURKA), and to evaluate which in vitro model system (monolayer or neurosphere) can predict therapeutic efficacy in vivo. Experimental Design: AURKA mRNA expressions were screened with qRT-PCR. In vitro antitumor effects were examined in three matching pairs of monolayer and neurosphere lines established from patient-derived orthotopic xenograft (PDOX) models of the untreated (IC-4687GBM), recurrent (IC-3752GBM), and terminal (IC-R0315GBM) tumors, and in vivo therapeutic efficacy through log rank analysis of survival times in two models (IC-4687GBM and IC-R0315GBM) following MLN8237 treatment (30 mg/kg/day, orally, 12 days). Drug concentrations in vivo and mechanism of action and resistance were also investigated. Results: AURKA mRNA overexpression was detected in 14 pGBM tumors, 10 PDOX models, and 6 cultured pGBM lines as compared with 11 low-grade gliomas and normal brains. MLN8237 penetrated into pGBM xenografts in mouse brains. Significant extension of survival times were achieved in IC-4687GBM of which both neurosphere and monolayer were inhibited in vitro, but not in IC-R0315GBM of which only neurosphere cells responded (similar to IC-3752GBM). Apoptosis-mediated MLN8237 induced cell death, and the presence of AURKA-negative and CD133 þ cells appears to have contributed to in vivo therapy resistance. Conclusions: MLN8237 successfully targeted AURKA in a subset of pGBMs. Our data suggest that combination therapy should aim at AURKA-negative and/or CD133 þ pGBM cells to prevent tumor recurrence.

AB - Purpose: Pediatric glioblastoma multiforme (pGBM) is a highly aggressive tumor in need of novel therapies. Our objective was to demonstrate the therapeutic efficacy of MLN8237 (alisertib), an orally available selective inhibitor of Aurora A kinase (AURKA), and to evaluate which in vitro model system (monolayer or neurosphere) can predict therapeutic efficacy in vivo. Experimental Design: AURKA mRNA expressions were screened with qRT-PCR. In vitro antitumor effects were examined in three matching pairs of monolayer and neurosphere lines established from patient-derived orthotopic xenograft (PDOX) models of the untreated (IC-4687GBM), recurrent (IC-3752GBM), and terminal (IC-R0315GBM) tumors, and in vivo therapeutic efficacy through log rank analysis of survival times in two models (IC-4687GBM and IC-R0315GBM) following MLN8237 treatment (30 mg/kg/day, orally, 12 days). Drug concentrations in vivo and mechanism of action and resistance were also investigated. Results: AURKA mRNA overexpression was detected in 14 pGBM tumors, 10 PDOX models, and 6 cultured pGBM lines as compared with 11 low-grade gliomas and normal brains. MLN8237 penetrated into pGBM xenografts in mouse brains. Significant extension of survival times were achieved in IC-4687GBM of which both neurosphere and monolayer were inhibited in vitro, but not in IC-R0315GBM of which only neurosphere cells responded (similar to IC-3752GBM). Apoptosis-mediated MLN8237 induced cell death, and the presence of AURKA-negative and CD133 þ cells appears to have contributed to in vivo therapy resistance. Conclusions: MLN8237 successfully targeted AURKA in a subset of pGBMs. Our data suggest that combination therapy should aim at AURKA-negative and/or CD133 þ pGBM cells to prevent tumor recurrence.

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U2 - 10.1158/1078-0432.CCR-17-2256

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