Use of an orthotopic xenograft model for assessing the effect of epidermal growth factor receptor amplification on glioblastoma radiation response

Jann N Sarkaria, Brett L. Carlson, Mark A. Schroeder, Patrick Grogan, Paul D. Brown, Caterina Giannini, Karla V. Ballman, Caspar J. Kitange, Abjahit Guha, Ajay Pandita, C. David James

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Abstract

Purpose: The influence of epidermal growth factor receptor (EGFR) amplification on glioblastoma patient prognosis following definitive radiotherapy has been extensively investigated in clinical studies, and yet the relationship between EGFR status and radiation response remains unclear. The intent of the current study was to address this relationship using several EGFR-amplified glioblastoma xenografts in an orthotopic athymic mouse model. Experimental Design: We examined the effect of radiation on the survival of nude mice with intracranial xenografts derived from 13 distinct patient tumors, 7 of which have amplified EGFR. Mice with established intracranial tumors were randomized to sham treatment or 12-Gy radiation in six fractions delivered over 12 days. Results: For six of the xenografts, radiation of mice with intracranial tumor significantly extended survival, and four of these xenografts had EGFR amplification. For seven other xenografts, radiation treatment did not significantly extend survival, and three of these, including GBM12, had EGFR amplification. Similar to EGFR, the tumor genetic status of p53 or PTEN did not show preferential association with radiation-sensitive or radiation-resistant xenografts whereas hyperphosphorylation of Akt on Ser473 was associated with increased radioresistance. To specifically investigate whether inhibition of EGFR kinase activity influences radiation response, we examined combined radiation and EGFR inhibitor treatment in mice with intracranial GBM12. The combination of oral erlotinib administered concurrently with radiation resulted only in additive survival benefit relative to either agent alone. Conclusions: Our results indicate that EGFR amplification, as a biomarker, is not singularly predictive of glioblastoma response to radiation therapy, nor does the inhibition of EGFR enhance the intrinsic radiation responsiveness of glioblastoma tumors. However, efficacious EGFR inhibitor and radiation monotherapy regimens can be used in combination to achieve additive antitumor effect against a subset of glioblastoma.

Original languageEnglish (US)
Pages (from-to)2264-2271
Number of pages8
JournalClinical Cancer Research
Volume12
Issue number7 I
DOIs
StatePublished - Apr 1 2006

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Glioblastoma
Epidermal Growth Factor Receptor
Heterografts
Radiation
Neoplasms
Nude Mice
Survival
Radiotherapy
Radiation Dosage
Radiation Effects
Research Design
Biomarkers
Placebos

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Use of an orthotopic xenograft model for assessing the effect of epidermal growth factor receptor amplification on glioblastoma radiation response. / Sarkaria, Jann N; Carlson, Brett L.; Schroeder, Mark A.; Grogan, Patrick; Brown, Paul D.; Giannini, Caterina; Ballman, Karla V.; Kitange, Caspar J.; Guha, Abjahit; Pandita, Ajay; James, C. David.

In: Clinical Cancer Research, Vol. 12, No. 7 I, 01.04.2006, p. 2264-2271.

Research output: Contribution to journalArticle

Sarkaria, Jann N ; Carlson, Brett L. ; Schroeder, Mark A. ; Grogan, Patrick ; Brown, Paul D. ; Giannini, Caterina ; Ballman, Karla V. ; Kitange, Caspar J. ; Guha, Abjahit ; Pandita, Ajay ; James, C. David. / Use of an orthotopic xenograft model for assessing the effect of epidermal growth factor receptor amplification on glioblastoma radiation response. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 7 I. pp. 2264-2271.
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AU - Carlson, Brett L.

AU - Schroeder, Mark A.

AU - Grogan, Patrick

AU - Brown, Paul D.

AU - Giannini, Caterina

AU - Ballman, Karla V.

AU - Kitange, Caspar J.

AU - Guha, Abjahit

AU - Pandita, Ajay

AU - James, C. David

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N2 - Purpose: The influence of epidermal growth factor receptor (EGFR) amplification on glioblastoma patient prognosis following definitive radiotherapy has been extensively investigated in clinical studies, and yet the relationship between EGFR status and radiation response remains unclear. The intent of the current study was to address this relationship using several EGFR-amplified glioblastoma xenografts in an orthotopic athymic mouse model. Experimental Design: We examined the effect of radiation on the survival of nude mice with intracranial xenografts derived from 13 distinct patient tumors, 7 of which have amplified EGFR. Mice with established intracranial tumors were randomized to sham treatment or 12-Gy radiation in six fractions delivered over 12 days. Results: For six of the xenografts, radiation of mice with intracranial tumor significantly extended survival, and four of these xenografts had EGFR amplification. For seven other xenografts, radiation treatment did not significantly extend survival, and three of these, including GBM12, had EGFR amplification. Similar to EGFR, the tumor genetic status of p53 or PTEN did not show preferential association with radiation-sensitive or radiation-resistant xenografts whereas hyperphosphorylation of Akt on Ser473 was associated with increased radioresistance. To specifically investigate whether inhibition of EGFR kinase activity influences radiation response, we examined combined radiation and EGFR inhibitor treatment in mice with intracranial GBM12. The combination of oral erlotinib administered concurrently with radiation resulted only in additive survival benefit relative to either agent alone. Conclusions: Our results indicate that EGFR amplification, as a biomarker, is not singularly predictive of glioblastoma response to radiation therapy, nor does the inhibition of EGFR enhance the intrinsic radiation responsiveness of glioblastoma tumors. However, efficacious EGFR inhibitor and radiation monotherapy regimens can be used in combination to achieve additive antitumor effect against a subset of glioblastoma.

AB - Purpose: The influence of epidermal growth factor receptor (EGFR) amplification on glioblastoma patient prognosis following definitive radiotherapy has been extensively investigated in clinical studies, and yet the relationship between EGFR status and radiation response remains unclear. The intent of the current study was to address this relationship using several EGFR-amplified glioblastoma xenografts in an orthotopic athymic mouse model. Experimental Design: We examined the effect of radiation on the survival of nude mice with intracranial xenografts derived from 13 distinct patient tumors, 7 of which have amplified EGFR. Mice with established intracranial tumors were randomized to sham treatment or 12-Gy radiation in six fractions delivered over 12 days. Results: For six of the xenografts, radiation of mice with intracranial tumor significantly extended survival, and four of these xenografts had EGFR amplification. For seven other xenografts, radiation treatment did not significantly extend survival, and three of these, including GBM12, had EGFR amplification. Similar to EGFR, the tumor genetic status of p53 or PTEN did not show preferential association with radiation-sensitive or radiation-resistant xenografts whereas hyperphosphorylation of Akt on Ser473 was associated with increased radioresistance. To specifically investigate whether inhibition of EGFR kinase activity influences radiation response, we examined combined radiation and EGFR inhibitor treatment in mice with intracranial GBM12. The combination of oral erlotinib administered concurrently with radiation resulted only in additive survival benefit relative to either agent alone. Conclusions: Our results indicate that EGFR amplification, as a biomarker, is not singularly predictive of glioblastoma response to radiation therapy, nor does the inhibition of EGFR enhance the intrinsic radiation responsiveness of glioblastoma tumors. However, efficacious EGFR inhibitor and radiation monotherapy regimens can be used in combination to achieve additive antitumor effect against a subset of glioblastoma.

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