Pathobiology and Mechanism of Progesterone Resistance in Human Endometrial Cancer

描述（申请人提供）：子宫内膜癌是一种常见的激素驱动肿瘤。孕激素通过孕激素受体（PR）发挥作用，可作为治疗子宫内膜癌亚群的有效药物。由于对子宫内膜癌病理生物学的了解有限，激素治疗并没有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。本研究的总体目标是阐明子宫内膜癌中黄体酮耐药的病理生物学和机制，并发现可以扩大黄体酮治疗临床应用的策略。该建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，上皮特异性PTEN缺失导致子宫内膜肿瘤，与人类疾病密切相关；2) PTEN上皮缺失导致的肿瘤对黄体酮敏感，而PTEN上皮缺失并激活Kras导致黄体酮耐药；3)在黄体酮耐药小鼠肿瘤基质中检测到PR的表观遗传沉默；4)基质特异性PR缺失将一种敏感激素转化为一种激素难治性子宫内膜癌；5)在小鼠激素难治性肿瘤基质中添加外源性PR，使其对黄体酮治疗增敏。我们的主要假设是：(a)肿瘤基质中PR的沉默是导致人类子宫内膜癌激素抗性的主要机制；(b)基质PR的表达或信号传导是激素敏感肿瘤患者前瞻性识别的有效生物标志物。具体目的：1)确定信号是否通过基质和/或上皮内质网？对黄体酮的抗肿瘤作用至关重要；2)检测肿瘤基质中PR的药理学恢复是否使孕酮难治性小鼠子宫内膜肿瘤对激素治疗敏感；3)建立体内激素难治性人子宫内膜肿瘤模型；4)确定人子宫内膜肿瘤对激素治疗反应的生物标志物。作为一名内科科学家，我们计划(a)确定基质PR表达是否是识别黄体酮敏感的人类癌症的生物标志物，(b)基于黄体酮敏感与耐药肿瘤的转录组分析确定独立的生物标志物，(c)确定PR是否在激素难制性人类肿瘤的基质中甲基化。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成为激素难治性肿瘤的机制。除了获得关于子宫内膜癌病理生物学的机制见解外，我们的提议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尚未获得的对激素治疗反应的生物标志物，并制定新的策略使激素难治性肿瘤对孕激素治疗敏感。

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.