Sarkaria Jann N, Carlson Brett L, Schroeder Mark A, Grogan Patrick, Brown Paul D, Giannini Caterina, Ballman Karla V, Kitange Gaspar J, Guha Abjahit, Pandita Ajay, James C David
Department of Radiation Oncology, Laboratory Medicine and Pathology, and Biostatistics, Mayo Clinic, Rochester, Minnesota, USA.
Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2264-71. doi: 10.1158/1078-0432.CCR-05-2510.
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.
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.
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.
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.
在临床研究中，已对表皮生长因子受体（EGFR）扩增对胶质母细胞瘤患者接受根治性放疗后预后的影响进行了广泛研究，但EGFR状态与放射反应之间的关系仍不清楚。本研究的目的是在原位无胸腺小鼠模型中使用几种EGFR扩增的胶质母细胞瘤异种移植来探讨这种关系。
我们检测了放疗对源自13个不同患者肿瘤的颅内异种移植裸鼠生存的影响，其中7个肿瘤有EGFR扩增。已形成颅内肿瘤的小鼠被随机分为假治疗组或接受12天内分6次给予的12 Gy放疗组。
对于6个异种移植瘤，颅内肿瘤小鼠接受放疗显著延长了生存期，其中4个异种移植瘤有EGFR扩增。对于另外7个异种移植瘤，放疗未显著延长生存期，其中3个（包括GBM12）有EGFR扩增。与EGFR类似，p53或PTEN的肿瘤基因状态与放射敏感或放射抗性异种移植瘤之间未显示出优先关联，而Akt在Ser(473)位点的过度磷酸化与放射抗性增加相关。为了具体研究抑制EGFR激酶活性是否影响放射反应，我们检测了颅内GBM12小鼠接受联合放疗和EGFR抑制剂治疗的情况。与单独使用任何一种药物相比，同时给予口服厄洛替尼与放疗仅产生了相加的生存获益。
我们的结果表明，EGFR扩增作为一种生物标志物，并非单独预测胶质母细胞瘤对放射治疗的反应，抑制EGFR也不会增强胶质母细胞瘤肿瘤的内在放射反应性。然而，有效的EGFR抑制剂和放射单药治疗方案可联合使用，以对一部分胶质母细胞瘤实现相加的抗肿瘤作用。
