Wang Xuerong, Sun Shi-Yong
Emory University School of Medicine, Winship Cancer Institute, Department of Hematology, Atlanta, GA 30322, USA.
Expert Opin Ther Targets. 2009 Oct;13(10):1193-203. doi: 10.1517/14728220903225008.
The mammalian target of rapamycin (mTOR) has emerged as an attractive cancer therapeutic target. Accordingly, several mTOR inhibitors (e.g., rapamycin and its analogs; rapalogs) are currently being tested in many cancer clinical trials. Despite the encouraging results showing that some rapalogs improved overall survival among patients with metastatic renal-cell carcinoma, the single-agent activity of rapalogs in most other tumor-types has been modest, at best.
To review the current understanding of the mTOR axis and discuss potential strategies to enhance mTOR-targeted cancer therapy.
Preclinical and clinical data in peer-reviewed reports on the novel biological and therapeutic parts of the mTOR axis are discussed.
The mTOR axis involves complex regulatory networks. Inhibition of the mTOR axis with a rapalog induces feedback activation of several survival signaling pathways such as Akt activation, which, in turn, blunt rapalogs' anticancer efficacy. Thus, blockage or prevention of the activation of these survival signaling pathways may enhance mTOR-targeted cancer therapy.
雷帕霉素的哺乳动物靶点（mTOR）已成为一个有吸引力的癌症治疗靶点。因此，几种mTOR抑制剂（如雷帕霉素及其类似物；雷帕霉素衍生物）目前正在许多癌症临床试验中进行测试。尽管有令人鼓舞的结果表明，一些雷帕霉素衍生物可改善转移性肾细胞癌患者的总生存期，但雷帕霉素衍生物在大多数其他肿瘤类型中的单药活性充其量只能说是适度的。
综述目前对mTOR轴的认识，并讨论增强mTOR靶向癌症治疗的潜在策略。
讨论同行评审报告中关于mTOR轴新的生物学和治疗部分的临床前和临床数据。
mTOR轴涉及复杂的调控网络。用雷帕霉素衍生物抑制mTOR轴会诱导几种生存信号通路的反馈激活，如Akt激活，这反过来又会削弱雷帕霉素衍生物的抗癌疗效。因此，阻断或预防这些生存信号通路的激活可能会增强mTOR靶向癌症治疗。
