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: 8811893
• 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/8811893
• 关键词: 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 Receptors; Estrogens; Fertility; Funding; Gene Expression Profile; Goals; Hormonal; Hormones; Human; Immune; Implant; Kidney; Knowledge; Laboratories; Lead; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Methylation; Modeling; Molecular; Mus; PTEN gene; Patients; Pharmaceutical Preparations; Physicians; Progesterone; Progesterone Receptors; Publishing; Receptor Gene; Receptor Signaling; Refractory; Repression; Resistance; Role; Sampling; Scientist; Signal Transduction; Technology; Testing; Therapeutic; Tissues; Translations; United States; Uterine Neoplasms; 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; prospective; public health relevance; receptor expression; response; restoration; statistics; steroid hormone receptor; success; 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且荷尔蒙驱动的肿瘤。孕酮通过孕激素受体（PR）发挥作用，可以是子宫内膜癌患者亚群的有效疗法。由于对子宫内膜癌病理生物学的理解有限，因此不能将荷尔蒙治疗作为治疗选择被广泛接受。随着癌症的发展，子宫内膜PR信号可能会改变孕酮耐药性。孕酮不敏感性的分子机制尚不清楚。该提案的总体目标是阐明在子宫内膜癌中引起孕激素耐药性的病理生物学和机制，并发现可以扩大孕酮治疗的临床应用的策略。该建议基于我的实验室的创新观察结果：1）在生理相关的小鼠模型中，PTEN的上皮特异性损失导致子宫内膜肿瘤紧密概括了人类疾病； 2）由PTEN上皮丧失引起的肿瘤是孕激素敏感的，而PTEN的上皮丧失并激活KRAS会导致孕激素耐药性肿瘤； 3）在孕激素肿瘤的基质中检测到PR的表观遗传沉默； 4）PR的基质特异性缺失转化了对激素难治性子宫内膜癌敏感的激素； 5）在小鼠激素难治性肿瘤基质中的外源性PR添加后添加添加，使其对孕酮治疗敏感。我们的中心假设是（a）肿瘤基质中PR的沉默是导致人子宫内膜癌中激素抗性的主要机制，并且（b）基质PR表达或信号传导是对激素敏感肿瘤患者的前瞻性生物标志物。具体目的：1）确定是否通过基质和/或上皮ER信号传导？对于孕酮的抗肿瘤作用至关重要。 2）测试肿瘤基质中PR的药理恢复是否会使孕激素折射小鼠子宫内膜肿瘤对激素疗法敏感； 3）发展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中对荷尔蒙治疗的反应的生物标志物。作为一名医师科学家，我们计划（a）确定基质PR表达是否是鉴定孕激素敏感人类癌症的生物标志物，（b）基于孕酮敏感性和耐药性肿瘤的转录组分析，识别独立的生物标记物，（C）确定在强烈的抑制人类抑制性人类肿瘤的基质中PR甲基化。这些结果将确定可预测激素敏感性的生物标志物，并定义人子宫内膜肿瘤成为激素难治性的机制。除了获得有关子宫内膜癌病理生物学的机理见解外，我们提案的另一个创新方面还涉及将相关的小鼠模型转换为使用团队率先使用策略的策略来分析患者样本。长期目标是发现急需的，但目前无法获得对荷尔蒙治疗的反应的生物标志物，并制定了新颖的策略，以使激素难治性肿瘤对孕酮治疗敏感。