Molecular Determinants of Androgen Receptor Pharmacology

描述（由申请人提供）：在核受体（NR）作用的经典模型中，认为配体的作用仅仅是将无活性受体转换为可正向或负向调节基因转录的受体的开关。然而，辅因子、辅激活因子和辅抑制因子的发现，以及对激素和抗激素的生物反应受这些不同蛋白质的绝对和相对水平影响的观察，显著改变了我们对NR信号传导的理解。最近已经清楚，核受体（NR）从事不同的辅因子在其调节活动的过程中，差异辅因子招聘的生物学后果是不相等的。因此，出现的挑战是（a）确定每种受体在其在细胞内参与的每种不同活动中使用的辅因子，以及（B）评估这些辅因子在诸如癌症的病理学中如何用于肿瘤的益处。正是在这一重要问题的背景下，我们在上一个资助期启动了一个项目，旨在确定与AR相互作用的辅因子，并确定这些因子如何使受体在不同细胞中表现出不同的活动。更具体地说，我们感兴趣的是鉴定AR在参与前列腺癌细胞生长、存活和转移所需过程时所利用的蛋白质。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种辅因子。一种化学生物学方法被用来证明，这些辅因子可以被分成不同的类的基础上，它们相互作用的受体上的表面。我们在这一领域持续努力的主要目标是确定这些不同的辅因子对前列腺癌细胞模型中雄激素调节过程的具体作用，这些细胞模型跟踪疾病进展。为实现这些目标，我们提出以下具体目标：（1）在前列腺癌细胞模型中由雄激素调节的生物学途径的定义，所述前列腺癌细胞模型在前列腺肿瘤中表现并随进展而跟踪，（2）在与前列腺癌发病机制相关的过程中由AR利用的辅因子的鉴定，和（3）特定AR辅因子在生长中的作用的定义，前列腺癌异种移植物的存活和转移。我们预计，这些研究的结果将是信息方面的雄激素信号在前列腺癌细胞，并可能揭示的分子事件，使细胞从一个依赖于雄激素的过渡到一个不依赖雄激素的状态。此外，所获得的信息还可以帮助鉴定靶点，利用所述靶点可以开发用于治疗前列腺癌的新疗法。公共卫生相关性：早期检测和治疗方案的进步已经改善了前列腺癌患者的总体结局。然而，晚期转移性疾病患者的药物治疗仍然有限。在这个项目中，我们概述了一个基础研究计划，旨在确定新的目标，在前列腺癌，将服从治疗干预。

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.