The Role of PDEF in Prostate Cancer

PDEF 在前列腺癌中的作用

• 批准号: 10385704
• 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/10385704
• 关键词: Address; Androgens; Binding Sites; Cancer Etiology; Cancer Patient; Cell Line; Cells; Cessation of life; ChIP-seq; Clinical; DNA Polymerase II; Data; Data Set; Development; EZH2 gene; Epithelial; Experimental Models; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genomics; Gleason Grade for Prostate Cancer; Goals; In Vitro; Intervention; Investigation; Knowledge; LNCaP; Malignant neoplasm of prostate; Mediating; Mission; Monitor; Neoplasm Metastasis; Pathway interactions; Patients; Phenotype; Prostate; Resistance; Role; Savings; 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; promoter; prostate cancer cell; prostate cancer cell line; prostate cancer metastasis; prostate cancer progression; recruit; response; stemness; targeted treatment; transcription factor; transcription factor S-II; transcriptomics; transgenic adenocarcinoma of mouse prostate; 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： 前列腺癌（PCa）在美国每年造成约30000例死亡。迫切需要，但尚未得到满足， 用于PCa治疗干预的新靶点的鉴定和表征。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， 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顺式组和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”。这种新的模式，意味着PDEF肿瘤进展的损失， 和治疗抗性，部分是通过允许AR重新靶向非经典AR顺式组，部分是通过 促进谱系可塑性和CRPC的出现，是一项突破性的概念进步，它认为 在CRPC中识别新的治疗靶点的翻译前景，迄今为止还没有治愈。我们 我们的新观察结果驱动了假设，即前列腺癌中PDEF水平存在分级降低 PDEF抑制细胞迁移、体外侵袭和肿瘤生长， 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和干性相关的基因组的表达， 并且在实验性（TRAMP）小鼠模型中PCa进展期间存在减少的PDEF。而且我们 观察到PDEF促进与典型AR顺反子和管腔相关的不同转录谱， 分化我们现在提出在三个具体目标中测试我们的假设：目的1）评估PDEF的作用 目的：2）确定PDEF在细胞可塑性和抗AR中的作用 途径抑制剂，和; AIM 3）为了评估PDEF丢失的前列腺癌是否对PDEF通路抑制剂更有利， AR靶向治疗（恩杂鲁胺（Enz）和EZH 2抑制剂（EPZ-6438）联合治疗，与Enz相比 一个人实现本文提出的目标应大大促进我们对 PDEF抑制前列腺癌进展和转移的机制。我们提议的调查是 与退伍军人事务部的使命高度相关，并可能对挽救退伍军人的生命产生重大影响， 表征在不久的将来用于干预前列腺癌的新靶点。