Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, One Blackfan Circle, Boston, MA 02115, USA.
Proc Am Thorac Soc. 2010 Feb;7(1):48-53. doi: 10.1513/pats.200909-104JS.
The pace of progress in lymphangioleiomyomatosis (LAM) is remarkable. In the year 2000, TSC2 gene mutations were found in LAM cells; in 2001 the tuberous sclerosis complex (TSC) genes were discovered to regulate cell size in Drosophila via the kinase TOR (target of rapamycin); and in 2008 the results were published of a clinical trial of rapamycin, a specific inhibitor of TOR, in patients with TSC and LAM with renal angiomyolipomas. This interval of just 8 years between a genetic discovery for which the relevant signaling pathway was as yet unknown, to the initiation, completion, and publication of a clinical trial, is an almost unparalleled accomplishment in modern biomedical research. This robust foundation of basic, translational, and clinical research in TOR, TSC, and LAM is now poised to optimize and validate effective therapeutic strategies for LAM. An immediate challenge is to deduce the mechanisms underlying the partial response of renal angiomyolipomas to rapamycin, and thereby guide the design of combinatorial approaches. TOR complex 1 (TORC1), which is known to be active in LAM cells, is a key inhibitor of autophagy. One hypothesis, which will be explored here, is that low levels of autophagy in TSC2-null LAM cells limits their survival under conditions of bioenergetic stress. A corollary of this hypothesis is that rapamycin, by inducing autophagy, promotes the survival of LAM cells, while simultaneously arresting their growth. If this hypothesis proves to be correct, then combining TORC1 inhibition with autophagy inhibition may represent an effective clinical strategy for LAM.
淋巴管平滑肌瘤病（LAM）的研究进展令人瞩目。2000 年，在 LAM 细胞中发现 TSC2 基因突变；2001 年，发现结节性硬化复合物（TSC）基因通过雷帕霉素靶蛋白（TOR）激酶调节果蝇细胞大小；2008 年，雷帕霉素（TOR 的特异性抑制剂）治疗 TSC 和 LAM 伴肾血管平滑肌脂肪瘤患者的临床试验结果公布。在一项遗传发现的 8 年时间内，相关信号通路尚不清楚，到临床试验的启动、完成和发表，这几乎是现代生物医学研究中前所未有的成就。TOR、TSC 和 LAM 的基础、转化和临床研究的强大基础，现在正准备优化和验证 LAM 的有效治疗策略。一个直接的挑战是推断雷帕霉素治疗肾血管平滑肌脂肪瘤部分反应的机制，从而指导组合方法的设计。TOR 复合物 1（TORC1）已知在 LAM 细胞中活跃，是自噬的关键抑制剂。这里将探讨的一个假设是，TSC2 缺失的 LAM 细胞中自噬水平较低，限制了它们在生物能量应激下的生存能力。这一假设的推论是，雷帕霉素通过诱导自噬促进 LAM 细胞的存活，同时阻止其生长。如果这一假设被证明是正确的，那么 TORC1 抑制与自噬抑制的联合可能代表 LAM 的一种有效临床策略。
