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

基本信息

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
项目类别：
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

项目摘要

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疗法（ADT）是转移性前列腺癌（mPC）治疗的基石，新的激素药物最近改善了一些患者的生存率。然而，ADT 的使用仍然是经验性的，并且随着新型激素药物的不断出现，越来越需要生物标志物来指导其最佳使用。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激素药物的临床反应显着相关。在这里，我们建议通过对针对 mPC 开始 ADT 的男性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 的初始反应和随后的抵抗是由雄激素途径的遗传和表达谱控制的。我们将在 SWOG 赞助的 III 期试验中检验这一假设，该试验对 1,500 名患有 mPC 的男性进行，使用亮丙瑞林（LHRH 激动剂）和比卡鲁胺（抗雄激素）或奥特罗奈（新型 CYP17,20 裂解酶抑制剂）启动 ADT。具体来说，我们将确定与治疗反应相关的雄激素途径表型，定义为 7 个月时的 PSA 和无进展生存期。雄激素途径将在 CLIA 认证的环境中使用试验期间获得的患者样本进行分析，如下所示： I 目标 1，我们将使用白细胞分析雄激素途径基因的种系序列变异；在目标 2 中，我们将分析研究开始时和去势抵抗时循环肿瘤细胞 (CTC) 中的体细胞序列变异以及雄激素途径基因的 mRNA 表达；在目标 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。在应答者和非应答者的探索性子集中，将对 CTC 和原发性肿瘤的整个转录组进行测序，以鉴定与 ADT 应答相关的其他新候选基因。总的来说，这些分析将产生前所未有的、全面的图景，说明激素治疗的临床反应如何与宿主（目标 1）、转移性癌细胞（目标 2）和原发肿瘤（目标 1）中雄激素途径生物学变化相关。 3）。同样重要的是，鉴于其异常大的队列规模和治疗同质性，这项由 SWOG 主导的研究将为识别和验证可靠的生物标志物提供独特的机会。基于雄激素通路生物学的新反应预测因子将推进激素治疗的机制驱动、个体化使用，并最终促进对 mPC 患者更有效的精准管理。