The Role of PDEF in Prostate Cancer

PDEF 在前列腺癌中的作用

• 批准号: 10697300
• 负责人: HARI K KOUL
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697300
• 关键词: Address; Androgens; Binding Sites; Cancer Etiology; Cancer Patient; Cell Line; Cell Migration Inhibition function; Cells; Cessation of life; ChIP-seq; Clinical; DNA Polymerase II; Data; Data Set; Development; EZH2 gene; Epithelium; Experimental Models; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genomics; Gleason Grade for Prostate Cancer; Goals; In Vitro; Intervention; Invaded; Investigation; Knowledge; LNCaP; Malignant neoplasm of prostate; Mediating; Mission; Monitor; Neoplasm Metastasis; Pathway interactions; Phenotype; Prostate; Prothrombin; Resistance; Role; Testing; The Cancer Genome Atlas; Therapeutic Intervention; Veterans; YY1 Transcription Factor; androgen deprivation therapy; castration resistant prostate cancer; cell motility; cohort; deprivation; enzalutamide; experimental study; in vivo; inhibitor; men; mouse model; new therapeutic target; novel; novel therapeutics; overexpression; promoter; prostate cancer cell; prostate cancer cell line; prostate cancer metastasis; prostate cancer progression; recruit; response; stemness; targeted treatment; transcription factor; transcriptomics; tumor; tumor progression

Project Summary: Prostate Cancer (PCa) accounts for ~30000 deaths annually in the USA. There is urgent, yet unmet, need for identification and characterization of new targets for therapeutic intervention in PCa. Our goal is to address this vital knowledge gap by characterizing the role of Prostate Derived Ets Transcription Factor (PDEF) in PCa, thereby reducing the prostate cancer-related deaths. Our central hypotheses are that, “PDEF suppresses CRPC phenotype and PCa metastasis in part by modulating AR cistrome and in part by restricting lineage plasticity and as such may help sensitize CRPC men to current therapies”. This novel paradigm, implies that loss of PDEF tumor progression and therapy resistance in part by allowing re-targeting of AR to non-canonical AR cistrome, and in part by promoting lineage plasticity and emergence of CRPC, is a groundbreaking conceptual advancement, which holds translational promise in identifying new therapeutic targets in CRPC, for which there is no cure to date. Our hypotheses are driven by our novel observations that there is graded decrease in PDEF levels in prostate cancer cells with increasing aggressive phenotype, and that PDEF inhibits cell migration, invasion in vitro, and tumor metastasis in vivo. We discovered that PDEF negatively enriches gene sets associated with cell migration and tumor metastasis. We observed that PDEF inhibits expression of sets of genes associated with EMT, NEPC and Stemness, and that there is decreased PDEF during PCa progression in experimental (TRAMP) mouse model. Moreover, we observed that PDEF promotes distinct transcription profiles related with canonical AR cistrome and luminal differentiation. We now propose to test our hypothesis in three specific aims: AIM 1) To evaluate the role of PDEF in modulating AR cistrome, AIM 2) To determine the role of PDEF in cellular plasticity and resistance to AR pathway inhibitors, and; AIM3) To evaluate if prostate cancers with PDEF loss respond more favorably to combination of AR targeted therapies (Enzalutamide (Enz) and EZH2 inhibitor (EPZ-6438) as compared to Enz alone. The accomplishment of the goals proposed herein should substantially advance our understanding of the mechanisms by which PDEF inhibits prostate cancer progression and metastasis. Our proposed investigation is highly relevant to the mission of VA and is likely to have a significant impact on saving lives of Veterans by characterizing novel targets for intervention against prostate cancer in the immediate future.

项目概要： 在美国，前列腺癌 (PCa) 每年导致约 30000 人死亡。有迫切但尚未满足的需求 PCa 治疗干预新靶点的识别和表征。我们的目标是解决这个问题 通过表征前列腺衍生 Ets 转录因子 (PDEF) 在 PCa 中的作用，从而实现重要的知识差距 减少前列腺癌相关的死亡。我们的中心假设是，“PDEF 抑制 CRPC 表型 和 PCa 转移，部分通过调节 AR 顺反子，部分通过限制谱系可塑性，因此可能 帮助 CRPC 男性对当前疗法敏感”。这种新颖的范例意味着 PDEF 肿瘤进展的丧失 和治疗抵抗，部分是通过允许 AR 重新靶向非经典 AR 顺反组，部分是通过 促进谱系可塑性和 CRPC 的出现，是一个突破性的概念进步，它认为 在确定 CRPC 的新治疗靶点方面具有转化前景，迄今为止尚无治愈方法。我们的 我们的新观察结果推动了这一假设，即前列腺癌中 PDEF 水平逐渐下降 具有增加侵袭性表型的细胞，并且 PDEF 抑制细胞迁移、体外侵袭和肿瘤 体内转移。我们发现 PDEF 负富集与细胞迁移和肿瘤相关的基因集 转移。我们观察到 PDEF 抑制与 EMT、NEPC 和 Stemness 相关的一组基因的表达， 在实验 (TRAMP) 小鼠模型中，PCa 进展期间 PDEF 降低。此外，我们 观察到 PDEF 促进与经典 AR 顺反子和 luminal 相关的不同转录谱 差异化。我们现在建议通过三个具体目标来检验我们的假设： AIM 1) 评估 PDEF 的作用 调节 AR 顺反子，AIM 2) 确定 PDEF 在细胞可塑性和 AR 抗性中的作用 途径抑制剂，以及； AIM3) 评估 PDEF 缺失的前列腺癌是否对 与 Enz 相比，AR 靶向疗法（恩杂鲁胺 (Enz) 和 EZH2 抑制剂 (EPZ-6438) 的组合） 独自的。此处提出的目标的实现将大大增进我们对 PDEF 抑制前列腺癌进展和转移的机制。我们建议的调查是 与退伍军人管理局的使命高度相关，并可能对拯救退伍军人的生命产生重大影响 描绘了不久的将来干预前列腺癌的新目标。