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

雄激素产生、摄取和代谢的相互作用对去势抵抗性前列腺癌预后的影响

• 批准号: 10460400
• 负责人: SUSAN HALABI
• 金额: $ 64.06万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460400
• 关键词: Acetates; Adrenal Glands; Adrenergic Antagonists; Affect; Agonist; Alleles; Androgen Metabolism; Androgen Receptor; Androgens; Androstenedione; Anions; Automobile Driving; Biological Factors; Biological Markers; Biology; Cessation of life; Clinical; Clinical Trials; Data; Development; Disease; Disease Progression; Dutasteride; Enzyme Inhibition; Enzymes; Evaluation; Failure; Fostering; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Hydroxysteroid Dehydrogenases; Individual; Ketoconazole; Malignant neoplasm of prostate; Mediating; Medical Genetics; Metabolism; Modeling; Neoadjuvant Therapy; Nomograms; Outcome; Oxidoreductase; Patient Outcomes Assessments; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase III Clinical Trials; Play; Population; Prevalence; Process; Production; Progression-Free Survivals; Race; Randomized; Residual Neoplasm; Resistance; Resistance profile; Risk; Role; SRD5A2 gene; Science; Selection Criteria; Selection for Treatments; Series; Serology; Serum; Symptoms; TP53 gene; Testing; Testosterone; Testosterone 5-alpha-Reductase; Variant; Work; abiraterone; acquired treatment resistance; arm; base; biomarker-driven; castration resistant prostate cancer; chemotherapy; dehydroepiandrosterone; design; efficacy testing; enzalutamide; experience; gain of function; genetic variant; genomic biomarker; high risk; inhibitor; inhibitor therapy; member; men; novel; patient population; phase 2 study; phase III trial; predicting response; prognostic model; prognostic of survival; prospective; radiological imaging; response; solute; study population; success; targeted treatment; therapy resistant; treatment strategy; tumor; tumor progression; uptake

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.

项目概要： 我们已经确定了一系列影响生产、吸收和转化变化的因素 雄激素能够激活雄激素受体并驱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因素的特定疗法的反应。 机制。我们假设 HSD3B1、SLCO2B1 和 SRD5A2 的遗传变异（每个关键驱动因素） 前列腺癌中雄激素产生、摄取和转化 (APUC) 的累积效应 人群的结果决定了对 AR 定向药物反应的高可能性和低可能性，并且可以 在治疗耐药的情况下形成有效的基于生物标志物的治疗选择方法。 继恩杂鲁胺和阿比特龙（由本提案的 PI 领导）成功开发后 未经化疗的 CRPC，我们团队的成员设计并完成了 A031201 随机 III 期临床试验 NCI 合作组试验恩杂鲁胺 (E) 与恩杂鲁胺+醋酸阿比特龙 (E/AA)。这次审判是 现已完成，数据最近已提交。几乎所有患者的临床和遗传数据都提供了 有机会根据 HSD3B1、SLCO2B1 和 SRD5A 基因型及其关系来评估结果 疾病生物学（例如野生型与改变的 TP53 等因素）和临床结果以指导未来 生物标志物驱动的治疗科学。 在此提案中，我们对患者遗传因素进行分析，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，我们定义了影响的普遍性和程度 与雄激素产生、摄取和转化（APUC）相关的遗传变异。接下来，我们寻求构建 一个多变量模型，用于识别“APUC敏感”和“APUC耐药”特征，整合疾病生物学 已知导致对阿比特龙原发性和获得性治疗耐药的因素，以及潜在的 恩杂鲁胺。最后，我们将测试阿比特龙代谢物 3-酮的药效学降低 5阿比特龙，具有激动剂能力，与药物度他雄胺一起治疗具有 1245c 变异的患者 HSD3B1 基因。 HSD3B1 的这种变体导致功能获得，我们假设 这种激动剂的积累会导致对阿比特龙的耐药性。度他雄胺抑制 5 还原酶，因此 产生具有 AR 激动剂作用的 5α 阿比特龙代谢物。根据 rPFS 数据，我们 可以通过合作组机制提出III期临床试验。我们会筛选 大约 300 名服用阿比特龙的个体随机分配 100 名患者接受度他雄胺治疗或观察。这 研究有足够的能力证明放射学无进展生存期 (rPFS) 具有有意义的益处。 我们将把我们的 APUC 模型融入到对这一 II 期研究结果的理解中。