A multiomic analysis of HER2/ERBB2 in African American men with prostate cancer

非洲裔美国前列腺癌​​男性 HER2/ERBB2 的多组学分析

• 批准号: 10800504
• 负责人: Leanne Burnham
• 金额: $ 31万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-07 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10800504
• 关键词: African American; African ancestry; Alabama; Androgen Suppression; Androgens; Area; Biological Assay; Blood specimen; California; Cancer Patient; Cell Death; Cell Line; Cell Separation; Cell physiology; Cells; Center for Translational Science Activities; Cities; Clinical; Clinical Trials; Collaborations; Comprehensive Cancer Center; DNA Methylation; Diagnosis; Disease; Distant Metastasis; ERBB2 gene; Epidermal Growth Factor Receptor; Epigenetic Process; European; Evaluation; Event; Flow Cytometry; Foundations; Future; Genes; Genetic; Genetic Variation; Genomics; Gleason Grade for Prostate Cancer; Goals; Health; Hormones; Human; Immunohistochemistry; Immunooncology; Institutional Review Boards; Investigation; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Molecular; Morehouse School of Medicine; Neoplasm Circulating Cells; Neoplasm Metastasis; Outcome; PSA level; Patients; Prognosis; Prospective Studies; Prostate; Proteins; Proteomics; RNA analysis; Race; Relapse; Research Proposals; Role; SNP genotyping; Sampling; Serum; Signal Pathway; Signal Transduction; Three-dimensional analysis; Tissue Sample; Tissues; Transfection; Treatment outcome; Tumor Biology; Tumor Tissue; United States; Universities; Validation; Variant; Western Blotting; advanced prostate cancer; androgen deprivation therapy; cancer therapy; chemotherapy; chromatin immunoprecipitation; determinants of treatment resistance; differential expression; genome wide methylation; genome-wide; health disparity; high risk; histone modification; liquid biopsy; men; migration; monolayer; mortality; mortality risk; multiple omics; outcome disparities; overexpression; peripheral blood; precision medicine; prostate cancer cell line; prostate cancer progression; protein expression; proteomic signature; public database; racial diversity; recruit; research study; stemness; survival outcome; taxane; therapy resistant; three dimensional cell culture; transcriptome sequencing; transcriptomics; treatment response; tumor

There is no cure for metastatic prostate cancer (PCa), and about 1 in 41 men in the United States (U.S.) will die of the disease. Since African American (AA) men are most likely to be diagnosed with metastatic PCa, the expansion of research studies that thoroughly evaluate the molecular mechanisms which drive PCa progression and metastasis leading to lethal outcomes in AA men remains a paramount goal. Metastatic PCa initially responds to suppression of androgen signaling through androgen deprivation therapy. However, relapse is inevitable and treatment options are limited. For this reason, a promising area of investigation focuses on inhibiting androgen-independent signaling pathways—such as human epidermal growth factor receptor 2 (HER2)—that promote metastasis. HER2 overexpression is remarkably frequent in PCa tumors and correlates with worse prognosis and treatment-resistance in PCa patients but has not been evaluated in studies with sufficient recruitment of HER2 positive patients or in studies inclusive of AA PCa patients or biospecimens. This research proposal is the first to investigate HER2 by race and evaluate its role in PCa outcome disparities. Preliminary analysis of RNA sequencing and immunohistochemistry of prostate tissue reveals HER2 overexpression in AA PCa patients and suggests a positive correlation with West African ancestry (WAA). We hypothesize that unique multiomic signatures contribute to HER2 overexpression in AA patients which worsens clinical features, treatment response, and survival outcomes to be evaluated with these aims: Aim 1: Confirm that HER2/ERBB2 overexpression is positively correlated with WAA and associated with worse tumor biology, disease stage, clinical features, treatment response, and survival outcomes. The effects of HER2/ERBB2 overexpression on cellular function and tumor biology will be evaluated in cells and 3D cultures. Correlations between HER2 overexpression and disease stage, clinical features, treatment response, and survival outcomes will be assessed in tumor tissue. All analyses will compare HER2 expression with WAA calculated using validated ancestry informative markers through single nucleotide polymorphism genotyping. Aim 2: Identify genetic variations associated with HER2/ERBB2 amplification using liquid biopsy. Circulating tumor cells isolated from patients with metastatic PCa will be characterized to identify genetic variations associated with HER2/ERBB2 amplification using single cell genomics. Aim 3: Determine multiomic signatures associated with HER2/ERBB2 overexpression. Epigenetic, transcriptomic, and proteomic analyses will be performed in cell lines and sera to identify unique signatures associated with HER2/ERBB2 overexpression that are predictive of treatment-resistance and poor survival. Relevance: Thorough evaluation of the molecular mechanisms by which HER2/ERBB2 overexpression steers PCa progression and treatment-resistance will provide the foundation to pursue future clinical trials with a precision medicine approach to have a major impact in reducing the higher risk of death in AA men.

转移性前列腺癌 (PCa) 无法治愈，美国 (U.S.) 大约每 41 名男性中就有 1 人死亡 由于非裔美国人 (AA) 男性最有可能被诊断出患有转移性 PCa，因此 全面评估驱动 PCa 进展的分子机制的研究扩展 导致 AA 男性死亡的转移仍然是转移性 PCa 的首要目标。 通过雄激素剥夺疗法抑制雄激素信号传导，但复发是可能的。 由于这个原因，一个有前途的研究领域集中在不可避免的情况和治疗选择上。 抑制雄激素非依赖性信号通路——例如人表皮生长因子受体 2 (HER2)——促进转移的 HER2 过度表达在 PCa 肿瘤中并不常见，并且具有相关性。 PCa 患者的预后和治疗耐药性较差，但尚未在研究中进行评估 充分招募 HER2 阳性患者或纳入 AA PCa 患者或生物样本的研究。 研究提案是第一个按种族调查 HER2 并评估其在 PCa 结果差异中的作用的研究提案。 前列腺组织 RNA 测序和免疫组织化学的初步分析揭示了 HER2 AA PCa 患者中过度表达，表明与西非血统 (WAA) 呈正相关。 研究发现，独特的多组学特征导致 AA 患者中 HER2 过度表达，这 恶化临床特征、治疗反应和生存结果，并通过以下目标进行评估： 目标 1：确认 HER2/ERBB2 过表达与 WAA 呈正相关并与 更糟糕的肿瘤生物学、疾病阶段、临床特征、治疗反应和生存结果。 将在细胞和 3D 中评估 HER2/ERBB2 过表达对细胞功能和肿瘤生物学的影响 HER2 过度表达与疾病阶段、临床特征、治疗反应之间的相关性， 所有分析都会将 HER2 表达与 WAA 进行比较。 使用通过单核苷酸多态性基因分型提供信息的经过验证的祖先标记进行计算。 目标 2：使用液体活检鉴定与 HER2/ERBB2 扩增相关的遗传变异。 从转移性 PCa 患者中分离的循环肿瘤细胞将被表征以鉴定遗传 与使用单细胞基因组学进行 HER2/ERBB2 扩增相关的变异。 目标 3：确定与 HER2/ERBB2 过度表达相关的多组学特征。 将在细胞系和血清中进行转录组和蛋白质组分析，以识别独特的特征 与 HER2/ERBB2 过度表达相关，可预测治疗抵抗和不良生存。 相关性：全面评估 HER2/ERBB2 过表达控制的分子机制 PCa 进展和治疗耐药将为未来的临床试验奠定基础 精准医疗方法对降低 AA 男性较高的死亡风险产生重大影响。