Differentiating mTOR inhibitors in renal cell carcinoma.
Differentiating mTOR inhibitors in renal cell carcinoma.
复制标题
区分肾细胞癌中的MTOR抑制剂。
DOI：
10.1016/j.ctrv.2012.12.015
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发表时间：
2013-11
影响因子：
11.8
通讯作者：
Quinn DI
中科院分区：
文献类型：
--
作者：
Pal SK;Quinn DI
PI3K/Akt/mTOR信号通路在包括肾细胞癌(RCC)在内的许多肿瘤中表达异常，该信号通路的激活与肾癌的侵袭性行为和不良预后有关。MTOR抑制在包括肾癌在内的许多癌症类型的靶向治疗中发挥着主要作用。尽管mTOR抑制剂具有相同的作用机制，但新陈代谢、配方和给药程序的差异支撑了不同的PK/PD特征，因此它们可能被区分用于不同的治疗利基。批准的mTOR抑制剂替西罗莫司和伊维洛莫斯在当前的肾癌治疗范例中是重要的治疗选择，尽管它们的推荐应用在环境和患者群体特征上有所不同。临床实践指南推荐泰西罗莫司用于任何组织学(主要是透明细胞或非透明细胞组织学)预后较差的转移性肾癌患者的治疗。依维莫司为转移性肾癌患者提供了一种标准的治疗方法，这些患者的病情在以前的血管内皮生长因子受体-酪氨酸激酶抑制剂治疗后有所进展。由于治疗失败影响绝大多数肾癌患者，可用药物的测序策略或同时靶向PI3K/Akt/mTOR通路的多个成员可能会提供额外的临床益处。目前正在研究针对PI3K/Akt/mTOR通路的各种药物，包括mTORC1/mTORC2激酶结构域抑制剂、mTOR/PI3K双重抑制剂、PI3K选择性抑制剂和程序性细胞死亡6调节剂。MTOR抑制剂在各种肿瘤类型中的临床试验正在进行中，mTOR抑制剂在肾癌治疗中的作用继续演变。
PI3K/Akt/mTOR signalling is dysregulated in many cancers, including renal cell carcinoma (RCC), and activation of this pathway has been suggested to correlate with aggressive behavior and poor prognosis in RCC tumors. mTOR inhibition plays a principal role in the targeted treatment of many cancer types, including RCC. Although mTOR inhibitors share the same mechanism of action, differences in metabolism, formulation and dosing schedule underpin distinct PK/PD profiles such that they may be differentiated for use in a variety of treatment niches. Approved mTOR inhibitors temsirolimus and everolimus serve as important therapeutic options within the current RCC treatment paradigm, although their recommended applications differ in setting and patient population characteristics. Clinical practice guidelines recommend temsirolimus for use in treatment-naive patients with poor-prognosis metastatic RCC of any histology (predominant clear cell or non-clear cell histology). Everolimus provides a standard-of-care therapy for patients with metastatic RCC whose disease has progressed after previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy. As therapeutic failure impacts the vast majority of patients with RCC, sequencing strategies of available agents or simultaneous targeting of multiple members of the PI3K/Akt/mTOR pathway may provide additional clinical benefit. Various classes of agents targeting the PI3K/Akt/mTOR pathway are currently being investigated, including mTORC1/mTORC2 kinase domain inhibitors, mTOR/PI3K dual inhibitors, PI3K-selective inhibitors, and programmed cell death 6 modulators. Clinical trials of mTOR inhibitors in a variety of tumor types are ongoing, and the role of mTOR inhibitors continues to evolve across the RCC treatment landscape.