Pathobiology and Mechanism of Progesterone Resistance in Human Endometrial Cancer

描述（由申请人提供）：子宫内膜癌是一种常见的、由卵巢驱动的肿瘤。孕激素通过孕激素受体（PR）发挥其作用，可以成为子宫内膜癌患者亚群的有效治疗方法。由于对子宫内膜癌病理生物学的了解有限，激素治疗未被广泛接受为治疗选择。随着癌症的进展，子宫内膜PR信号可能发生变化，导致孕酮抵抗。孕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中孕酮抵抗的病理生物学和机制，并发现可以扩大孕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）在生理学相关的小鼠模型中，上皮特异性的PTEN缺失导致与人类疾病密切重演的子宫内膜肿瘤; 2）由上皮缺失的PTEN导致的肿瘤是孕酮敏感的，而上皮缺失的PTEN与Kras的激活导致孕酮抗性肿瘤; 3）在孕酮抗性小鼠肿瘤的基质中检测到PR的表观遗传沉默; 4）PR的基质特异性缺失将激素敏感性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回外源性PR，使它们对孕酮治疗敏感。我们的中心假设是：（a）肿瘤间质中PR的沉默是导致人子宫内膜癌中激素抵抗的主要机制，（B）间质PR表达或信号传导是前瞻性鉴定激素敏感性肿瘤患者的有效生物标志物。具体目的：1）确定是否通过基质和/或上皮ER的信号？是孕酮的抗肿瘤作用所必需的; 2）测试肿瘤间质中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疗法敏感; 3）开发体内激素难治性人子宫内膜肿瘤模型; 4）鉴定人子宫内膜肿瘤中对激素疗法的响应的生物标志物。作为一名医师科学家，我们计划（a）确定间质PR表达是否是识别孕激素敏感性人类癌症的生物标志物，（B）基于孕激素敏感性与耐药肿瘤的转录组分析来识别独立的生物标志物，以及（c）确定PR是否在激素难治性人类肿瘤的间质中甲基化。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的机制。除了获得关于子宫内膜癌病理生物学的机械见解外，我们提案的另一个创新方面涉及使用我们团队开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的生物标志物，并开发新的策略，使激素难治性肿瘤对孕酮治疗敏感。

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.