Project 3: Prognostic and Functional Role of a Gene Expression Signature in Melanoma Patients

项目 3：基因表达特征在黑色素瘤患者中的预后和功能作用

• 批准号: 10188451
• 负责人: Eva Hernando
• 金额: $ 34.2万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188451
• 关键词: Adjuvant Therapy; Aggressive behavior; American Joint Committee on Cancer; Biological; Biological Assay; Biology; CRISPR/Cas technology; Candidate Disease Gene; Cells; Clinical; Clinical Management; Clonal Evolution; Collaborations; Custom; Data; Diagnosis; Disease; Disease Progression; Epigenetic Process; Event; Excision; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Growth; Guide RNA; Histologic; Human; Immune; Immune response; Individual; Lesion; Libraries; Malignant Neoplasms; Measurable; Measures; Mediator of activation protein; Melanoma Cell; Metastatic Melanoma; Metastatic Neoplasm to the Lung; MicroRNAs; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Mutation; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Patient risk; Patient-Focused Outcomes; Patients; Pattern; Phenotype; Population; Primary Lesion; Primary Neoplasm; Prognosis; Prognostic Marker; Property; Recurrence; Research Design; Role; Sampling; Site; Specimen; Staging System; Stratification; TNM; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; Transcription Alteration; Tumor Tissue; Variant; base; clinical biomarkers; cohort; follow-up; high risk; improved; improved outcome; in vivo; individual patient; insight; melanoma; melanoma biomarkers; member; molecular marker; mortality; nano-string; neoplastic cell; new therapeutic target; novel; novel therapeutics; outcome prediction; primary outcome; prognostic; prognostic assays; prognostic signature; prognostic value; prospective; protein expression; survival outcome; targeted treatment; tumor growth; tumor initiation; tumorigenesis; tumorigenic

PROJECT SUMMARY Despite recent therapeutic advances, metastatic melanoma remains a disease with poor prognosis. Patients with primary melanomas that are clinically and histologically similar at the time of initial diagnosis often have vastly different outcomes, from patients who are cured after initial surgical resection to those that develop recurrence(s), metastatic progression, and eventually die. Such highly variable outcomes suggest underlying biological differences in patient tumors (cell-intrinsic) or the patients themselves (cell-extrinsic, e.g. immune response). Recent studies suggest that early tumorigenic events can reflect a melanoma's potential to spread. Conceptually, if such molecular alterations can be robustly measured at the time of melanoma diagnosis, they may be useful prognostic markers. Moreover, some of these markers may also be functional drivers of disease progression, thus their study may yield novel insights into melanoma biology and new therapeutic targets. We hypothesize that altered gene expression can predict patient outcome and, moreover, that some prognostic biomarkers are functional drivers of melanoma progression. Our group and others have observed that expression of various mRNA and microRNA (miRNA) may have prognostic value for patients with primary melanoma. We propose to examine the expression of a panel of ~230 mRNA/miRNA previously associated to poor outcomes in melanoma in a multi-institutional cohort of primary melanoma patients (n = 1000, stages IIA- IIIB at diagnosis) with extensive clinical follow-up. Using this expression data, we propose to develop and validate a refined tissue-based, molecular prognostic mRNA/miRNA signature for stages IIA to IIIB melanomas (Aims 1 and 2). In addition, we will investigate if candidate prognostic genes (as defined by each of the P01 projects) can be functional mediators of the aggressive phenotype. We propose to perform in vivo pooled library-based functional screens to examine the effects of modulation of candidate prognostic genes on tumor growth and metastatic potential of melanoma cells (Aim 3.1). Moreover, we will investigate cellular properties underlying the effects of functionally relevant candidate genes identified in in vivo screens (Aim 3.2). A molecular signature that, at initial diagnosis, can reliably predict outcomes for primary melanoma patients could transform clinical management of these individuals, informing selection of higher-risk patients for increased surveillance and/or adjuvant therapy. The hope is that better melanoma patient management will lead to improved outcomes, such as prolonging patient survival or reducing morbidity and mortality. In addition, the described functional studies will reveal candidate genes (from all projects of the P01) that contribute to melanoma progression and metastasis, which might open new therapeutic avenues against this devastating disease. !

项目摘要 尽管最近的治疗进展，转移性黑色素瘤仍然是一种预后不良的疾病。 原发性黑色素瘤患者在初次诊断时临床和组织学上相似， 从最初手术切除后治愈的患者到那些 复发、转移进展，并最终死亡。这种高度可变的结果表明， 患者肿瘤（细胞内源性）或患者自身（细胞外源性，例如免疫 响应）。最近的研究表明，早期的致瘤事件可以反映黑色素瘤的扩散潜力。 从概念上讲，如果这种分子改变可以在黑色素瘤诊断时可靠地测量， 可能是有用的预后标志物。此外，这些标记物中的一些也可能是疾病的功能驱动因素 因此，他们的研究可能会对黑色素瘤生物学和新的治疗靶点产生新的见解。 我们假设基因表达的改变可以预测患者的预后，而且， 预后生物标志物是黑色素瘤进展的功能驱动因素。我们小组和其他人观察到 各种mRNA和microRNA（miRNA）的表达可能对原发性肝癌患者具有预后价值。 黑素瘤我们建议检测一组约230种mRNA/miRNA的表达，这些mRNA/miRNA以前与 在原发性黑色素瘤患者的多机构队列中，黑色素瘤的不良结局（n = 1000，IIA-10期） 诊断时IIIB），并进行广泛的临床随访。利用这些表达数据，我们建议开发和 验证IIA至IIIB期黑色素瘤的精细的基于组织的分子预后mRNA/miRNA特征 (Aims 1和2）。此外，我们将研究候选预后基因（如每个P01 项目）可以是侵袭性表型的功能性介导物。我们建议在体内进行合并 基于文库的功能筛选，以检查候选预后基因对肿瘤的调节作用 黑色素瘤细胞的生长和转移潜力（目的3.1）。此外，我们将研究细胞特性 作为体内筛选中鉴定的功能相关候选基因的作用的基础（Aim 3.2）。 一种在初次诊断时可以可靠预测原发性黑色素瘤患者结局的分子特征 可以改变这些人的临床管理，为选择高风险患者提供信息， 增加监测和/或辅助治疗。希望是更好的黑色素瘤患者管理将 导致改善的结果，例如延长患者存活或降低发病率和死亡率。此外，本发明还提供了一种方法， 所描述的功能性研究将揭示候选基因（来自P01的所有项目）， 黑色素瘤的进展和转移，这可能会开辟新的治疗途径，对这种毁灭性的 疾病 !