Towards selective androgen deprivation by targeting androgen activation of SRF

描述（由申请人提供）：尽管雄激素受体（AR）在前列腺癌（CaP）进展中起着中心作用，但对雄激素控制驱动CaP进展的细胞过程的特定分子机制的认识仍然很难理解。缺乏这方面的知识是一个重要的问题，因为没有它，开发新的治疗方法，特别是针对雄激素依赖性事件的致命表型是不可能的。长期目标是了解雄激素控制CaP细胞中临床相关基因表达的机制如何被操纵用于治疗干预。目的是确定雄激素控制血清反应因子（SRF）活性的分子机制以及这些机制与CaP进展的相关性。中心假设是，雄激素调节基因的SRF应答亚组通过雄激素激活RhoA信号传导轴和RhoA效应物PKN 1和CIT而导致侵袭性CaP表型。这一假设是根据申请人实验室的初步工作提出的。拟定研究的基本原理是，一旦了解了雄激素如何调节CaP中的SRF作用，就有可能选择与疾病进展相关的雄激素作用靶点。通过追求3个特定目标来测试中心假设：1）定义RhoA、PKN 1和CIT在SRF靶基因的雄激素调节中的贡献; 2）确定雄激素调节基因的SRF响应子集在CaP细胞运动性和侵袭行为中的临床前作用;和3）确定RhoA、PKN 1和CIT依赖性雄激素响应SRF作用的临床相关性。目的1使用定制的基因表达测定来确定RhoA、PKN 1和CIT对SRF靶基因的雄激素调节的贡献，并建立PKN 1和CIT将雄激素控制传递给SRF的方式。目的2使用临床前模型来鉴定SRF靶基因、PKN 1和CIT作为削弱CaP细胞侵袭力的靶标。目的3使用计算机分析和组织微阵列分析的组合来确定PKN 1、CIT和SRF效应基因与CaP进展的相关性。这项研究是创新的，因为它专注于一种完全不同的方法来靶向CaP中的雄激素作用：解开和靶向AR下游的雄激素依赖性信号通路，该通路控制与CaP进展相关的基因表达。这一贡献是重要的，因为它是连续研究的第一步，预计将导致开发新的治疗方式，特异性靶向雄激素介导的基因表达，这是致命的CaP表型的基础。关于预期的结果，拟议的研究将确定雄激素作用的SRF依赖性机制引起侵袭性CaP表型的分子机制。这些结果将产生重要的积极影响，因为它们将从根本上推进对CaP中雄激素作用的认识，并为CaP特异性治疗提供新的靶点。

DESCRIPTION (provided by applicant): Despite the central role of androgen receptor (AR) in prostate cancer (CaP) progression, insights into the specific molecular mechanisms by which androgens control the cellular processes that drive CaP progression remain largely elusive. Lack of this knowledge is an important problem, because without it, development of novel therapeutic approaches that target specifically androgen-dependent events underlying the lethal phenotype is unlikely. The long-term goal is to understand how the mechanism(s) by which androgens control clinically relevant gene expression in CaP cells can be manipulated for therapeutic intervention. The objective is to determine the molecular mechanism(s) by which androgens control activity of Serum Response Factor (SRF) and the relevance of these mechanisms for CaP progression. The central hypothesis is that the SRF- responsive subset of androgen-regulated genes is responsible for the aggressive CaP phenotype via androgen activation of the RhoA signaling axis and the RhoA effectors PKN1 and CIT. This hypothesis is formulated based on preliminary work produced in the applicant's laboratory. The rationale for the proposed studies is that, once it is understood how androgen regulation of SRF action in CaP occurs, select targeting of androgen action that is relevant to disease progression will be possible. The central hypothesis is tested by pursuing 3 specific aims: 1) define the contribution of RhoA, PKN1 and CIT in androgen regulation of SRF target genes; 2) determine the preclinical role of the SRF-responsive subset of androgen-regulated genes in CaP cell motility and invasive behavior; and 3) determine the clinical relevance of RhoA-, PKN1-, and CIT-dependent androgen- responsive SRF action. Aim 1 uses a custom gene expression assay to determine the contribution of RhoA, PKN1 and CIT to androgen regulation of SRF target genes, and the manner in which PKN1 and CIT convey androgen control to SRF is established. Aim 2 uses preclinical models to identify SRF target genes, PKN1 and CIT as targets to impair CaP cell invasiveness. Aim 3 uses a combination of in silico analysis and tissue microarray analyses to determine the relevance of PKN1, CIT and SRF effector genes for CaP progression. The proposed research is innovative because it focuses on an entirely different approach to target androgen action in CaP: unraveling and targeting an androgen-dependent signaling pathway downstream of AR that controls the expression of genes that are relevant for CaP progression. This contribution is significant because is it the first step in a continuum of research that is expected to lead to the development of novel treatment modalities that target specifically androgen-mediated gene expression that underlies the lethal CaP phenotype. With respect to expected outcomes, the proposed studies will identify the molecular mechanisms by which the SRF-dependent mechanism of androgen action gives rise to the aggressive CaP phenotype. These results will have an important positive impact because they will fundamentally advance knowledge about androgen action in CaP, in general, and provide new targets for CaP-specific therapy, specifically.