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色男性和亚裔男性。 虽然社会经济地位和其他环境和文化因素造成了这种差异， 新出现的证据表明，遗传因素也起着关键作用。该建议旨在增加相关的 正在进行的一项针对接受转移性乳腺癌治疗的不同种族男性队列的临床试验 PARP抑制剂talazoparib联合标准一线激素治疗与雄激素治疗的前列腺癌 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，他们在定义当前一线治疗的关键试验中代表性不足。目标 入组70例受试者，其中30%为非洲裔美国人，30%为亚裔美国人。这很重要 因为这些组在雄激素受体（AR）中具有高度不同的三重重复长度， 影响AR的功能，因此可能影响对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标本，作为已经资助的、正在进行的 进行相关研究的试验，以确定从治疗中获益最多的患者的生物标志物， 我们将：1）在不同的前列腺癌患者人群中确定基因组改变如何与 与治疗结果，以及它们如何在癌症进展时演变; 2）将基因组研究结果与 分析AR三重重复序列和Wnt/Myc信号传导，以了解这些在不同的 3）利用数字空间病理学来描述原发性免疫系统中的适应性免疫反应。 肿瘤，并测量与基因组特征、AR重复序列和对治疗的反应的任何关联。 这一独特的多样化前列腺癌患者群体将为研究 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认证的测定。此外，这项研究将使用数字空间技术生成非常新颖的数据， 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 最终综合分析基因组改变如何与AR进行比较或互补 变异，Wnt/Myc信号传导和肿瘤免疫浸润，并有助于确定肿瘤免疫的分子特征。 反应性人群-最终通过改善治疗方案获得更好的患者结局。