Prolonged inhibition of glioblastoma xenograft initiation and clonogenic growth following in vivo Notch blockade

Qian Chu, Brent A. Orr, Samantha Semenkow, Eli E. Bar, Charles G Eberhart

Research output: Contribution to journalArticle

Abstract

Purpose: To examine the effects of clinically relevant pharmacologic Notch inhibition on glioblastoma xenografts. Experimental Design: Murine orthotopic xenografts generated from temozolomide-sensitive and -resistant glioblastoma neurosphere lines were treated with the γ-secretase inhibitor MRK003. Tumor growth was tracked by weekly imaging, and the effects on animal survival and tumor proliferation were assessed, along with the expression of Notch targets, stem cell, and differentiation markers, and the biology of neurospheres isolated from previously treated xenografts and controls. Results: Weekly MRK003 therapy resulted in significant reductions in growth as measured by imaging, as well as prolongation of survival. Microscopic examination confirmed a statistically significant reduction in cross-sectional tumor area and mitotic index in a MRK003-treated cohort as compared with controls. Expression of multiple Notch targets was reduced in the xenografts, along with neural stem/progenitor cell markers, whereas glial differentiation was induced. Neurospheres derived from MRK003-treated xenografts exhibited reduced clonogenicity and formed less aggressive secondary xenografts. Neurospheres isolated from treated xenografts remained sensitive to MRK003, suggesting that therapeutic resistance does not rapidly arise during in vivo Notch blockade. Conclusions: Weekly oral delivery of MRK003 results in significant in vivo inhibition of Notch pathway activity, tumor growth, stem cell marker expression, and clonogenicity, providing preclinical support for the use of such compounds in patients with malignant brain tumors. Some of these effects can persist for some time after in vivo therapy is complete.

Original languageEnglish (US)
Pages (from-to)3224-3233
Number of pages10
JournalClinical Cancer Research
Volume19
Issue number12
DOIs
StatePublished - Jun 15 2013

Fingerprint

Glioblastoma
Heterografts
Growth
temozolomide
Stem Cells
Neoplasms
Amyloid Precursor Protein Secretases
Mitotic Index
Neural Stem Cells
Neoplastic Stem Cells
Differentiation Antigens
Brain Neoplasms
Neuroglia
MRK 003
Cell Differentiation
Research Design
Therapeutics
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Prolonged inhibition of glioblastoma xenograft initiation and clonogenic growth following in vivo Notch blockade. / Chu, Qian; Orr, Brent A.; Semenkow, Samantha; Bar, Eli E.; Eberhart, Charles G.

In: Clinical Cancer Research, Vol. 19, No. 12, 15.06.2013, p. 3224-3233.

Research output: Contribution to journalArticle

Chu, Qian ; Orr, Brent A. ; Semenkow, Samantha ; Bar, Eli E. ; Eberhart, Charles G. / Prolonged inhibition of glioblastoma xenograft initiation and clonogenic growth following in vivo Notch blockade. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 12. pp. 3224-3233.
@article{f56c1dc061734ec69e0864578251dd95,
title = "Prolonged inhibition of glioblastoma xenograft initiation and clonogenic growth following in vivo Notch blockade",
abstract = "Purpose: To examine the effects of clinically relevant pharmacologic Notch inhibition on glioblastoma xenografts. Experimental Design: Murine orthotopic xenografts generated from temozolomide-sensitive and -resistant glioblastoma neurosphere lines were treated with the γ-secretase inhibitor MRK003. Tumor growth was tracked by weekly imaging, and the effects on animal survival and tumor proliferation were assessed, along with the expression of Notch targets, stem cell, and differentiation markers, and the biology of neurospheres isolated from previously treated xenografts and controls. Results: Weekly MRK003 therapy resulted in significant reductions in growth as measured by imaging, as well as prolongation of survival. Microscopic examination confirmed a statistically significant reduction in cross-sectional tumor area and mitotic index in a MRK003-treated cohort as compared with controls. Expression of multiple Notch targets was reduced in the xenografts, along with neural stem/progenitor cell markers, whereas glial differentiation was induced. Neurospheres derived from MRK003-treated xenografts exhibited reduced clonogenicity and formed less aggressive secondary xenografts. Neurospheres isolated from treated xenografts remained sensitive to MRK003, suggesting that therapeutic resistance does not rapidly arise during in vivo Notch blockade. Conclusions: Weekly oral delivery of MRK003 results in significant in vivo inhibition of Notch pathway activity, tumor growth, stem cell marker expression, and clonogenicity, providing preclinical support for the use of such compounds in patients with malignant brain tumors. Some of these effects can persist for some time after in vivo therapy is complete.",
author = "Qian Chu and Orr, {Brent A.} and Samantha Semenkow and Bar, {Eli E.} and Eberhart, {Charles G}",
year = "2013",
month = "6",
day = "15",
doi = "10.1158/1078-0432.CCR-12-2119",
language = "English (US)",
volume = "19",
pages = "3224--3233",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "12",

