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

项目总结 尽管最近治疗取得了进展，转移性黑色素瘤仍然是一种预后很差的疾病。 初次诊断时临床和组织学相似的原发性黑色素瘤患者通常 有非常不同的结果，从最初手术切除后治愈的患者到发展为 复发(S)，转移进展，最终死亡。这种高度可变的结果表明，潜在的 患者肿瘤(细胞内的)或患者本身(细胞外的，例如免疫)的生物学差异 回应)。最近的研究表明，早期的致癌事件可以反映黑色素瘤的扩散潜力。 从概念上讲，如果在黑色素瘤诊断时能够有力地测量到这种分子变化，他们 可能是有用的预后标志物。此外，这些标记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，一些 预后生物标记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 多种信使核糖核酸和微核糖核酸(MiRNA)的表达可能对原发性肝癌患者的预后有意义。 黑色素瘤。我们建议检测一个由~230个mRNA/miRNA组成的面板的表达，该面板以前与 多机构队列的原发黑色素瘤患者的不良预后(n=1000，IIA期- 诊断时的IIIB)，并进行广泛的临床随访。使用这个表达数据，我们建议开发和 验证IIA至IIIB期黑色素瘤改进的基于组织、分子预后的mRNA/miRNA签名 (目标1和2)。此外，我们将调查候选预后基因(如每个P01所定义的 项目)可以是攻击性表型的功能性中介。我们建议在活体内进行混合 基于文库的功能筛选研究候选预后基因的调控对肿瘤的影响 黑色素瘤细胞的生长和转移潜能(目标3.1)。此外，我们还将研究细胞属性 体内筛选中确定的功能相关候选基因的影响(目标3.2)。 一种分子标记，在最初诊断时可以可靠地预测原发性黑色素瘤患者的预后 可以改变对这些人的临床管理，为选择高危患者提供信息 加强监测和/或辅助治疗。希望更好的黑色素瘤患者管理将 导致改善结果，例如延长患者的生存时间或降低发病率和死亡率。此外, 描述的功能研究将揭示候选基因(来自P01的所有项目)，它们有助于 黑色素瘤的进展和转移，这可能会开辟新的治疗途径来对抗这种毁灭性的 疾病。 好了！

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. !