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由激素驱动的肿瘤。孕酮通过孕激素受体(PR)发挥作用，是治疗子宫内膜癌患者亚群的有效方法。由于对子宫内膜癌的病理生物学了解有限，激素治疗并未被广泛接受为一种治疗选择。随着肿瘤的进展，子宫内膜PR信号可能发生改变，导致孕激素抵抗。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孕酮耐药的病理生物学和机制，并发现可以扩大孕激素治疗临床应用的策略。这一建议基于我的实验室的以下创新观察：1)在生理学相关的小鼠模型中，PTEN的上皮特异性缺失会导致与人类疾病密切相关的子宫内膜肿瘤；2)PTEN上皮缺失导致的肿瘤是孕酮敏感的，而PTEN伴随Kras激活的上皮缺失会导致孕酮耐药肿瘤；3)在孕酮耐药小鼠肿瘤的间质中检测到PR的表观遗传沉默；4)间质中PR的基质特异性缺失可将一种激素转换为一种激素难治性子宫内膜癌；5)在小鼠激素难治性肿瘤的间质中回加外源性PR，使其对孕酮治疗敏感。我们的中心假设是：(A)肿瘤间质中PR的沉默是导致子宫内膜癌激素抵抗的主要机制，(B)间质PR的表达或信号是前瞻性识别激素敏感型肿瘤患者的有效生物标志物。具体目标：1)确定信号是否通过间质和/或上皮性内质网？这些研究包括：1)研究孕酮的抗癌作用；2)检测肿瘤间质中PR的药理修复是否会使孕酮难治性小鼠子宫内膜肿瘤对激素治疗增敏；3)建立激素难治性人体子宫内膜肿瘤模型；4)确定激素治疗后子宫内膜肿瘤的反应生物标志物。作为一名内科科学家，我们计划(A)确定间质PR表达是否是识别孕激素敏感的人类癌症的生物标记物，(B)基于对黄体酮敏感肿瘤与耐药肿瘤的转录组分析来确定独立的生物标记物，以及(C)确定激素难治性人类肿瘤的间质中PR是否甲基化。这些结果将确定预测激素敏感性的生物标记物，并确定人类子宫内膜肿瘤变得激素耐药的机制。除了获得关于子宫内膜癌病理生物学的机械性见解外，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与疾病相关的小鼠模型转换为对患者样本的分析。长期目标是发现激素治疗反应的迫切需要但目前还没有可用的生物标志物，并开发新的策略来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.