Nuclear Factor I/B Action in Castrate Resistant Prostate Cancer

核因子 I/B 在去势抵抗性前列腺癌中的作用

• 批准号: 9248124
• 负责人: Magdalena Malgorzata Grabowska
• 金额: $ 2.24万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248124
• 关键词: Nuclear; Factor; Action; Castrate; Resistant

 DESCRIPTION (provided by applicant): Candidate Background: I received my Ph.D. from the University of Michigan for my dissertation studies with Dr. Mark L. Day, focusing on soluble E-cadherin signaling through EGFR in benign prostatic hyperplasia and prostate cancer (PCa). I am continuing my PCa research studies with Dr. Robert J. Matusik at Vanderbilt University as a postdoctoral research fellow by focusing on how androgen receptor (AR) cofactors can support progression to castrate resistant PCa (CRPCa) and therapy acquired neuroendocrine PCa (NEPCa). Career Goals and Objectives: My career goal is to become an independent, tenure-track faculty member at a high-caliber research institution, working with an interdisciplinary team, and focusing on identifying new therapies for CRPCa. Achievement of my career goals requires additional mentored time through the K99/R00. Career Development and Training Activities: My training plan revolves around mentorship, didactic training, and protected research time to support my transition to independence. Dr. Matusik will serve as my primary mentor; he will train me in animal husbandry, mouse model characterization, and personnel management. Dr. Peter Clark, a urologic oncologist, will serve as my clinical mentor, and Dr. Simon Hayward will provide mentorship in tumor microenvironment. I will also complete a biostatistics course and ASPIRE modules, attend immunology seminars, and continue responsible conduct in research (RCR) training. Research Strategy: Significance and Innovation: This project is significant because it examines how NFIB drives lethal CRPCa and supports progression from neuroendocrine differentiation (NED) to therapy acquired NEPCa. This project is innovative because it explores how NFIB can drive resistance to androgen deprivation therapy (castrate resistance) through interactions with AR and AR splice variants (AR-V), as well as induce IL-1β, which supports NED. It also explores how NFIB mediates communication between distinct CRPCa tumor cells. Approach: Patients with advanced PCa inevitably progress to CRPCa following androgen deprivation therapy. Progression to CRPCa can be achieved through multiple mechanisms, including expression of AR-V and NED. AR-V lack the ligand binding domain of full length AR and are therefore constitutively active and unresponsive to therapies which block AR activity. AR is lost altogether in areas of NED or therapy-acquired NEPCa. NED is a focal change whereby PCa begins to lose AR expression, and gains neuroendocrine marker expression. Focal NED occurs in 40-100% of CRPCa samples, and it is common to observe areas of NED within adenocarcinomas. Importantly, secretions from these areas can support castrate resistance of the adenocarcinoma. NED can also be progressive, and 25% of CRPCa patients treated with next generation androgen deprivation therapy will develop therapy-induced NEPCa through NED. Successful treatment of CRPCa, therefore, requires therapies targeting AR action independently of the ligand binding domain. I have discovered that nuclear factor I/B (NFIB) is a potent modulator of AR action. CRPCa samples strongly express NFIB, and NFIB is upregulated in PCa cells which have become castrate resistant through NED. Significantly, knockdown of NFIB prevents NED in vitro. NFIB also appears to be critical for expression of IL-1β which has been implicated in NED in vitro. Based on these observations, I hypothesize that NFIB is a major driver of CRPCa by supporting AR-target gene expression and driving expression of pro-tumorigenic cytokines. Specific Aim 1: Examine how NFIB interacts with the AR/FOXA1 complex to drive CRPCa. 1a) Determine whether NFIB, FOXA1, AR and AR-V interact in PCa cell lines. 1b) Examine the consequences of NFIB knockout on AR and AR-V action in CRPCa cell lines. 1c) Explore the consequences of NFIB overexpression on AR and AR-V action in PCa cell lines capable of undergoing NED. Specific Aim 2: Determine whether NFIB expression is required for progression to CRPCa and/or NEPCa. 2a) Characterize the consequences of NFIB loss in a mouse model of CRPCa. 2b) Determine the consequence of NFIB loss in a mouse model of CRPCa progression to NEPCa. Specific Aim 3: Characterize how NFIB expression supports NED through IL-1β secretion. 3a) Explore changes in IL-1β in response to NFIB modulation. 3b) Determine how changes in IL-1β drive castrate resistant growth. 3c) Evaluate whether secreted IL-1β drives CRPCa. Successful completion of these studies will determine the consequences of NFIB expression in CRPCa. These studies will serve as the basis for an NCI R01 application to be submitted during the end of my third year. Transition to Independence: I will transition to independence by applying to faculty positions during the K99 phase and accepting a tenure track position at a new institution to complete the R00 phase. I have designed these aims independent of Dr. Matusik, and he will not pursue projects relating to NFIB in PCa.

