Oncotarget

Research Papers:

Combination of an anti-EGFRvIII antibody CH12 with Rapamycin synergistically inhibits the growth of EGFRvIII+PTENglioblastoma in vivo

Wen Xu, Yanyu Bi, Juan Kong, Jiqin Zhang, Biao Wang, Kesang Li, Mi Tian, Xiaorong Pan, Bizhi Shi, Jianren Gu, Hua Jiang, Xianming Kong and Zonghai Li _

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Oncotarget. 2016; 7:24752-24765. https://doi.org/10.18632/oncotarget.8407

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Abstract

Wen Xu1,2, Yanyu Bi2, Juan Kong2, Jiqin Zhang2, Biao Wang2, Kesang Li2, Mi Tian2, Xiaorong Pan2, Bizhi Shi2, Jianren Gu2, Hua Jiang2, Xianming Kong3, Zonghai Li2

1Medical School of Fudan University, Shanghai, China

2State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

3Renji 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 GBM, CH12, rapamycin, STAT5

Received: October 17, 2015     Accepted: February 28, 2016     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 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 GBM, which might have a potential clinical application in the future.


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