Molecular Determinants of Androgen Receptor Pharmacology

描述(申请人提供)：在核受体(NR)作用的经典模型中，认为配体的作用仅仅是将不活跃的受体转换为能够积极或消极地调节基因转录的开关。然而，辅助因子、辅助激活因子和辅助抑制因子的发现，以及观察到对激素和抗激素的生物反应受到这些不同蛋白质的绝对和相对水平的影响，极大地改变了我们对NR信号的理解。最近发现，核受体在其调节活动过程中使用不同的辅因子，并且不同辅因子招募的生物学后果并不相等。因此，出现的挑战是(A)确定每个受体在细胞内参与的每种不同活动中使用的辅因子，以及(B)评估在癌症等病理学中这些辅因子是如何用于肿瘤的。正是在这一重要问题的背景下，我们在之前的资助期间启动了一个项目，旨在确定与AR相互作用的辅助因素，并确定这些因素如何使受体在不同的细胞中表现出不同的活动。更具体地说，我们感兴趣的是，当AR参与前列腺癌细胞生长、存活和转移所需的过程时，它所利用的蛋白质。我们最近完成了对雄激素反应组织中表达的AR相互作用蛋白的全面筛选，产生了近300个辅因子。化学生物学方法被用来证明这些辅助因子可以根据它们与之相互作用的受体上的表面被分成不同的类别。我们在这一领域继续努力的主要目标是确定这些不同的辅助因素在前列腺癌细胞模型中阐述的雄激素调节过程中的特定作用，该模型跟踪疾病的进展。为了实现这些目标，我们提出了以下具体目标：(1)明确前列腺癌细胞模型中雄激素调节的生物通路，这些通路明显存在于前列腺癌并跟踪进展；(2)确定AR在前列腺癌发病过程中所利用的辅因子；(3)明确特定的AR辅因子在前列腺癌异种移植瘤生长、存活和转移中的作用。我们预计，这些研究的结果将对前列腺癌细胞中的雄激素信号转导提供信息，并可能阐明使细胞从激素依赖状态转变为激素非依赖状态的分子事件。此外，获得的信息还可能有助于识别靶点，利用这些靶点可以开发治疗前列腺癌的新疗法。公共卫生相关性：早期发现和治疗方案的进步导致前列腺癌患者总体预后的改善。然而，对晚期转移性疾病患者的医疗治疗仍然有限。在这个项目中，我们概述了一个基础研究计划，旨在确定前列腺癌的新靶点，这些靶点将服从于治疗干预。

DESCRIPTION (provided by applicant): In the classic models of nuclear receptor (NR) action, it was held that the role of ligand was merely that of a switch converting an inactive receptor to one that could positively or negatively regulate gene transcription. However, the discovery of cofactors, coactivators and corepressors, and the observation that the biological responses to hormones and anti-hormones is influenced by the absolute and relative levels of these different proteins, has significantly changed our understanding of NR signaling. It has recently become clear that nuclear receptors (NRs) engage different cofactors in the course of their regulatory activities and that the biological consequences of differential cofactor recruitment are not equivalent. The challenge that has arisen therefore is to (a) define the cofactors used by each receptor in each of the different activities in which it is engaged within the cell and (b) evaluate how in pathologies such as cancer these cofactors are used for the benefit of the tumor. It was within the background of this important issue that we initiated a project, during the previous funding period, aimed at identifying the cofactors that interact with AR and defining how these factors enable the receptor to manifest different activities in different cells. More specifically, we were interested in identifying the proteins utilized by AR when it is engaged in processes required for the growth, survival and metastasis of prostate cancer cells. We have recently completed a comprehensive screen for AR interacting proteins expressed in androgen- responsive tissues that yielded close to 300 cofactors. A chemical biology approach was used to demonstrate that these cofactors can be separated into different classes based on the surfaces on the receptor with which they interact. The primary goal of our continued efforts in this area is to define the specific roles of these different cofactors on androgen-regulated processes elaborated in cellular models of prostate cancer that track with disease progression. To accomplish these goals we propose the following specific aims: (1) Definition of the biological pathways regulated by androgens in cellular models of prostate cancer that are manifest in prostate tumors and track with progression, (2) Identification of the cofactors utilized by AR in processes linked to prostate cancer pathogenesis, and (3) Definition of the roles of specific AR cofactors in the growth, survival and metastasis of prostate cancer xenografts. We anticipate that the results of these studies will be informative with respect to androgen signaling in prostate cancer cells and may shed light on the molecular events that allow cells to transition from a hormone-dependent to a hormone-independent state. Additionally, the information obtained may also assist in the identification of targets with which novel therapeutics can be developed for the treatment of prostate cancer. PUBLIC HEALTH RELEVANCE: Early detection and advancements in therapeutic options have resulted in an improvement in the overall outcome of patients with prostate cancer. However, the medical treatments for patients with advanced metastatic disease remain limited. In this project, we outline a basic research program aimed at identifying new targets in prostate cancer that will be amenable to therapeutic intervention.