The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer
The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer
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DOI：
10.1158/1078-0432.ccr-06-1986
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发表时间：
2007-01-15
影响因子：
11.5
通讯作者：
Atkins, Michael B.
中科院分区：
文献类型：
--
作者：
Cho, Daniel;Signoretti, Sabina;Atkins, Michael B.
哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂在晚期肾细胞癌（RCC）患者的早期试验中显示出有希望的疗效。大多数RCC已被证明在von Hippel-Lindau（VHL）基因中具有双等位基因改变，导致缺氧诱导因子1 α和2 α以及其下游靶点（包括血管内皮生长因子（VEGF））的积累。mTOR抑制剂在RCC患者中观察到的临床疗效可能部分由有效低氧诱导因子翻译对mTOR通路的依赖性介导。mTOR抑制剂已经作为单一药物或与其他靶向药物或IFN组合进入更高级阶段的临床试验，这可能最终导致一种或多种药物的监管批准。鉴于mTOR抑制剂和VEGF通路靶向药物的作用机制可能不重叠，如果联合给药或在对VEGF抑制剂耐药后给药，mTOR抑制剂可能会证明是有用的。随着越来越多的活性药物用于治疗RCC患者，必须继续努力开发基于预测性生物标志物的患者选择模型，以指导对适当患者的治疗。
Inhibitors of the mammalian target of rapamycin (mTOR) have shown promising efficacy in early-stage trials in patients with advanced renal cell carcinoma (RCC). Most RCCs have been shown to possess biallelic alterations in the von Hippel-Lindau (VHL) gene, resulting in accumulation of hypoxia-inducible factors 1 alpha and 2 alpha, as well as their downstream targets including vascular endothelial growth factor (VEGF). The observed clinical efficacy of mTOR inhibitors in patients with RCC may be mediated in part by the dependence of efficient hypoxia-inducible factor translation on the mTOR pathway. mTOR inhibitors have entered more advanced phase clinical trials either as single agents or in combination with other targeted agents or IFN, which might ultimately result in regulatory approval of one or more agents. Given the likely nonoverlapping mechanism of action of mTOR inhibitors and VEGF pathway-targeted agents, mTOR inhibitors may prove useful if administered in combination or after resistance to VEGF inhibitors. With an increasing number of active agents for treatment of patients with RCC, efforts must continue to develop patient selection models based on predictive biomarkers to direct therapy to appropriate patients.