Restoring Progestin Sensitivity in Endometrial Cancer

项目概要/摘要 虽然许多类型的癌症的结果有了实质性的改善，但子宫内膜癌的发病率和 死亡人数正在上升，今天的五年生存率比三十年前更差;主要原因是 目前的治疗无效。由于肿瘤对促生长作用非常敏感， 雌激素和孕激素的生长限制作用，使用激素治疗子宫内膜癌 孕激素是传统的治疗选择。它在短期内非常有效;然而， 由于孕激素受体（PR）表达的丧失，反应性随时间减弱， 共同迫切需要确定战略，以改善或恢复对药物滥用的反应， 治疗，我们建议，分子增强的liquestin治疗将产生重大的积极影响， 子宫内膜癌患者的生存率。本申请的目的是鉴定 子宫内膜癌患者PR下调的驱动机制，并确定新的策略 以进一步增强雷公藤多甙治疗的有效性。我们将开发分子药剂组合， 孕激素将显著增强体外肿瘤细胞分化并改善小鼠存活率 人子宫内膜癌的异种移植模型。我们的中心假设是，针对PR阻遏物， 增强子宫内膜中最重要的肿瘤抑制因子PR的表达，从而改善 对维生素A治疗的反应。这一假设源于我们最近发表的关于子宫内膜癌的有力数据。 癌细胞PR表达通过不同的分子机制下调， 调节剂有效地增加PR表达和肿瘤抑制活性。我们现在已经确定了额外的 PR抑制剂有可能更清楚地定义PR抑制的多种机制， 子宫内膜癌，为新的治疗机会奠定了基础。在目标1中，我们将确定 表观遗传调节剂对子宫内膜癌患者PR表达和活性的影响 试验NRG-GY 011结果;在目标2中，我们将使用小分子药物和试验药物增强PR表达 使用体外和体内子宫内膜癌模型的疗效。在目标3中，我们将确定新的PR 使用全基因组基因沉默的下调机制。在完成这些研究后，我们 期望我们将确定激素抵抗的机制，成功地整合创新的 在临床前和临床研究中，将分子疗法应用于增强的雷公藤多甙治疗方案，并为 用于未来子宫内膜癌临床试验的设计。因此，这些研究具有很大的潜力， 影响子宫内膜癌生存率下降的惊人趋势。

Project Summary/Abstract While outcomes have substantially improved for many types of cancer, endometrial cancer incidences and deaths are on the rise, with the five year survival rate worse today than three decades ago; owing largely to the ineffectiveness of current treatments. As a tumor is exquisitely sensitive to the growth promoting effects of estrogen and the growth limiting effects of progesterone, hormonal therapy for endometrial cancer using progestins has been a traditional choice for treatment. It is highly effective in the short term; however, responsiveness wanes over time due to loss of progesterone receptor (PR) expression, and recurrences are common. There is a critical need to identify strategies to improve or restore responsiveness to progestin therapy, and we propose that molecularly enhanced progestin therapy will make a major positive impact on survival of patients with endometrial cancer. The objective of this application is to identify the molecular mechanisms driving the downregulation of the PR in endometrial cancer patients and identify novel strategies to further enhance the effectiveness of progestin therapy. We will develop molecular agent combinations with progestins that will significantly enhance tumor cell differentiation in vitro and improve survival in mouse xenograft models of human endometrial cancer. Our central hypothesis is that targeting PR repressors will enhance the expression of PR, the most important tumor suppressor in the endometrium, thereby improving response to progestin therapy. This hypothesis stems from our strong recently published data in endometrial cancer cells that PR expression is downregulated through distinct molecular mechanisms, and epigenetic modulators potently increase PR expression and tumor suppressor activity. We have now identified additional PR suppressors that have the potential to more clearly define the multiple mechanisms of PR inhibition in endometrial cancer, setting the stage for new therapeutic opportunities. In Aim 1, we will determine the impact of epigenetic modulators on PR expression and activity in endometrial cancer patients from our related clinical trial NRG-GY011 results; in Aim 2, we will enhance PR expression using small molecular drugs and test drug efficacy using in vitro and in vivo endometrial cancer models. In Aim 3, we will identify novel PR downregulation mechanisms using genome-wide gene silencing. At the completion of these studies, it is our expectation that we will have identified mechanisms of hormonal resistance, successfully integrated innovative molecular therapies into enhanced progestin therapeutic regimens in preclinical and clinical studies, and inform for the design of future endometrial cancer clinical trials. As such, these studies have a strong potential to impact the alarming trend towards declining survival in endometrial cancer.