Xu Wen, Bi Yanyu, Kong Juan, Zhang Jiqin, Wang Biao, Li Kesang, Tian Mi, Pan Xiaorong, Shi Bizhi, Gu Jianren, Jiang Hua, Kong Xianming, Li Zonghai
Medical School of Fudan University, Shanghai, China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Oncotarget. 2016 Apr 26;7(17):24752-65. doi: 10.18632/oncotarget.8407.
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.
胶质母细胞瘤（GBM）是全球最常见且侵袭性最强的脑肿瘤，其治疗仍存在未满足的医学需求。表皮生长因子受体III型变异体（EGFRvIII）在约30%的GBM中过表达，被视为一个潜在的治疗靶点。在本研究中，我们证明抗EGFRvIII单克隆抗体CH12可在体内显著抑制EGFRvIII阳性GBM的生长；然而，GBM中PTEN的缺失通过减弱其对PI3K/AKT/mTOR通路的作用而降低了CH12的疗效。为克服这一问题，将CH12与mTOR抑制剂雷帕霉素联合使用，在体内对EGFRvIII阳性、PTEN缺失的GBM产生协同抑制作用。机制上，通过更有效地减弱EGFR和PI3K/AKT/mTOR通路以及逆转雷帕霉素治疗引起的STAT5激活，实现了协同抗肿瘤作用。此外，联合治疗更有效地抑制血管生成并诱导癌细胞凋亡。总之，这些结果表明CH12和雷帕霉素可协同抑制EGFRvIII阳性、PTEN缺失的GBM的生长，这可能在未来具有潜在的临床应用价值。
