Integrated Genotypic, Phenotypic and Immunologic Analysis of Ethnically Diverse Prostate Cancers

不同种族前列腺癌的综合基因型、表型和免疫学分析

• 批准号: 10436113
• 负责人: Tanya Dorff
• 金额: $ 24.68万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-10 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436113
• 关键词: African American; Androgen Receptor; Asian; Asian Americans; Assessment tool; Behavior; Biological; Biological Assay; CLIA certified; Cancer Etiology; Cancer Patient; Castration; Cessation of life; Characteristics; Clinical Trials; Clinical Trials Design; Communities; Correlative Study; DNA Repair; DNA Sequence Alteration; Data; Defect; Disease; Disease remission; Early treatment; Enrollment; Ethnic group; Evaluation; Funding; Future; Genetic; Genomics; Genotype; Heterogeneity; Immune; Immune response; Immunologics; Impairment; Incidence; Infiltration; Investigational Therapies; Length; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Metastatic Prostate Cancer; Minority Groups; Minority Recruitment; Molecular; Not Hispanic or Latino; PARP inhibition; Pathology; Patient-Focused Outcomes; Patients; Phase II Clinical Trials; Phenotype; Play; Population; Population Heterogeneity; Primary Neoplasm; Prostate Cancer therapy; Resistance; Resources; Role; Signal Pathway; Signal Transduction; Socioeconomic Status; Subgroup; Testing; Time; Tissues; Treatment outcome; Tumor Biology; Tumor-infiltrating immune cells; United States; Variant; abiraterone; adaptive immune response; androgen deprivation therapy; base; biomarker panel; castration resistant prostate cancer; cohort; digital; ethnic diversity; hormone therapy; improved; inhibitor; inhibitor therapy; insight; men; minority patient; minority subjects; mortality; novel; patient biomarkers; patient population; personalized medicine; pre-clinical; precision medicine; prospective; prostate cancer progression; response; response biomarker; targeted treatment; tool; treatment response; tumor; tumor progression

Project Summary Abstract Prostate cancer is the leading cause of cancer-related death among men in the United States, and its incidence and mortality rate is markedly higher in African-American men than in non-Hispanic White men and Asian men. Although socio-economic status and other environmental and cultural factors contribute to this disparity, emerging evidence indicates that genetic factors also play critical roles. This proposal seeks to add correlative studies to an ongoing clinical trial of an ethnically diverse cohort of men undergoing treatment for metastatic prostate cancer with the PARP inhibitor talazoparib plus standard first-line hormone therapy with androgen deprivation therapy plus abiraterone. A key aspect of the clinical trial design is to enrich recruitment of minority subjects, who have been under-represented in the critical trials that defined current first-line therapy. The target accrual is 70 subjects, with 30% intended to be African-American and 30% Asian-American. This is important because these groups have highly divergent lengths of triplicate repeats in the androgen receptor (AR), which impacts the function of AR and could thus impact depth or duration of response to AR targeted therapy The objective of this proposal is to leverage biospecimens collected as part of this already funded, ongoing trial to conduct correlative studies that will identify biomarkers of patients who benefit most from the treatment, We will: 1) determine in a diverse population of prostate cancer patients how genomic alterations are associated with treatment outcomes, and how they evolve upon cancer progression; 2) integrate the genomic findings with profiling of AR triplicate repeats and Wnt/Myc signaling to understand how these are distributed among different ethnic groups; and 3) utilize digital spatial pathology to describe the adaptive immune response in the primary tumor and measure any associations with genomic features, AR repeats, and response to treatment. This uniquely diverse population of prostate cancer patients will create a critical resource to study differences in tumor biology and host response. Tissue genomics as well as ctDNA analysis will be performed using commercial CLIA-certified assays. Furthermore, this study will generate extremely novel data using digital spatial pathology to describe immune infiltration and how infiltration interacts with tumor response. These data will culminate in an integrated analysis of how genomic alterations compare or are complementary with AR variations, Wnt/Myc signaling, and tumor immune infiltration and help to define molecular characteristics of responsive populations—ultimately leading to better patient outcome through improved treatment options.

项目摘要摘要 前列腺癌是美国男性癌症相关死亡的主要原因，其发病率 非洲裔美国男性的死亡率明显高于非西班牙裔白人男性和亚洲男性。 尽管社会经济地位和其他环境和文化因素造成了这种差距， 新出现的证据表明，遗传因素也起着关键作用。这项建议旨在增加相关的 正在进行的一项针对接受转移治疗的不同种族男性队列的临床试验的研究 前列腺癌PARP抑制剂他唑帕利布联合雄激素标准一线治疗 剥夺疗法加阿比特龙。临床试验设计的一个关键方面是丰富少数民族的招募 受试者，在定义当前一线治疗的关键试验中代表性不足。目标是 应计受试者有70人，其中30%是非洲裔美国人，30%是亚裔美国人。这事很重要 因为这些群体在雄激素受体(AR)中具有高度不同的三倍体重复长度，这 影响AR的功能，从而可能影响AR靶向治疗的深度或持续时间 这项提议的目标是利用收集的生物制品，作为已经资助的、正在进行的 进行相关研究，以确定从治疗中受益最大的患者的生物标志物， 我们将：1)在前列腺癌患者的不同人群中确定基因组改变是如何关联的 与治疗结果，以及它们如何在癌症进展中演变；2)将基因组发现与 分析AR三倍体重复序列和Wnt/Myc信号以了解这些信号如何在不同的 3)利用数字空间病理学描述小学生的获得性免疫反应 并测量与基因组特征、AR重复和治疗反应之间的任何关联。 这一独特的多样化前列腺癌患者群体将创造一个关键的资源，用于研究 肿瘤生物学和宿主反应。组织基因组学和ctDNA分析将使用 商业CLIA认证的化验。此外，这项研究将使用数字空间生成非常新颖的数据 病理学描述免疫侵袭以及侵袭如何与肿瘤反应相互作用。这些数据将 在对基因组变化如何与AR进行比较或互补的综合分析中达到高潮 变异、Wnt/Myc信号转导和肿瘤免疫渗透有助于确定肿瘤的分子特征 反应灵敏的人群--通过改进治疗方案，最终带来更好的患者结果。