Novartis Pharmaceuticals, Inc., 180 Park Avenue, Florham Park, NJ 07932, USA +1 862 778 7218 ;
Expert Opin Drug Discov. 2011 Mar;6(3):323-38. doi: 10.1517/17460441.2011.558079. Epub 2011 Feb 17.
The critical role of increased activity of mammalian target of rapamycin (mTOR) in the pathophysiology of multiple diseases is well established. Inhibition of the mTOR pathway may block disease progression and improve patient outcomes. Everolimus, an mTOR inhibitor, began in clinical development as part of a regimen (Certican, Zortress) for prevention of organ transplant rejection and is now an approved oncology agent.
The objective of this review is to discuss the history of key findings and innovative cancer research undertaken to successfully develop everolimus as an oncology therapy (Afinitor) now approved for patients with advanced renal cell carcinoma (RCC) and for subependymal giant cell astrocytomas (SEGAs) associated with tuberous sclerosis. In addition, data for the use of everolimus in the treatment of other cancers and rare diseases are also discussed. A PubMed search of English articles without time restrictions was conducted using the search terms 'everolimus or rapamycin' and 'cancer'. Bibliographies of retrieved articles were manually searched for additional relevant articles. Major cancer congresses were also searched.
The clinical efficacy of everolimus alone and in combination with other agents has been observed in recently completed Phase II-III studies in a wide spectrum of tumors, including RCC, neuroendocrine tumors, tuberous sclerosis complex, SEGAs and angiomyolipomas, lymphoma and gastric, breast and hepatocellular cancers. These findings emphasize the importance of mTOR in diverse cancers and rare diseases and underscore the potential role for everolimus as an effective agent in multiple indications.
哺乳动物雷帕霉素靶蛋白（mTOR）活性增加在多种疾病的病理生理学中起着至关重要的作用，这一点已得到充分证实。抑制 mTOR 通路可能会阻止疾病进展并改善患者的预后。依维莫司（everolimus）是一种 mTOR 抑制剂，最初作为一种预防器官移植排斥的方案（Certican、Zortress）的一部分进入临床开发，现已被批准用于肿瘤治疗。
本综述的目的是讨论关键发现的历史和开创性的癌症研究，这些研究成功地将依维莫司开发为一种肿瘤治疗药物（Afinitor），目前已被批准用于治疗晚期肾细胞癌（RCC）和与结节性硬化症相关的室管膜下巨细胞星形细胞瘤（SEGA）的患者。此外，还讨论了依维莫司在治疗其他癌症和罕见疾病中的应用数据。在没有时间限制的情况下，通过使用“everolimus 或 rapamycin”和“cancer”这两个搜索词，对 PubMed 中的英文文章进行了检索。检索到的文章的参考文献被手动搜索，以获取其他相关文章。还搜索了主要的癌症大会。
在最近完成的多项 II 期-III 期研究中，依维莫司单独或与其他药物联合使用的临床疗效已在广泛的肿瘤中得到观察，包括 RCC、神经内分泌肿瘤、结节性硬化症、SEGA 和血管平滑肌脂肪瘤、淋巴瘤以及胃癌、乳腺癌和肝癌。这些发现强调了 mTOR 在多种癌症和罕见疾病中的重要性，并强调了依维莫司作为多种适应症的有效药物的潜在作用。
