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: 10268364
• 负责人: Eva Hernando
• 金额: $ 1.2万
• 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/10268364
• 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; Data Set; Diagnosis; Disease; Disease Progression; Epigenetic Process; Event; Excision; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Growth; Guide RNA; Histologic; Human; Immune; Immune response; Immunotherapy; 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; Oncogenes; Operative Surgical Procedures; Outcome; Patient risk; Patient-Focused Outcomes; Patients; Pattern; Phenotype; Population; Primary Lesion; Primary Neoplasm; Prognostic Marker; Property; Recurrence; Research Design; Role; Sampling; Sex Differences; Site; Specimen; Staging System; Stratification; TNM; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; Transcription Alteration; Tumor Tissue; Variant; Xenograft procedure; base; cohort; follow-up; high risk; improved; improved outcome; in vivo; individual patient; insight; melanoma; member; methylome; molecular marker; mortality; nano-string; neoplastic cell; new therapeutic target; novel; novel therapeutics; outcome forecast; outcome prediction; primary outcome; prognostic; prognostic assays; prognostic signature; prognostic value; prospective; protein expression; survival outcome; targeted treatment; tumor growth; tumor initiation; tumor progression; tumorigenesis; tumorigenic

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 IIAIIIB 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.

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。