Genomic Analysis of Tumor Context Vulnerabilities in Human Metastatic Melanoma

人类转移性黑色素瘤肿瘤背景脆弱性的基因组分析

• 批准号: 7914519
• 负责人: Bradford R Brooks
• 金额: $ 3.05万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-08-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914519
• 关键词: Biological Assay; Clinical; Clinical effectiveness; Combined Modality Therapy; Diagnosis; Disease; Effectiveness; Exhibits; Functional RNA; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Human; In Vitro; Intervention; Mediating; Melanoma Cell; Metastatic Melanoma; Mutation; Patients; RNA Interference; Research; Resistance; Screening procedure; Small Interfering RNA; Staging; Survival Rate; Validation; Xenograft Model; advanced disease; base; chemotherapy; functional genomics; improved; in vivo; melanoma; outcome forecast; public health relevance; response; tumor; tumor progression

DESCRIPTION (provided by applicant): Despite decades of research, metastatic malignant melanoma remains an incurable disease. Only a small percentage of patients diagnosed with metastatic disease exhibit a clinical response to chemotherapy. Fewer still are cured. The five-year survival rate for those with metastatic disease ranges from 5-18%. Therefore, the focus of this study is to identify those genetic changes within melanoma, confirmed through functional genomic screening and in vivo validation, which provide a context of genetic vulnerability that can be exploited in advanced disease. Specifically, the applicant is proposing to perform high-throughput functional RNA interference (RNAi) screen to systematically identify genes that mediate melanoma cell sensitivity (Specific Aim 1). Subsequently, those targets identified will be validated (Specific Aim 2) by confirming siRNA-mediated gene knockdown in vitro, performing high-content mechanistic assays to elucidate the mechanism by which these genes mediate melanoma cell sensitivity in vitro, and evaluating the effectiveness of inhibiting these genes in vitro in combination with the selecting agent. Finally, the applicant will evaluate whether validated genetic targets can add to molecularly-informed combination therapies in vivo against xenograft models of melanoma (Specific Aim 3). The applicant hypothesizes that this functionally-based genomic approach will identify the context of genetic aberrations associated with tumor progression that are critical to rendering melanoma cells more resistant to chemotherapy. These validated genes could facilitate the combined targeting of these tumor-context vulnerabilities and could be of direct relevance to clinical exploitation. PUBLIC HEALTH RELEVANCE: The long-term prognosis for those afflicted with advanced stage metastatic melanoma is bleak, with a five-year survival rate ranging from 5-18%. The proposed research aims to identify genetic vulnerabilities acquired by metastatic melanoma cells that may be exploited to improve the effectiveness of clinical intervention in this disease.

描述（由申请人提供）：尽管进行了数十年的研究，但转移性恶性黑色素瘤仍然是一种无法治愈的疾病。只有一小部分被诊断为转移性疾病的患者表现出对化学疗法的临床反应。更少的治愈。转移性疾病患者的五年生存率范围为5-18％。因此，这项研究的重点是通过功能性基因组筛查和体内验证确认黑色素瘤内的遗传变化，这些遗传验证提供了可以在晚期疾病中利用的遗传脆弱性的背景。具体而言，申请人提议执行高通量功能RNA干扰（RNAI）筛选，以系统地识别介导黑色素瘤细胞敏感性的基因（特定目标1）。随后，通过确认siRNA介导的基因敲低的基因敲低的基因敲低，进行高内含机理测定法，以阐明这些基因在体外介导黑色素瘤细胞敏感性，并评估与选择剂结合抑制这些基因的有效性。最后，申请人将评估是否可以针对黑色素瘤的异种移植模型在体内添加验证的遗传靶标（特定目标3）。申请人假设这种基于功能的基因组方法将确定与肿瘤进展相关的遗传畸变的背景，这对于使黑色素瘤细胞对化学疗法具有更耐药性至关重要。这些经过验证的基因可以促进这些肿瘤神经膜漏洞的联合靶向，并且可能与临床开发直接相关。 公共卫生相关性：患有晚期阶段转移性黑色素瘤的人的长期预后是黯淡的，五年的生存率从5-18％不等。拟议的研究旨在鉴定转移性黑色素瘤细胞获得的遗传脆弱性，这些遗传脆弱性可能被利用以提高临床干预对该疾病的有效性。