Interactions of Androgen Production, Uptake and Metabolism on outcome in Castration Resistant Prostate Cancer

项目总结： 我们已经确定了一系列影响生产、吸收和转化的可变性的因素 雄激素能够激活雄激素受体并推动前列腺癌的肿瘤进展。 然而，矛盾的是，这些相同的因素可能会预测针对这些疾病的特定疗法的反应。 机械装置。我们假设HSD3B1、SLCO2B1和SRD5A2的遗传变异都是关键的驱动因素 前列腺癌中雄激素的产生、吸收和转化(APUC)的累积效应 决定对AR导向药物反应的高可能性和低可能性的人群的结果，并且可以 在治疗耐药的背景下形成有效的基于生物标记物的治疗选择方法。 在#年成功开发了苯扎鲁胺和阿比特龙(由本提案的PI领导)之后 化疗天真的CRPC，我们团队的成员设计并完成了A031201 a随机第三阶段 NCI协作组试验：恩扎鲁胺(E)与恩扎鲁胺+醋酸阿比拉通(E/AA)。这场审判是 现已完成，数据已于最近公布。几乎所有患者的临床和基因数据都能提供 根据HSD3B1、SLCO2B1和SRD5A基因评估预后的机会及其关系 根据疾病生物学(野生型与突变的TP53等因素)和临床结果来指导未来 生物标记物驱动的治疗科学。 在这个建议中，我们对患者的遗传因素进行分析，并将其与临床结果和雄激素相匹配。 基于APUC模型的代谢物。在第一个目标中，我们定义了影响的流行和程度 与雄激素产生、摄取和转化相关的遗传变异(APUC)。接下来，我们寻求构建 结合疾病生物学特征识别“APUC敏感”和“APUC抗性”的多变量模型 已知的使阿比特龙和潜在的获得性治疗耐药的因素 苯扎鲁胺。最后，我们将测试阿比特龙代谢物3-酮的药效还原作用。 5阿比特龙，具有激动剂能力，与杜他斯特胺联合应用于携带1245c变异的患者 HSD3B1基因。HSD3B1的这种变体导致了功能的增加，我们假设 这种激动剂的积累导致了对阿比特龙的耐药性。度他雄胺抑制5-还原酶，因此 作为AR激动剂的5阿比特龙代谢物的产生。基于我们的rPFS数据 可通过合作小组机制提出III期临床试验。我们会放映 大约300人服用阿比特龙，将100名患者随机服用度他雄胺或观察组。这个 这项研究有足够的力量证明有意义的放射学无进展生存(RPFS)益处。 我们将把我们的APUC模型整合到对这项第二阶段研究结果的理解中。

Project Summary: We have identified a collective series of factors that affect variability in the production, uptake and conversion of androgens capable of activating the androgen receptor and driving tumor progression in prostate cancer. Paradoxically, however, these same factors may predict response to specific therapies that target these mechanisms. We hypothesize that genetic variation in HSD3B1, SLCO2B1, and SRD5A2, each critical drivers of androgen production, uptake and conversion (APUC) in prostate cancer, confer cumulative effects on outcome in populations determining both high and low likelihoods of response to AR directed agents, and can form effective biomarker-based therapy selection approaches in the context of treatment resistance. Following successful development of both enzalutamide and abiraterone (led by the PI of this proposal) in chemotherapy naïve CRPC, members of our team designed and completed A031201 a randomized phase III NCI Cooperative Group trial of Enzalutamide (E) vs Enzalutamide+Abiraterone Acetate (E/AA). This trial is now complete and the data were recently presented. Clinical and genetic data from nearly all patients affords the opportunity to evaluate outcomes based on HSD3B1, SLCO2B1 and SRD5A genotype, their relationship to disease biology (factors such as wild type versus altered TP53) and clinical outcomes to guide future biomarker-driven treatment science. In this proposal we perform analyses of patient genetic factors and match it to clinical outcome and androgen metabolites based on the APUC model. In the first aim we define the prevalence and magnitude of effect of variants in genetic related to androgen production, uptake and conversion (APUC). Next, we seek to construct a multivariable model to identify “APUC sensitive” and “APUC resistant” profiles integrating disease biological factors known to confer primary and acquired treatment resistance to abiraterone and potentially enzalutamide. Finally, we will test the pharmacodynamic reduction of an abiraterone metabolite, 3-keto 5abiraterone, with agonist capabilities, with the drug Dutasteride in patients who harbor the 1245c variation in the HSD3B1 gene. This variant of HSD3B1 leads to a gain of function and we hypothesize that the accumulation of this agonist drives resistance to abiraterone. Dutasteride inhibits 5 reductase, and therefore the production of the 5 abiraterone metabolite that functions as an AR agonist. Based on the rPFS data we may propose a phase III clinical trial through the cooperative group mechanisms. We will screen approximately 300 individuals on abiraterone to randomize 100 patients to dutasteride or observation. The study has adequate power to demonstrate a meaningful radiographic progression free survival (rPFS) benefit. We will integrate our APUC model into an understanding of the outcomes of this phase II study.