Pathobiology and Mechanism of Progesterone Resistance in Human Endometrial Cancer

人类子宫内膜癌黄体酮抵抗的病理生物学和机制

• 批准号: 9222716
• 负责人: Sanaz Memarzadeh
• 金额: $ 35.23万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222716
• 关键词: Anti-Progestin; Back; Bioinformatics; Biological Markers; Cancer Patient; Cells; Clinic; Clinical; Clinical Trials; Collaborations; Development; Disease; Endometrial; Endometrial Carcinoma; Endometrial Neoplasms; Endometrium; Ensure; Epigenetic Process; Epithelial; Epithelium; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Fertility; Funding; Goals; Hormonal; Hormones; Human; Immune; Implant; Knowledge; Laboratories; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Methylation; Modeling; Molecular; Mus; PTEN gene; Patients; Pharmaceutical Preparations; Pharmacology; Physicians; Physiological; Progesterone; Progesterone Receptors; Publishing; Receptor Gene; Receptor Signaling; Refractory; Repression; Resistance; Role; Sampling; Scientist; Signal Transduction; Study models; Technology; Testing; Tissues; Translations; United States; Uterine Neoplasms; Viral; Woman; antitumor effect; base; clinical application; drug testing; effective therapy; empowered; endometrial stroma; hormone resistance; hormone therapy; human disease; in vivo; innovation; insight; knock-down; malignant breast neoplasm; mouse model; multidisciplinary; novel strategies; pre-clinical; predictive marker; prospective; public health relevance; receptor expression; response; response biomarker; restoration; statistics; steroid hormone receptor; success; therapeutic evaluation; transcriptome; tumor

DESCRIPTION (provided by applicant): Endometrial cancer is a common and hormonally driven tumor. Progesterone, which exerts its effects through the progesterone receptor (PR), can be an effective therapy for subsets of endometrial cancer patients. Due to limited understanding of pathobiology of endometrial cancer, hormonal therapy is not widely embraced as a treatment option. With progression to cancer, endometrial PR signaling may change resulting in progesterone resistance. The molecular mechanisms underlying progesterone insensitivity are unknown. The overall goal of this proposal is to elucidate the pathobiology and mechanisms that cause progesterone resistance in endometrial carcinoma and to discover strategies that can broaden the clinical application of progesterone therapy. This proposal is based on following innovative observations from my laboratory: 1) Epithelial specific loss of PTEN in a physiologically relevant mouse model results in endometrial tumors that closely recapitulate human disease; 2) tumors resulting from epithelial loss of PTEN are progesterone sensitive while epithelial loss of PTEN with activation of Kras results in progesterone resistant tumors; 3) Epigenetic silencing of PR is detected in the stroma of progesterone resistant mouse tumors; 4) Stromal specific deletion of PR converts a hormone sensitive to a hormone refractory endometrial cancer; 5 ) Add-back of exogenous PR in the stroma of mouse hormone refractory tumors, sensitizes them to progesterone therapy. Our central hypotheses are that (a) silencing of PR in the tumor stroma is the primary mechanism leading to hormone resistance in human endometrial cancers and (b) stromal PR expression or signaling is a valid biomarker in prospective identification of patients with hormone sensitive tumors. Specific Aims: 1) Determine if signaling through stromal and/or epithelial ER? is essential for the anti-tumor effects of progesterone; 2) Test if pharmacologic restoration of PR in the tumor stroma sensitizes progesterone refractory mouse endometrial tumors to hormonal therapy; 3) Develop an in vivo hormone refractory human endometrial tumor model; 4) Identify biomarkers of response to hormonal therapy in human endometrial tumors. Being a physician scientist, here we plan to (a) determine if stromal PR expression is a biomarker for identifying progesterone sensitive human cancers, (b) identify independent biomarkers based on transcriptome analysis of progesterone sensitive vs. resistant tumors and (c) determine if PR is methylated in stroma of hormone refractory human tumors. These results will identify biomarkers predictive of hormonal sensitivity and define mechanisms by which human endometrial tumors become hormone refractory. In addition to gaining mechanistic insight about the pathobiology of endometrial cancer, another innovative aspect of our proposal involves translation of a disease-relevant mouse model to the analysis of patient samples using strategies pioneered by our team. The long term goal is to discover much needed but currently unavailable biomarkers of response to hormonal therapy and develop novel strategies to sensitize hormone refractory tumors to progesterone therapy.

描述（由申请人提供）：子宫内膜癌是一种常见的、由激素驱动的肿瘤。黄体酮通过黄体酮受体（PR）发挥作用，可以成为治疗部分子宫内膜癌患者的有效疗法。由于对子宫内膜癌病理学的了解有限，激素疗法并未被广泛接受作为一种治疗选择。随着癌症的进展，子宫内膜 PR 信号可能发生变化，导致黄体酮抵抗。黄体酮不敏感的分子机制尚不清楚。该提案的总体目标是阐明导致子宫内膜癌孕激素抵抗的病理生物学和机制，并发现可以拓宽孕激素治疗临床应用的策略。该提议基于我实验室的以下创新观察：1）在生理相关的小鼠模型中，PTEN 上皮特异性缺失导致子宫内膜肿瘤，与人类疾病密切相关； 2) 上皮细胞PTEN缺失导致的肿瘤对孕激素敏感，而上皮细胞PTEN缺失伴随Kras激活导致孕激素耐药肿瘤； 3）在孕激素抗性小鼠肿瘤的基质中检测到PR的表观遗传沉默； 4) 间质特异性删除PR，将激素敏感转化为激素难治性子宫内膜癌； 5）在小鼠激素难治性肿瘤的基质中添加外源PR，使它们对黄体酮治疗敏感。我们的中心假设是（a）肿瘤间质中 PR 的沉默是导致人类子宫内膜癌激素抵抗的主要机制，（b）间质 PR 表达或信号传导是前瞻性识别激素敏感肿瘤患者的有效生物标志物。具体目标： 1) 确定信号传导是否通过基质和/或上皮 ER？对于黄体酮的抗肿瘤作用至关重要； 2) 测试肿瘤基质中 PR 的药理学恢复是否会使孕酮难治性小鼠子宫内膜肿瘤对激素治疗敏感； 3）开发体内激素难治性人子宫内膜肿瘤模型； 4) 识别人类子宫内膜肿瘤激素治疗反应的生物标志物。作为一名医师科学家，我们计划 (a) 确定基质 PR 表达是否是识别孕酮敏感人类癌症的生物标志物，(b) 基于孕酮敏感与耐药肿瘤的转录组分析识别独立的生物标志物，以及 (c) 确定是否PR 在激素难治性人类肿瘤的基质中被甲基化。这些结果将确定预测激素敏感性的生物标志物，并确定人类子宫内膜肿瘤变得激素难治的机制。除了获得有关子宫内膜癌病理学的机制见解外，我们提案的另一个创新方面涉及使用我们团队首创的策略将疾病相关小鼠模型转化为患者样本分析。长期目标是发现急需但目前无法获得的激素治疗反应生物标志物，并开发新的策略来使激素难治性肿瘤对黄体酮治疗敏感。