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共同的因素，这些因素影响着生物质的生产、吸收和转化的可变性。 雄激素能够激活雄激素受体并驱动前列腺癌中的肿瘤进展。 然而，奇怪的是，这些相同的因素可能预测对针对这些疾病的特定疗法的反应。 机制等我们假设，HSD 3B 1、SLCO 2B 1和SRD 5A 2的遗传变异，每一个关键的驱动因素， 前列腺癌中雄激素的产生、摄取和转化（APUC）， 在人群中的结果决定了对AR导向剂的应答的高可能性和低可能性，并且可以 在治疗耐药性的背景下形成有效的基于生物标志物的治疗选择方法。 在成功开发Enzalutamide和阿比特龙（由本提案的PI领导）后， 化疗初治CRPC，我们的团队成员设计并完成了A031201， Enzalutamide（E）与Enzalutamide+醋酸阿比特龙（E/AA）的NCI合作组试验。这次审判是 目前已完成，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 评估基于HSD 3B 1、SLCO 2B 1和SRD 5A基因型的结局的机会， 疾病生物学（野生型与改变的TP 53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进行匹配。 基于APUC模型的代谢物。在第一个目标中，我们定义了 与雄激素产生、摄取和转换相关的遗传变异（APUC）。接下来，我们试图构建 一个多变量模型，以确定“APUC敏感”和“APUC耐药”概况整合疾病生物学 已知赋予阿比特龙原发性和获得性治疗耐药性的因素， 恩杂鲁胺。最后，我们将测试阿比特龙代谢产物3-酮的药效学降低， 5阿那比特龙，具有激动剂的能力，与药物度他雄胺在患者谁拥有1245 c变异， HSD 3B 1基因HSD 3B 1的这种变体导致功能的增加，我们假设， 这种激动剂的积累驱动对阿比特龙的抗性。度他雄胺抑制5-羟色胺还原酶，因此 作为AR激动剂的5-阿比特龙代谢物的产生。基于rPFS数据，我们 可通过合作组机制提出III期临床试验。我们将筛选 大约300名个体接受阿比特龙，100名患者随机接受度他雄胺或观察。的 研究有足够的把握度证明有意义的放射学无进展生存期（rPFS）获益。 我们将把我们的APUC模型整合到对第二阶段研究结果的理解中。