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: 10589064
• 负责人: Tanya Dorff
• 金额: $ 20.16万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589064
• 关键词: African American; American; Androgen Receptor; Asian; Asian Americans; Assessment tool; Behavior; Biological; Biological Assay; CLIA certified; Cancer Etiology; Cancer Patient; Castrate sensitive prostate cancer; Castration; Cessation of life; Characteristics; Clinical Trials; Clinical Trials Design; Communities; Correlative Study; DNA Repair; DNA Sequence Alteration; Data; Defect; Disease; Disease remission; Disparity; Early treatment; Ethnic Population; Evaluation; Funding; Future; Genetic; Genomics; Genotype; Heterogeneity; Immune; Immune response; Immunologics; Immunophenotyping; 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; Poly(ADP-ribose) Polymerase Inhibitor; 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; biomarker identification; biomarker panel; castration resistant prostate cancer; cohort; digital; ethnic diversity; hormone therapy; immune cell infiltrate; improved; inhibitor therapy; insight; men; minority patient; minority subjects; mortality; novel; participant enrollment; 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.

项目概要 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。 尽管社会经济地位以及其他环境和文化因素造成了这种差异， 新出现的证据表明遗传因素也发挥着关键作用。该提案旨在增加相关 对正在接受转移性治疗的不同种族男性队列进行的一项临床试验的研究 使用 PARP 抑制剂他佐帕尼加标准一线雄激素激素疗法治疗前列腺癌 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族裔的招募 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 应计对象为 70 名，其中 30% 为非裔美国人，30% 为亚裔美国人。这很重要 因为这些基团在雄激素受体 (AR) 中具有高度不同的三重重复序列长度， 影响 AR 的功能，从而影响 AR 靶向治疗的反应深度或持续时间 该提案的目的是利用收集的生物样本，作为该项目的一部分，该项目已经获得资助，正在进行中 进行相关研究的试验，以确定从治疗中受益最多的患者的生物标志物， 我们将：1）确定不同前列腺癌患者群体中基因组改变之间的关系 治疗结果，以及它们如何随着癌症进展而演变； 2）将基因组研究结果与 对 AR 三重重复序列和 Wnt/Myc 信号传导进行分析，以了解它们如何在不同的重复序列之间分布 族裔群体； 3）利用数字空间病理学来描述原发性中的适应性免疫反应 肿瘤并测量与基因组特征、AR 重复和治疗反应的任何关联。 这种独特的多样化前列腺癌患者群体将为研究差异提供重要资源。 肿瘤生物学和宿主反应。组织基因组学以及 ctDNA 分析将使用 商业 CLIA 认证的检测。此外，这项研究将利用数字空间生成极其新颖的数据 病理学来描述免疫浸润以及浸润如何与肿瘤反应相互作用。这些数据将 最终对基因组改变如何与 AR 进行比较或互补进行综合分析 变异、Wnt/Myc 信号传导和肿瘤免疫浸润，并有助于定义 反应人群——最终通过改进治疗方案带来更好的患者结果。