Resveratrol and Sirolimus in LAM Trial (RESULT)

摘要 淋巴管肌瘤病(LAM)是一种罕见的女性为主的低级别转移性肿瘤。 以肺实质进行性浸润为特征，伴有异常的平滑肌细胞。林灿 可见于结节性硬化症(TSC-LAM)，或散在发生(S-LAM)。TSC和TSC- LAM和S-LAM的发生是由于两个TSC基因中的一个突变导致结构性激活 雷帕霉素(MTOR)途径的机制靶点，驱动细胞增殖和淋巴管生成(in 部分)通过产生血管内皮生长因子--血管内皮生长因子-C和血管内皮生长因子-D。西罗莫司与mTOR结合 并阻断下游激酶的激活，恢复TSC功能缺陷细胞的动态平衡。在一个 最近的研究表明，西罗莫司可以稳定肺功能下降，改善慢性阻塞性肺疾病患者的生活质量 林。但停用西罗莫司后，肺功能恢复下降，血管内皮生长因子-D水平再次升高， 提示西罗莫司的作用是抑制而不是诱导缓解。此外，从长远来看， 西罗莫司治疗LAM的安全性和有效性尚不清楚。西罗莫司的这些局限性突出了迫切需要 为LAM患者探索新的治疗方案。白藜芦醇是一种天然存在的多酚，具有 已证明能抑制mTOR、Akt和S6K1的活性。最近对TSC2零进行的临床前研究 细胞和小鼠模型已经证明，白藜芦醇和西罗莫司的组合会导致 下调自噬并促进TSC2缺失细胞的凋亡，降低TSC2缺失细胞的转移能力 子宫肌瘤来源的平滑肌细胞，并导致子宫肌瘤的大小和生长显著减少 TSC2缺陷型异种移植瘤。我们假设西罗莫司联合治疗LAM患者 白藜芦醇耐受性好，比单用西罗莫司更有效。然而，我们需要确定 白藜芦醇在LAM中最有效和耐受性最好的剂量。因此，我们计划进行一次开放标签、剂量- 西罗莫司联合白藜芦醇治疗LAM的II期安全性和有效性研究 他们之前一直在接受西罗莫斯的稳定治疗。我们提案的具体目标1将评估这一变化 白藜芦醇和西罗莫司治疗24周后血清血管内皮生长因子-D水平与基线比较 患者单用稳定剂量西罗莫司后的血管内皮生长因子-D水平。具体目标2将决定 白藜芦醇联合西罗莫司治疗LAM具体目标3将评估 白藜芦醇和西罗莫司对肺功能和生活质量的影响。我们的项目非常有意义，因为它提出了 对患者进行诱导缓解(细胞毒性)而不是抑制性(细胞抑制)治疗的试验 和林一起。成功完成我们的研究将确定白藜芦醇在LAM中的最佳剂量，并提供 信息既是必要的也是充分的，以便设计一个明确的、多中心的、随机的、 白藜芦醇联合西罗莫司治疗LAM的临床对照试验。

Abstract Lymphangioleiomyomatosis (LAM) is a rare, female-predominant, low-grade, metastasizing neoplasm characterized by the progressive infiltration of lung parenchyma with abnormal smooth muscle cells. LAM can be seen in association with Tuberous Sclerosis Complex (TSC-LAM), or occur sporadically (S-LAM). Both TSC- LAM and S-LAM occur as a result of mutations in one of the two TSC genes leading to constitutive activation of the mechanistic target of rapamycin (mTOR) pathway, which drives cell proliferation and lymphangiogenesis (in part) through production of vascular endothelial growth factors - VEGF-C and VEGF-D. Sirolimus binds to mTOR and blocks activation of downstream kinases, restoring homeostasis in cells with defective TSC function. In a recent study, sirolimus was shown to stabilize lung function decline and improve quality of life in patients with LAM. However, lung function decline resumed, and VEGF-D levels increased again, after stopping sirolimus, suggesting that the role of sirolimus is suppressive rather than remission inducing. In addition, the long term safety and efficacy of sirolimus in LAM remains unclear. These limitations of sirolimus highlight the critical need to explore novel treatment options for patients with LAM. Resveratrol is a naturally occurring polyphenol and has been shown to inhibit the activities of mTOR, Akt, and S6K1. Recent pre-clinical studies performed on TSC2 null cells and murine models have demonstrated that a combination of resveratrol and sirolimus leads to downregulation of autophagy and promotes apoptosis in TSC2 null cells, decreases the metastatic capability of uterine leiomyoma-derived smooth muscle cells, and causes a significant reduction in the size and growth of TSC2 deficient xenograft tumors. We hypothesize that treatment of LAM patients with a combination of sirolimus and resveratrol will be well tolerated and more effective than sirolimus alone. However, we need to determine the most effective and well-tolerated dose of resveratrol in LAM. Thus, we plan to conduct an open-label, dose- escalating, phase II safety and efficacy study of a combination of sirolimus and resveratrol in patients with LAM who are previously on a stable regimen of sirolimus. Specific aim 1 of our proposal will assess the change in serum VEGF-D after 24 weeks of treatment with resveratrol and sirolimus, as compared to the baseline VEGF-D level in patients on a stable dose of sirolimus alone. Specific aim 2 will determine the safety of combined resveratrol and sirolimus in patients with LAM. Specific aim 3 will assess the effect of resveratrol and sirolimus on lung function and quality of life. Our project is highly significant as it proposes the trial of a remission inducing (cytotoxic) as opposed to a suppressive (cytostatic) treatment option for patients with LAM. Successful completion of our study will determine the optimal dose of resveratrol in LAM, and provide information that is both necessary and sufficient in order to design a definitive, multicenter, randomized, controlled clinical trial of combined resveratrol and sirolimus in LAM.