Steroid Metabolism in Castration-Resistant Prostate Cancer

项目总结（见说明）： 雄激素调节基因在CRPC中几乎普遍表达的观察结果促使人们寻找在去势环境中促进雄激素受体（AR）激活的过程。虽然导致前列腺癌生长和AR信号传导的途径可能完全不依赖于配体，但迄今为止确定的许多过程仍然需要配体或通过配体的存在而增强。 我们假设去势抵抗性前列腺癌是通过涉及AR配体生物合成的代谢适应过程而产生的，而不是携带有利基因组突变/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制定有效的治疗策略，重点是调节类固醇生成机制具有重要意义。因此，我们还假设靶向雄激素代谢组分将抑制CRPC的发生或进展。该提案将i）评估在代谢适应去势期间出现的前列腺肿瘤细胞的表型;和ii）定义出现的AR配体生成途径，提供关于适合作为治疗靶点开发的关键节点的新数据，并对患者进行分层以进行适当干预。我们提出以下具体目标： AIM 1.确定类固醇生物合成酶对肿瘤内肿瘤生成的贡献。 CRPC中的雄激素和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，决定了 反应，并确定雄激素代谢增强是否有助于肿瘤进展。 AIM 2.确定雄激素生物合成酶的协调调节和雄激素全身减少后前列腺癌中AR基因表达程序的激活的潜在机制。 AIM 3.确定CRPC中雄激素代谢进行性抑制的治疗效果，并确定代谢导向治疗的耐药机制。这些研究将确定进行性重度AR通路阻断对抑制瘤内雄激素产生的疗效，评价对CRPC的伴随作用，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