Cho Daniel, Signoretti Sabina, Regan Meredith, Mier James W, Atkins Michael B
Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
Clin Cancer Res. 2007 Jan 15;13(2 Pt 2):758s-763s. doi: 10.1158/1078-0432.CCR-06-1986.
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 1alpha and 2alpha, 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.
雷帕霉素哺乳动物靶点（mTOR）抑制剂在晚期肾细胞癌（RCC）患者的早期试验中已显示出有前景的疗效。大多数肾细胞癌已被证明在冯·希佩尔-林道（VHL）基因中存在双等位基因改变，导致缺氧诱导因子1α和2α以及它们的下游靶点（包括血管内皮生长因子（VEGF））积累。mTOR抑制剂在肾细胞癌患者中观察到的临床疗效可能部分是由有效的缺氧诱导因子翻译对mTOR途径的依赖性介导的。mTOR抑制剂已作为单一药物或与其他靶向药物或干扰素联合进入更高级别的临床试验阶段，这最终可能导致一种或多种药物获得监管批准。鉴于mTOR抑制剂和VEGF途径靶向药物可能具有不重叠的作用机制，如果联合使用或在对VEGF抑制剂耐药后使用，mTOR抑制剂可能会被证明是有用的。随着用于治疗肾细胞癌患者的活性药物数量不断增加，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，以便将治疗导向合适的患者。
