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与癌症有关的主要原因，其事件 非裔美国人的死亡率明显高于非西班牙裔白人和亚洲男人。 尽管社会经济地位以及其他环境和文化因素导致了这种差异，但 新兴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性 对正在进行的临床试验进行的研究，该试验是接受转移治疗的男性的种族多样性的研究 PARP抑制剂talazoparib加上标准的一线马龙治疗雄激素的前列腺癌 剥夺疗法加上阿比罗酮。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的代表性不足。目标 应计为70名受试者，有30％的受试者为非裔美国人和30％的亚裔美国人。这很重要 因为这些基团在雄激素受体（AR）中具有高度分歧的一式三份重复序列，因此 影响AR的功能，因此可能影响对AR靶向治疗的响应的深度或持续时间 该提案的目的是利用收集的生物测量，作为已经持续的，正在进行的一部分 进行相关研究的试验，这些研究将确定从治疗中受益最多的患者的生物标志物， 我们将：1）确定在前列腺癌患者的潜水人群中，基因组改变如何相关 随着治疗结果以及它们如何在癌症进展中进化； 2）将基因组发现与 AR一式三份重复序列和Wnt/MYC信号的分析，以了解它们是如何分布在不同的 种族群体； 3）利用数字空间病理来描述初级的适应性免疫反应 肿瘤并测量与基因组特征，AR重复和对治疗反应的任何关联。 这种独特多样化的前列腺癌患者将创造一个关键的资源来研究 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认证的测定法。此外，这项研究将使用数字空间生成极其新颖的数据 描述免疫浸润以及浸润如何与肿瘤反应相互作用的病理。这些数据将 在基因组改变如何与AR进行比较或完成的综合分析中达到最终形式 变化，WNT/MYC信号传导和肿瘤免疫浸润，有助于定义分子特征 反应迅速的人群 - 通过改进的治疗选择，从而导致更好的患者结局。