Restoring Progestin Sensitivity in Endometrial Cancer

恢复子宫内膜癌的孕激素敏感性

• 批准号: 10165666
• 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/10165666
• 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/antagonist; 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 虽然许多类型的癌症的预后有了实质性的改善，但子宫内膜癌的发病率和 死亡人数正在上升，今天的五年存活率比30年前更差；这主要是由于 目前的治疗方法无效。作为一种肿瘤，它对生长促进作用非常敏感 雌激素与孕酮、激素治疗子宫内膜癌的生长限制作用 孕激素一直是治疗的传统选择。它在短期内是非常有效的；然而， 随着时间的推移，由于孕激素受体(PR)表达的丧失，反应性减弱，并且复发 很普通。迫切需要确定改善或恢复对孕激素反应性的策略 治疗，我们认为分子增强孕酮治疗将对 子宫内膜癌患者的存活率。这个应用程序的目的是识别分子 子宫内膜癌患者PR下调的机制及新的治疗策略 以进一步提高孕激素治疗的有效性。我们将开发分子制剂组合，与 孕激素能显著促进肿瘤细胞的体外分化并提高小鼠的存活率 人子宫内膜癌异种移植模型的建立。我们的中心假设是，以公关抑制者为目标 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 对孕激素治疗的反应。这一假说源于我们最近在子宫内膜上发表的强有力的数据 通过不同的分子机制下调PR表达的癌细胞，以及表观遗传学 调节剂有效地增加PR的表达和肿瘤抑制活性。我们现在已经确定了其他 PR抑制因子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，我们将确定影响 表观遗传调节因子对子宫内膜癌患者PR表达和活性的影响 NRG-GY011试验结果；在目标2中，我们将使用小分子药物和测试药物增强PR的表达 采用体外和体内子宫内膜癌模型进行疗效观察。在目标3中，我们将确定新的公关 使用全基因组基因沉默的下调机制。在完成这些研究后，我们的 预期我们将识别荷尔蒙抵抗的机制，成功整合创新 在临床前和临床研究中将分子疗法转变为增强型孕激素治疗方案，并告知 用于设计未来子宫内膜癌的临床试验。因此，这些研究具有很强的潜力 对子宫内膜癌存活率下降这一令人震惊的趋势的影响。