Mechanisms of actions(s) of simvastatin in uterine leiomyoma

项目总结 子宫肌瘤是一个具有巨大经济负担的重大医学挑战。带着一个 据估计，到50岁时发病率为70-80%，它们是女性生殖系统最常见的肿瘤 在美国，估计每年的成本为59亿至344亿美元。目前的激素治疗方法有 限制；因此，迫切需要新的非激素疗法。 我们最近发现：1)他汀类(HMG-CoA还原酶抑制剂)目前用于治疗 高胆固醇血症)的使用与子宫肌瘤和子宫肌瘤相关症状的风险较低相关 一项回顾性研究；2)辛伐他汀抑制患者来源的异种移植动物模型中的肿瘤生长；3) 辛伐他汀在体外抑制人子宫肌瘤细胞增殖和诱导细胞凋亡；最重要的是，4) 辛伐他汀和醋酸利普利酯对子宫肌瘤细胞的抗增殖作用具有协同作用。因此，进一步 有必要对辛伐他汀治疗子宫肌瘤进行评估。而他汀类药物是FDA批准的 都是常用的药物，但它们对子宫肌瘤的影响尚未得到系统评价。我们假设 辛伐他汀通过抑制甲氧戊酸途径治疗子宫肌瘤 包括RAS和Rho激活所需的类异戊二烯中间体，这些效应起作用 通过调节孕酮信号与醋酸利普列酯协同作用。这样做的目的是 研究目的是检查辛伐他汀作为抗子宫肌瘤治疗药物的作用机制。 体内和体外的影响。 第一个目标是二期随机临床试验，以确定可行性、安全性和初步临床试验。 辛伐他汀治疗子宫肌瘤的疗效。第二个目标是一项翻译研究，以描述 辛伐他汀对来自AIM 1的子宫肌瘤组织的分子、细胞和组织学影响 辛伐他汀抑制细胞增殖、诱导细胞凋亡、抑制干细胞增殖和改变细胞外基质 肌瘤的结构和机械信号。第三个目标将集中在(S)的机制上 辛伐他汀对子宫肌瘤的影响，包括干细胞、生长因子信号、细胞外基质 生产，性类固醇的生物合成和信号传递。我们还研究了协同作用的机制。 辛伐他汀与醋酸利普司他汀之间的相互作用。成功者 该项目的完成是实现新的子宫非激素治疗的下一步。 并提供了对关键肌瘤通路的新的治疗调节的洞察力。这项研究 该提案高度响应了RFA以及NICHD和NIH的总体使命。

PROJECT SUMMARY Uterine fibroids represent a significant medical challenge with an immense economic burden. With an estimated incidence of 70-80% by the age of 50, they are the most common tumors of the female reproductive tract and the estimated annual costs in the US are $5.9-34.4 billion. Current hormonal treatments have limitations; therefore, there is an urgent need for new non-hormonal therapies. We recently discovered the following: 1) statin (HMG-CoA reductase inhibitors currently used in treating hypercholesterolemia) use was associated with a lower risk of uterine fibroids and fibroid-related symptoms in a retrospective study; 2) simvastatin inhibited tumor growth in a patient-derived xenograft animal model; 3) simvastatin inhibited proliferation and induced apoptosis in human fibroid cells in vitro; and most importantly, 4) the antiproliferative effects of simvastatin and ulipristal acetate on fibroid cells were synergistic. Thus, further evaluation of simvastatin as a treatment for uterine fibroids is needed. While statins are FDA-approved and are in common usage, their effect on fibroids has not been systematically evaluated. We hypothesize that simvastatin has therapeutic effects on leiomyomas, through inhibiting the mevalonate pathway including isoprenoid intermediates necessary for Ras and Rho activation and these effects operate synergistically with ulipristal acetate through modulation of progesterone signaling. The objective of this study is to examine simvastatin as an anti-leiomyoma therapeutic and determine the mechanisms of these effects, in vivo and in vitro. The first aim is a phase II randomized clinical trial to determine feasibility, safety and preliminary clinical efficacy of simvastatin in uterine leiomyoma. The second aim is a translational study to characterize the molecular, cellular and histologic effects of simvastatin on leiomyoma tissues from Aim 1. We expect that simvastatin inhibits proliferation; induces apoptosis, inhibits stem cell proliferation; and alters ECM structure and mechanical signaling in leiomyomas. The third aim will focus on the mechanism(s) of simvastatin’s effects on leiomyoma, including stem cells, growth factor signaling, extracellular matrix production, and sex steroid biosynthesis and signaling. We also examine the mechanisms of synergistic action between simvastatin and ulipristal acetate through modulation of progesterone signaling. The successful completion of this project is the next step toward implementation of a new non-hormonal treatment for uterine fibroids and provides insight into novel therapeutic modulation of critical fibroid pathways. This research proposal is highly response to the RFA and the overall mission of NICHD and NIH.