The Role of PDEF in Prostate Cancer

项目总结： 在美国，前列腺癌每年造成约30000人死亡。有迫切但尚未得到满足的需求 用于前列腺癌治疗干预的新靶点的识别和表征。我们的目标是解决这个问题 前列腺源性ETS转录因子(PDEF)在前列腺癌中的作用 减少与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周期，部分通过限制谱系可塑性，因此可能 帮助CRPC男性对当前的治疗方法敏感“。这一新的范例，意味着PDEF肿瘤进展的丧失 和治疗耐药性，部分是通过允许将AR重新靶向到非典型性AR周期，以及部分通过 促进谱系可塑性和CRPC的出现，是一项开创性的概念进步，它坚持 在确定CRPC新的治疗靶点方面的翻译承诺，到目前为止还没有治愈的方法。我们的 假设是由我们新的观察结果驱动的，即前列腺癌患者的PDEF水平有逐渐下降的趋势 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负性丰富了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和茎的相关基因的表达， 在实验性(TRAMP)小鼠模型中，在PCA进展过程中，PDEF降低。此外，我们 观察到PDEF促进与典型AR周期和鲁米那相关的不同转录谱 差异化。我们现在建议在三个具体目标上检验我们的假设：目标1)评估PDEF的作用 在调节AR信号通路中，目的2)确定PDEF在细胞可塑性和AR抵抗中的作用 途径抑制剂，和；AIM3)以评估PDEF缺失的前列腺癌是否对 AR靶向治疗的组合(恩扎鲁胺(ENZ)和EZH2抑制剂(EPZ-6438)与ENZ的比较 独自一人。在此提出的目标的实现应大大促进我们对 PDEF抑制前列腺癌进展和转移的机制。我们建议的调查是 与退伍军人管理局的使命高度相关，并可能通过以下方式对拯救退伍军人的生命产生重大影响 描述近期干预前列腺癌的新靶点。

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.