 描述（由申请人提供）：候选人背景：我获得了博士学位。来自密歇根大学，我的博士论文研究与马克L。日，重点是可溶性E-钙粘蛋白信号通过EGFR在良性前列腺增生和前列腺癌（PCa）。我正在继续我的前列腺癌研究与博士.罗伯特J. Matusik在范德比尔特大学作为博士后研究员，通过专注于雄激素受体（AR）辅因子如何可以支持进展到去势抵抗性前列腺癌（CRPCa）和治疗获得性神经内分泌前列腺癌（NEPCa）.职业目标和目的：我的职业目标是成为一个独立的，终身教职的教师在一个高素质的研究机构，与一个跨学科的团队工作，并专注于确定CRPCa的新疗法。我的职业目标的实现需要通过K99/R 00额外的辅导时间。职业发展和培训活动：我的培训计划围绕指导，教学培训和保护研究时间，以支持我向独立过渡。Matusik博士将担任我的主要导师;他将在动物饲养、小鼠模型表征和人员管理方面对我进行培训。泌尿肿瘤学家彼得·克拉克博士将担任我的临床导师，西蒙海沃德博士将提供肿瘤微环境方面的指导。我还将完成生物统计学课程和ASPIRE模块，参加免疫学研讨会，并继续进行负责任的研究（RCR）培训。研究策略：意义与创新：该项目意义重大，因为它研究了NFIB如何驱动致命的CRPCa，并支持从神经内分泌分化（NED）到治疗获得性NEPCa的进展。该项目具有创新性，因为它探索了NFIB如何通过与AR和AR剪接变体（AR-V）的相互作用来驱动对雄激素剥夺疗法的抵抗（去势抵抗），以及诱导支持NED的IL-1β。它还探讨了NFIB如何介导不同CRPCa肿瘤细胞之间的通信。方法：晚期PCa患者在雄激素剥夺治疗后不可避免地进展为CRPCa。CRPCa的进展可以通过多种机制实现，包括AR-V和NED的表达。AR-V缺乏全长AR的配体结合结构域，因此具有组成性活性，对阻断AR活性的疗法无反应。AR在NED或治疗获得性NEPCa的区域完全丢失。NED是PCa开始失去AR表达并获得神经内分泌标志物表达的局灶性变化。局灶性NED发生在40-100%的CRPCa样本中，并且在腺癌内观察到NED区域是常见的。重要的是，来自这些区域的分泌物可以支持腺癌的去势抵抗。NED也可能是进行性的，25%接受下一代雄激素剥夺治疗的CRPCa患者将通过NED发展为治疗诱导的NEPCa。因此，CRPCa的成功治疗需要独立于配体结合结构域的靶向AR作用的疗法。我发现核因子I/B（NFI B）是AR作用的有效调节剂。CRPCa样品强烈表达NFIB，并且NFIB在通过NED变得去势抗性的PCa细胞中上调。显著地，NFIB的敲低在体外防止NED。NFIB似乎也对IL-1β的表达至关重要，IL-1β在体外与NED有关。基于这些观察，我假设NFIB是CRPCa的主要驱动因素，通过支持AR靶基因表达和驱动促肿瘤细胞因子的表达。具体目标1：研究NFIB如何与AR/FOXA 1复合物相互作用以驱动CRPCa。1a）确定NFIB、FOXA 1、AR和AR-V是否在PCa细胞系中相互作用。1b）检查NFIB敲除对CRPCa细胞系中AR和AR-V作用的后果。1c）探索NFIB过表达对能够经历NED的PCa细胞系中AR和AR-V作用的后果。具体目标2：确定NFIB表达是否是进展为CRPCa和/或NEPCa所必需的。2a）表征CRPCa小鼠模型中NFIB损失的后果。2b）确定CRPCa进展为NEPCa的小鼠模型中NFIB损失的后果。具体目标3：表征NFIB表达如何通过IL-1β分泌支持NED。3a）探索响应于NFIB调节的IL-1β的变化。3b）确定IL-1β的变化如何驱动去势抵抗性生长。3c）评估分泌的IL-1β是否驱动CRPCa。这些研究的成功完成将确定CRPCa中NFIB表达的后果。这些研究将作为我在第三年年底提交NCI R 01申请的基础。向独立过渡：我将通过在K99阶段申请教师职位并接受新机构的终身职位来完成R 00阶段，从而过渡到独立。我独立于Matusik博士设计了这些目标，他将不会在PCa进行与NFIB相关的项目。