Resveratrol and Sirolimus in LAM Trial (RESULT)

LAM 试验中的白藜芦醇和西罗莫司（结果）

• 批准号: 9374597
• 负责人: Nishant Gupta
• 金额: $ 25万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9374597
• 关键词: Adverse effects; Adverse event; Apoptosis; Autophagocytosis; Binding; Bronchodilator Agents; Cell Proliferation; Cell model; Cells; Clinical Data; Clinical Trials; Combined Modality Therapy; Common Terminology Criteria for Adverse Events; Cytostatics; Data; Disease; Disease remission; Dose; Down-Regulation; FRAP1 gene; Female; Female of child bearing age; Frequencies; Growth; Homeostasis; Infiltration; Knowledge; Lung; Lung diseases; Lymphangiogenesis; Lymphangioleiomyomatosis; Measures; Mutation; Neoplasm Metastasis; Neoplasms; Null Lymphocytes; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phase III Clinical Trials; Phonation; Phosphotransferases; Production; Pulmonary Function Test/Forced Expiratory Volume 1; Quality of life; Questionnaires; Randomized Controlled Clinical Trials; Regimen; Respiratory physiology; Resveratrol; Role; SLC12A3 gene; Safety; Serum; Severities; Sirolimus; Smooth Muscle Myocytes; Spirometry; Structure of parenchyma of lung; TSC2 gene; Telephone; Testing; Tuberous sclerosis protein complex; Uterine Fibroids; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factors; Visit; base; body system; cytotoxic; design; effective therapy; efficacy study; improved; inhibitor/antagonist; mouse model; novel; open label; polyphenol; pre-clinical; preclinical study; profiles in patients; rate of change; safety study; treatment effect; tumor xenograft

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.

摘要 淋巴管平滑肌瘤病是一种罕见的，女性为主，低级别，转移性肿瘤 其特征在于异常平滑肌细胞对肺实质的进行性浸润。林灿 与多发性硬化症（TSC-LAM）相关，或偶发性发生（S-LAM）。TSC- LAM和S-LAM的发生是由于两个TSC基因之一的突变，导致TSC的组成性激活。 驱动细胞增殖和淋巴管生成的雷帕霉素（mTOR）途径的机制靶点（在 部分）通过产生血管内皮生长因子- VEGF-C和VEGF-D。西罗莫司与mTOR结合 并阻断下游激酶的激活，恢复TSC功能缺陷细胞的体内平衡。中 最近的一项研究表明，西罗莫司可以稳定肺功能下降，改善患者的生活质量。 Lam.然而，停止西罗莫司后，肺功能恢复下降，VEGF-D水平再次升高， 这表明西罗莫司的作用是抑制性的而不是缓解诱导性的。此外，长期 西罗莫司在LAM中的安全性和有效性仍不清楚。西罗莫司的这些局限性突出了 探索LAM患者的新治疗方案。白藜芦醇是一种天然存在的多酚， 已显示抑制mTOR、Akt和S6 K1的活性。最近对TSC 2 null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导致 下调自噬并促进TSC 2缺失细胞的凋亡，降低了肿瘤的转移能力。 子宫平滑肌瘤来源的平滑肌细胞，并导致在大小和生长的显着减少， TSC 2缺陷型异种移植肿瘤。我们假设用西罗莫司联合治疗LAM患者 并且白藜芦醇将被良好耐受并且比单独的西罗莫司更有效。但是我们需要确定 最有效和耐受性最好的剂量的白藜芦醇在LAM。因此，我们计划进行一项开放标签、剂量- 西罗莫司和白藜芦醇联合治疗LAM患者的一项逐步升级的II期安全性和疗效研究 他们之前都在接受稳定的西罗莫司治疗我们提案的具体目标1将评估这一变化 与基线相比，白藜芦醇和西罗莫司治疗24周后血清VEGF-D 接受稳定剂量西罗莫司单药治疗患者的VEGF-D水平。具体目标2将确定 联合白藜芦醇和西罗莫司治疗LAM患者。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。我们的项目非常重要，因为它提出 缓解诱导（细胞毒性）与抑制（细胞抑制）治疗方案的试验 在LAM。我们的研究的成功完成将确定LAM中白藜芦醇的最佳剂量，并提供 为了设计一个确定的、多中心的、随机的、 联合应用白藜芦醇和西罗莫司治疗LAM的临床对照试验。