mTOR Inhibitors in Tuberous Sclerosis Complex
mTOR Inhibitors in Tuberous Sclerosis Complex
复制标题
DOI：
10.2174/157015912804143595
复制
发表时间：
2012-12-01
影响因子：
5.3
通讯作者：
Moavero, Romina
中科院分区：
文献类型：
--
作者：
Curatolo, Paolo;Moavero, Romina
多发性硬化症（TSC）是一种遗传性多器官系统疾病，其特征在于肿瘤样病变（错构瘤）和神经发育障碍的发展。TSC 1和TSC 2肿瘤抑制基因的突变发生在大多数TSC患者中，导致雷帕霉素（mTOR）信号通路的哺乳动物靶标的过度激活和随后的许多细胞过程的异常。因此，mTOR抑制剂如西罗莫司和依维莫司有可能为TSC患者提供靶向治疗。依维莫司是第一种mTOR抑制剂，在美国和欧洲被批准作为与TSC相关的室管膜下巨细胞星形细胞瘤（SEGA）患者的治疗选择。迄今为止的临床证据支持mTOR抑制剂在多种TSC相关疾病表现中的使用，包括SEGA、肾血管平滑肌脂肪瘤、皮肤表现和癫痫。此外，正在进行的评估TSC中mTOR抑制剂的临床试验正在进行中，这些研究的结果预计将提供进一步的证据，将坚定地确立其在这种情况下的作用。本文将讨论mTOR通路在TSC中的作用，并回顾mTOR抑制剂的药代动力学，药效学，临床疗效和耐受性，沿着它们目前在临床实践中的地位。
Tuberous sclerosis complex (TSC) is a genetic multiple organ system disorder that is characterized by the development of tumor-like lesions (hamartomas) and neurodevelopmental disorders. Mutations in the TSC1 and TSC2 tumor suppressor genes occur in the majority of patients with TSC, resulting in hyperactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for patients with TSC. Everolimus is the first mTOR inhibitor approved as a treatment option in the USA and in Europe for patients with subependymal giant-cell astrocytomas (SEGAs) associated with TSC. The clinical evidence to date supports the use of mTOR inhibitors in a variety of TSC-associated disease manifestations, including SEGAs, renal angiomyolipoma, skin manifestations, and epilepsy. Furthermore, ongoing clinical trials evaluating mTOR inhibitors in TSC are underway, and the results of these studies are expected to provide further evidence that will firmly establish their role in this setting. This article will discuss the role of the mTOR pathway in TSC and review the pharmacokinetics, pharmacodynamics, clinical efficacy, and tolerability of mTOR inhibitors, along with their current place in clinical practice.