Oncology & Hematology, St. Luke's Cancer Center, 801 Ostrum Street, Bethlehem, Pennsylvania 18015, USA.
Oncologist. 2010;15(3):236-45. doi: 10.1634/theoncologist.2009-0141. Epub 2010 Mar 9.
Historically, there have been few treatment options for patients with advanced renal cell carcinoma (RCC) besides immunotherapy with interleukin-2 and interferon (IFN)-alpha. Targeted therapies have improved clinical outcomes over the past several years. These include the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors sunitinib and sorafenib, which inhibit angiogenic signaling in endothelial cells and vascular pericytes predominantly through VEGFR and platelet-derived growth factor receptor beta. Also included is the anti-VEGF monoclonal antibody bevacizumab used in combination with IFN-alpha. These agents mediate their antitumor effects by interfering with the VEGF signaling pathway, thereby inhibiting angiogenesis and causing tumor shrinkage. However, ultimately, most patients develop resistance and experience disease progression during VEGF/VEGFR-targeted therapy, and until the recent approval of the mammalian target of rapamycin (mTOR) inhibitor everolimus (RAD001), there were no agents available with proven activity in this setting. This review describes the clinical development of everolimus in advanced RCC and the rationale for the use of mTOR inhibitors after failure of VEGF/VEGFR inhibitors.
从历史上看，晚期肾细胞癌 (RCC) 患者除了接受白细胞介素-2 和干扰素 (IFN)-α 的免疫治疗外，几乎没有其他治疗选择。靶向治疗在过去几年中改善了临床结果。这些治疗方法包括血管内皮生长因子受体 (VEGFR) 酪氨酸激酶抑制剂舒尼替尼和索拉非尼，它们主要通过 VEGFR 和血小板衍生生长因子受体β抑制内皮细胞和血管周细胞的血管生成信号。还包括与 IFN-α 联合使用的抗 VEGF 单克隆抗体贝伐珠单抗。这些药物通过干扰 VEGF 信号通路来发挥其抗肿瘤作用，从而抑制血管生成并导致肿瘤缩小。然而，最终，大多数患者在 VEGF/VEGFR 靶向治疗期间会产生耐药性并出现疾病进展，并且直到最近雷帕霉素 (mTOR) 抑制剂依维莫司 (RAD001) 获得批准之前，在这种情况下还没有具有明确活性的药物。这篇综述描述了依维莫司在晚期 RCC 中的临床开发情况，以及在 VEGF/VEGFR 抑制剂治疗失败后使用 mTOR 抑制剂的原理。
