Steroid Metabolism in Castration-Resistant Prostate Cancer

项目总结(见说明)： 观察到雄激素调节基因在CRPC中几乎普遍表达，这促使人们寻找在去势环境中参与雄激素受体(AR)激活的过程。虽然导致前列腺癌生长和AR信号转导的途径可能完全不依赖于配体，但到目前为止已发现的许多过程仍然需要或被配体的存在所增强。 我们假设，耐去势前列腺癌是通过代谢适应过程产生的，该过程涉及AR配体的生物合成，而不是具有有利基因组突变/染色体改变的罕见肿瘤细胞的选择性繁殖。确定关键的适应性成分对于制定以调节类固醇生成机制为重点的有效治疗策略具有重要意义。因此，我们还假设，雄激素代谢的靶向成分将抑制CRPC的发展或进展。这项建议将：i)评估去势代谢适应过程中产生的前列腺肿瘤细胞的表型(S)；ii)定义出现的AR配体生成途径，提供关于可用作治疗靶点的关键节点的新数据，并用于患者分层以进行适当的干预。我们提出了以下具体目标： 目的1.确定类固醇生物合成酶在肿瘤发生中的作用 雄激素与CRPC中随后的肿瘤细胞存活。这些研究将确定频率和 前列腺肿瘤从头合成雄激素的机制(S)决定了前列腺癌的生长限速 反应，并确定增强的雄激素代谢是否有助于肿瘤进展。 目的2.探讨雄激素系统减少后前列腺癌雄激素生物合成酶的协同调节和AR基因表达程序激活的机制(S)。 目的3.确定进行性抑制雄激素代谢的治疗效果，并确定代谢导向治疗的耐药机制。这些研究将确定逐渐严重的AR途径阻断在抑制肿瘤内雄激素产生方面的有效性，评估伴随而来的对CRPC的影响，并确定导致肿瘤进一步进展/耐药的机制。

PROJECT SUMMARY (See instructions): The observation that androgen-regulated genes are almost universally expressed in CRPC has prompted a search for processes that contribute to androgen receptor (AR) activation in the castrate environment. While pathways leading to prostate cancer growth and AR signaling may be entirely ligand-independent, many of the processes identified to date either still require or are enhanced by the presence of ligand. We hypothesize that castration-resistant prostate cancers arise through a process of metabolic adaptation involving the biosynthesis of AR ligands, rather than the selective propagation of rare tumor cells harboring advantageous genomic mutations/chromosomal alterations. Determining the key adaptive components has important implications for developing effective treatment strategies focused on modulating steroidogenic mechanisms. Thus, we also hypothesize that targeting components of androgen metabolism will inhibit the development or progression of CRPC. This proposal will i) evaluate the phenotype(s) of prostate tumor cells arising during metabolic adaptation to castration; and ii) define the AR ligand-generating pathways that emerge, providing novel data on critical nodes amenable to exploitation as therapeutic targets and for stratification of patients for appropriate interventions. We propose the following Specific Aims: AIM 1. Determine the contribution of steroid biosynthetic enzymes to the generation of intratumoral androgens and consequent tumor cell survival in CRPC. These studies will determine the frequency and mechanism(s) by which prostate tumors synthesize androgens de novo, determine the rate-limiting reactions, and determine if enhanced androgen metabolism contributes to tumor progression. AIM 2. Determine the mechanism(s) underlying the coordinate regulation of androgen biosynthetic enzymes and activation of the AR gene expression program in prostate cancers following the systemic reduction of androgens. AIM 3. Determine the therapeutic effectiveness of progressive inhibition of androgen metabolism and identify resistance mechanisms to metabolism-directed therapy in CRPC. These studies will determine the efficacy of progressively severe AR-pathway blockade on inhibiting intratumoral androgen production, evaluate the attendant effects on CRPC, and identify mechanisms leading to further tumor progression/resistance