Restoring Progestin Sensitivity in Endometrial Cancer

恢复子宫内膜癌的孕激素敏感性

• 批准号: 10402826
• 负责人: Shujie Yang
• 金额: $ 35.34万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402826
• 关键词: Aftercare; Apoptosis; Area; Automobile Driving; Biopsy; Cancer Model; Cancer Patient; Cell Differentiation process; Cell Line; Cessation of life; Clinical; Clinical Research; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Down-Regulation; Drug Screening; Effectiveness; Endometrial; Endometrial Carcinoma; Endometrium; Enrollment; Epigenetic Process; Estrogens; Future; Gene Silencing; Genes; Genomics; Goals; Growth; HDAC2 gene; HDAC4 gene; Histologic; Histone Deacetylase Inhibitor; Hormonal; Hormone Receptor; Human; Hysterectomy; In Vitro; Incidence; Intervention; Knock-out; Laboratories; Libraries; MAP Kinase Gene; Measures; Medroxyprogesterone 17-Acetate; Molecular; Mus; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pilot Projects; Prior Therapy; Progesterone; Progesterone Receptors; Progestin Therapy; Progestins; Publishing; Randomized; Receptor Inhibition; Recurrence; Regimen; Reporter Genes; Repression; Research; Resistance; SETDB1 gene; Specimen; Survival Rate; Testing; Therapeutic Intervention; Time; Tumor Suppressor Proteins; United States National Institutes of Health; Uterus; Work; Xenograft Model; analog; base; cancer cell; cancer clinical trial; cancer type; design; drug candidate; drug efficacy; drug testing; evidence base; expectation; first-in-human; genome-wide; hormone therapy; human model; human tissue; improved; improved outcome; in vitro Model; in vivo; inhibitor; innovation; knock-down; medication safety; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; preclinical study; public health relevance; receptor downregulation; receptor expression; recruit; response; safety and feasibility; small molecule; stem; treatment choice; trend; tumor; tumor xenograft

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.

项目摘要/摘要 虽然在许多类型的癌症，子宫内膜癌的事件和 死亡人数正在上升，今天的五年生存率比三十年前更糟糕。主要归功于 当前治疗的无效性。因为肿瘤对促进生长的促进作用非常敏感 雌激素和孕酮的生长限制作用，荷尔蒙治疗对子宫内膜癌的使用 孕激素一直是传统的治疗选择。在短期内非常有效；然而， 由于孕酮受体（PR）表达的丧失，反应能力随着时间的流逝而逐渐减弱，并且复发是 常见的。迫切需要确定改善或恢复对孕激素的响应能力的策略 治疗，我们建议分子增强的孕激素治疗将对 子宫内膜癌患者的存活率。该应用的目的是确定分子 在子宫内膜癌患者中推动PR下调的机制，并确定新型策略 进一步提高孕激素治疗的有效性。我们将与 孕激素将显着增强体外肿瘤细胞分化并改善小鼠的存活率 人子宫内膜癌的异种移植模型。我们的中心假设是针对PR阻遏物将 增强PR的表达，PR是子宫内膜中最重要的肿瘤抑制剂，从而改善 对孕激素治疗的反应。该假设源于我们最近在子宫内膜中发表的强大数据 PR表达通过不同的分子机制下调的癌细胞和表观遗传学 调节剂有效地增加了PR表达和肿瘤抑制活性。我们现在已经确定了其他 PR抑制器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AIM 1中，我们将确定影响 来自我们相关临床的子宫内膜癌患者的PR表达和活性的表观遗传调节剂 试验NRG-GY011结果；在AIM 2中，我们将使用小分子药物和测试药物增强PR表达 使用体外和体内子宫内膜癌模型的功效。在AIM 3中，我们将确定新颖的PR 使用全基因组基因沉默的下调机制。这些研究完成后，这是我们的 期望我们将确定荷尔蒙抵抗的机制，成功整合了创新 在临床前和临床研究中，将分子疗法用于增强的孕激素治疗方案，并告知 用于未来子宫内膜癌临床试验的设计。因此，这些研究具有强大的潜力 影响子宫内膜癌生存下降的令人震惊的趋势。