}

TY - JOUR

T1 - Prolonged inhibition of glioblastoma xenograft initiation and clonogenic growth following in vivo Notch blockade

AU - Chu, Qian

AU - Orr, Brent A.

AU - Semenkow, Samantha

AU - Bar, Eli E.

AU - Eberhart, Charles G

PY - 2013/6/15

Y1 - 2013/6/15

N2 - Purpose: To examine the effects of clinically relevant pharmacologic Notch inhibition on glioblastoma xenografts. Experimental Design: Murine orthotopic xenografts generated from temozolomide-sensitive and -resistant glioblastoma neurosphere lines were treated with the γ-secretase inhibitor MRK003. Tumor growth was tracked by weekly imaging, and the effects on animal survival and tumor proliferation were assessed, along with the expression of Notch targets, stem cell, and differentiation markers, and the biology of neurospheres isolated from previously treated xenografts and controls. Results: Weekly MRK003 therapy resulted in significant reductions in growth as measured by imaging, as well as prolongation of survival. Microscopic examination confirmed a statistically significant reduction in cross-sectional tumor area and mitotic index in a MRK003-treated cohort as compared with controls. Expression of multiple Notch targets was reduced in the xenografts, along with neural stem/progenitor cell markers, whereas glial differentiation was induced. Neurospheres derived from MRK003-treated xenografts exhibited reduced clonogenicity and formed less aggressive secondary xenografts. Neurospheres isolated from treated xenografts remained sensitive to MRK003, suggesting that therapeutic resistance does not rapidly arise during in vivo Notch blockade. Conclusions: Weekly oral delivery of MRK003 results in significant in vivo inhibition of Notch pathway activity, tumor growth, stem cell marker expression, and clonogenicity, providing preclinical support for the use of such compounds in patients with malignant brain tumors. Some of these effects can persist for some time after in vivo therapy is complete.

AB - Purpose: To examine the effects of clinically relevant pharmacologic Notch inhibition on glioblastoma xenografts. Experimental Design: Murine orthotopic xenografts generated from temozolomide-sensitive and -resistant glioblastoma neurosphere lines were treated with the γ-secretase inhibitor MRK003. Tumor growth was tracked by weekly imaging, and the effects on animal survival and tumor proliferation were assessed, along with the expression of Notch targets, stem cell, and differentiation markers, and the biology of neurospheres isolated from previously treated xenografts and controls. Results: Weekly MRK003 therapy resulted in significant reductions in growth as measured by imaging, as well as prolongation of survival. Microscopic examination confirmed a statistically significant reduction in cross-sectional tumor area and mitotic index in a MRK003-treated cohort as compared with controls. Expression of multiple Notch targets was reduced in the xenografts, along with neural stem/progenitor cell markers, whereas glial differentiation was induced. Neurospheres derived from MRK003-treated xenografts exhibited reduced clonogenicity and formed less aggressive secondary xenografts. Neurospheres isolated from treated xenografts remained sensitive to MRK003, suggesting that therapeutic resistance does not rapidly arise during in vivo Notch blockade. Conclusions: Weekly oral delivery of MRK003 results in significant in vivo inhibition of Notch pathway activity, tumor growth, stem cell marker expression, and clonogenicity, providing preclinical support for the use of such compounds in patients with malignant brain tumors. Some of these effects can persist for some time after in vivo therapy is complete.

UR - http://www.scopus.com/inward/record.url?scp=84879487108&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879487108&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-12-2119

DO - 10.1158/1078-0432.CCR-12-2119

M3 - Article

C2 - 23630166

AN - SCOPUS:84879487108

VL - 19

SP - 3224

EP - 3233

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 12

ER -