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


METHODS
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 Ser(473) 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.
Sarkaria
Jann N
JN
Department of Radiation Oncology, Laboratory Medicine and Pathology, and Biostatistics, Mayo Clinic, Rochester, Minnesota, USA. sarkaria.jann@mayo.edu
Carlson
Brett L
BL
Schroeder
Mark A
MA
Grogan
Patrick
P
Brown
Paul D
PD
Giannini
Caterina
C
Ballman
Karla V
KV
Kitange
Gaspar J
GJ
Guha
Abjahit
A
Pandita
Ajay
A
James
C David
CD
D000328:Adult; D000368:Aged; D000818:Animals; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005260:Female; D005784:Gene Amplification; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D011799:Quinazolines / Q000494:pharmacology; D015996:Survival Rate; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors