Combination of an anti-EGFRvIII antibody CH12 with Rapamycin synergistically inhibits the growth of EGFRvIII+PTEN− glioblastoma <i>in vivo</i>

Abstract

// Wen Xu 1, 2 , Yanyu Bi 2 , Juan Kong 2 , Jiqin Zhang 2 , Biao Wang 2 , Kesang Li 2 , Mi Tian 2 , Xiaorong Pan 2 , Bizhi Shi 2 , Jianren Gu 2 , Hua Jiang 2 , Xianming Kong 3 , Zonghai Li 2 1 Medical School of Fudan University, Shanghai, China 2 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China 3 Renji Hospital, Medical School of Shanghai Jiaotong University, Shanghai, China Correspondence to: Zonghai Li, e-mail: Zonghaili@shsmu.edu.cn Hua Jiang, e-mail: Jianghuapy@163.com Xianming Kong, e-mail: kongxianming@renji.com Keywords: EGFRvIII + PTEN &ndash; GBM, CH12, rapamycin, STAT5 Received: October 17, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: February 28, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: March 26, 2016 ABSTRACT There are still unmet medical needs for the treatment of glioblastoma (GBM), the most frequent and aggressive brain tumor worldwide. EGFRvIII, overexpressed in approximately 30% of GBM, has been regarded as a potential therapeutic target. In this study, we demonstrated that CH12, an anti-EGFRvIII monoclonal antibody, could significantly suppress the growth of EGFRvIII + GBM in vivo ; however, PTEN deficiency in GBM reduced the efficacy of CH12 by attenuating its effect on PI3K/AKT/mTOR pathway. To overcome this problem, CH12 was combined with the mTOR inhibitor rapamycin, leading to a synergistic inhibitory effect on EGFRvIII + PTEN &ndash; GBM in vivo . Mechanistically, the synergistic antitumor effect was achieved via attenuating EGFR and PI3K/AKT/mTOR pathway more effectively and reversing the STAT5 activation caused by rapamycin treatment. Moreover, the combination therapy suppressed angiogenesis and induced cancer cell apoptosis more efficiently. Together, these results indicated that CH12 and rapamycin could synergistically suppress the growth of EGFRvIII + PTEN &ndash; GBM, which might have a potential clinical application in the future.