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.

项目摘要： 在美国，前列腺癌（PCA）每年约30000人死亡。有紧急但未满足的需要 对PCA治疗干预的新目标的识别和表征。我们的目标是解决这个问题 通过表征前列腺衍生的ETS转录因子（PDEF）在PCA中的作用来表征重要知识差距，从而 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转移部分是通过调节Ar Cistrome和部分限制谱系可塑性的部分原因 有助于感知CRPC男性对当前疗法”。这种新型范式意味着PDEF肿瘤进展的损失 部分通过允许将AR重新定位为非典型AR cistrome，部分原因是 促进CRPC的谱系可塑性和出现是一种开创性的概念进步， 转化的承诺在CRPC中识别新的治疗靶标，迄今为止尚无治愈方法。我们的 假设是由我们新颖的观察结果驱动的，即前列腺癌的PDEF水平的分级降低 侵袭性表型增加的细胞，PDEF抑制细胞迁移，体外侵袭和肿瘤 体内转移。我们发现PDEF会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相关的基因集的表达， 并且在实验（Tramp）小鼠模型中PCA进展过程中PDEF降低。而且，我们 观察到PDEF促进了与规范AR Cistrom和Luminal相关的不同转录曲线 分化。现在，我们建议以三个特定目的检验我们的假设：目标1）评估PDEF的作用 在调节AR Cistrome时，目标2）确定PDEF在细胞塑性中的作用和对AR的抗性 途径抑制剂和； AIM3）评估患有PDEF损失的前列腺癌是否对 与ENZ相比 独自的。实现此处提出的目标，应大大提高我们对 PDEF抑制前列腺癌进展和转移的机制。我们提出的调查是 与VA的任务高度相关，很可能会对挽救退伍军人的生命产生重大影响 表征在不久的将来针对前列腺癌进行干预的新目标。