Biomarkers of Hormone Therapy Response in a Multicenter Prostate Cancer Trial

多中心前列腺癌试验中激素治疗反应的生物标志物

• 批准号: 8754475
• 负责人: Amir Goldkorn
• 金额: $ 67.45万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8754475
• 关键词: Androgen Antagonists; Androgen Receptor; Androgens; Bicalutamide; Biological; Biological Markers; Biology; Blood specimen; CYP17A1 gene; Cancer Patient; Candidate Disease Gene; Castration; Cells; Clinical; Clinical Research; Clinical Trials; DNA; Data; Disease; Disseminated Malignant Neoplasm; Gene Expression Profile; Genes; Genetic; Genomics; Heterogeneity; High-Throughput Nucleotide Sequencing; Hormonal; Hormones; Individual; Leukocytes; Leuprolide; Luteinizing Hormone-releasing Hormone Agonist; Lyase; Malignant neoplasm of prostate; Measures; Medicine; Messenger RNA; Metastatic Prostate Cancer; Molecular Profiling; Neoplasm Circulating Cells; New Agents; Outcome; Participant; Pathway interactions; Patients; Phase; Phase III Clinical Trials; Phenotype; Positioning Attribute; Primary Neoplasm; Progression-Free Survivals; Prostatectomy; Randomized; Research Personnel; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Specimen; Technology; Testing; Time; Tissue Sample; Tissue-Specific Gene Expression; Transcript; Tumor Tissue; Variant; abiraterone; abstracting; arm; base; cancer cell; cohort; deprivation; early experience; experience; genetic profiling; genetic variant; hormone therapy; improved; inhibitor/antagonist; insight; mRNA Expression; man; men; neoplastic cell; novel; oncology; prospective; public health relevance; response; standard care; therapy resistant; tumor

DESCRIPTION (provided by applicant): Biomarkers of Hormone Therapy Response in a Multicenter Prostate Cancer Trial Abstract Androgen deprivation therapy (ADT) is the cornerstone of treatment for metastatic prostate cancer (mPC), and new hormonal agents have recently improved survival for some patients. However, the use of ADT remains empiric, and as novel hormonal agents continue to emerge there is a growing need for biomarkers to guide their optimal use. Preliminary data from our group and others suggest that variations in genomic and expression profiles within the androgen pathway are significantly associated with clinical response to hormonal agents. Here, we propose to expand upon our findings by undertaking a comprehensive analysis of tumor and host androgen pathway genes in men initiating ADT for mPC. We hypothesize that the initial response and subsequent resistance to ADT is governed by the genetic and expression profiles of the androgen pathway. We will test this hypothesis in a Phase III SWOG- sponsored trial of 1,500 men with mPC initiating ADT with leuprolide (LHRH agonist) and either bicalutamide (anti-androgen) or orteronel (novel CYP17,20 lyase inhibitor). Specifically, we will identify androgen pathway phenotypes associated with therapy response, defined as PSA at 7 months and progression-free survival. The androgen pathway will be analyzed in a CLIA- certified setting using patient samples obtained during the trial as follows: I Aim 1, we will analyze germline sequence variation in androgen pathway genes using white blood cells; in Aim 2, we will analyze somatic sequence variation as well as mRNA expression of androgen pathway genes in circulating tumor cells (CTCs) at study onset and upon castration resistance; in Aim 3, we will analyze somatic sequence variation and mRNA expression of androgen pathway genes in primary tumor specimens. In an exploratory subset of responders and non- responders, whole transcriptomes will be sequenced from CTCs and primary tumors to identify additional novel gene candidates associated with response to ADT. Collectively, these analyses will yield an unprecedented, comprehensive picture of how clinical response to hormonal therapy is associated with variations in androgen pathway biology in the host (Aim 1), in metastatic cancer cells (Aim 2), and in the primary tumor (Aim 3). As importantly, this SWOG- led study will offer a unique opportunity both to identify and to validate reliable biomarkers give its exceptionally large cohort size and treatment homogeneity. New predictors of response based on androgen pathway biology will advance the mechanism-driven, individualized use of hormonal therapy and ultimately will promote more effective precision management of patients with mPC.

描述（由申请人提供）：多中心前列腺癌试验中激素治疗反应的生物标志物摘要雄激素剥夺治疗（ADT）是转移性前列腺癌（MPC）治疗的基石，以及新的激素剂最近对某些患者改善了生存率。但是，ADT的使用仍然是经验性的，随着新型激素剂继续出现，生物标志物的需求越来越多，才能指导其最佳使用。来自我们小组和其他人的初步数据表明，雄激素途径内基因组和表达谱的变化与对激素剂的临床反应显着相关。在这里，我们建议通过对MPC启动ADT的男性中的肿瘤和宿主雄激素途径基因进行全面分析来扩展我们的发现。我们假设对ADT的初始反应和后续抗性受雄激素途径的遗传和表达谱的控制。我们将在1,500名使用Leuprolide（LHRH激动剂）和Bicalutamide（抗雄激素）或Orteronel（新型CYP17,20 lyase抑制剂）的1,500名男性（新的CYPC17,20裂解酶抑制剂）中，对1,500名MPC启动ADT的男性进行ADT的试验进行检验。具体而言，我们将鉴定与治疗反应相关的雄激素途径表型，该表型在7个月时定义为PSA和无进展的生存率。雄激素途径将在试验期间获得的患者样品在CLIA认证的设置中进行分析：我AIM 1，我们将使用白细胞分析雄激素途径基因中的生殖线序列变化；在AIM 2中，我们将分析研究发作和cast割耐药性时循环肿瘤细胞（CTC）中雄激素途径基因（CTC）中雄激素途径基因的mRNA表达；在AIM 3中，我们将分析原发性肿瘤标本中雄激素途径基因的体细胞序列变异和mRNA表达。在响应者和非响应者的探索性子集中，将从CTC和原发性肿瘤中测序整个转录组，以鉴定与ADT反应相关的其他新型基因候选者。总的来说，这些分析将产生前所未有的，全面的图景，说明对荷尔蒙治疗的临床反应如何与宿主中雄激素途径生物学的变化相关（AIM 1），转移性癌细胞（AIM 2）和原发性肿瘤中（AIM 3）（AIM 3）。重要的是，这项摇摆的研究将提供一个独特的机会来识别和验证可靠的生物标志物，使其具有极大的队列大小和治疗均匀性。基于雄激素途径生物学的反应的新预测指标将推动机制驱动的，个性化的荷尔蒙治疗，最终将促进对MPC患者的更有效的精确管理。