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; 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.

项目摘要： 我们已经确定了一系列因素，这些因素会影响生产，吸收和转换的变异性 能够激活前列腺癌中雄激素受体并驱动肿瘤进展的雄激素。 但是，矛盾的是，这些相同的因素可能会预测针对这些针对这些疗法的反应 机制。我们假设HSD3B1，SLCO2B1和SRD5A2中的遗传变异 雄激素产生，摄取和转化率（APUC）在前列腺癌中，赋予对累积影响对 确定对AR定向剂反应的高和低可能性的人群的结果，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方法。 在成功开发了Enzalutamide和Abiraterone（由本提案的PI领导）之后 化学疗法幼稚的CRPC，我们团队的成员设计并完成了A031201随机阶段III NCI恩扎拉胺（E）与恩扎拉丁胺+阿比罗酮醋酸酯（E/AA）的NCI合作组试验。这个试验是 现在完成并最近介绍了数据。来自几乎所有患者的临床和遗传数据 根据HSD3B1，SLCO2B1和SRD5A基因型评估结果的机会 疾病生物学（诸如野生型与改变TP53的因素）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。在第一个目的中，我们定义了 与雄激素产生，摄取和转化（APUC）有关的遗传变体。接下来，我们试图建造 一个可识别“ APUC敏感”和“ APUC抗性”曲线的多变量模型，整合了疾病生物学 会议主要和获得的治疗耐药性的因素，可能 最后，我们将测试Abiraterone代谢物3-酮的药效学还原 5abiraterone，具有激动剂能力，具有1245c变异的患者的药物dutasteride HSD3B1基因。 HSD3B1的这种变体导致功能的增长，我们假设 这种激动剂的积累驱动了对阿比罗酮的抵抗力。 dutasteride抑制5减少，因此 可作为AR激动剂起作用的5abiraterone代谢产物的产生。基于RPFS数据我们 可以通过合作组机制提出III期临床试验。我们将筛选 大约有300名阿比罗酮患者将100名患者随机添加到Dutasteride或观察。这 研究具有足够的能力，可以证明有意义的放射线前进无生存（RPF）益处。 我们将将我们的APUC模型整合到对这项II阶段研究结果的理解中。