Validation of Genomic Targets in Melanoma

描述（由申请人提供）：我们实验室最近的研究提出了黑色素瘤进展的新方法，可以作为开发黑色素瘤新生物标志物和治疗靶点的基础。在这个提议中，我们的目标是在一个前瞻性队列中进行生物标志物分析，即大剂量干扰素辅助治疗的随机组间试验（Eastern Cooperative Group trial E1690）。我们的目标是验证ECOG队列中多标记预后分析（在两个不同的队列中确认预后影响）的作用。其次，我们的目标是在小鼠模型中验证胎儿阿尔茨海默氏症（FALZ）基因在黑色素瘤进展中的功能作用。第三，我们的目标是在大量黑色素瘤患者中鉴定具有预后意义的microRNAs （miRNAs）。重要的是，这些不同的靶点是通过它们在痣、原发性和转移性黑色素瘤的相同组织队列的谱分析研究中的差异表达来确定的。我们的三个具体目标是：目标1：对E1690队列进行分子预后因素分析。为此，我们建议对E1690试验患者群体的组织进行相关研究。我们建议在E1690队列中验证多标记免疫组织化学检测的预后作用，并确定其在评估干扰素辅助治疗获益方面的预测作用。目的2：在小鼠模型中验证FALZ基因在黑色素瘤进展中的作用。我们将通过检测靶向sirna介导的FALZ抑制在体内人类黑色素瘤进展中的作用来表征FALZ基因在黑色素瘤进展中的功能重要性。目的3：开发用于原发性黑色素瘤预后评估的microRNA谱。我们实验室最近获得的结果已经在黑色素瘤进展的已知转变中确定了差异表达的mirna。我们将在大量黑色素瘤患者中使用TaqMan分析来检查10种mirna的预后作用。如果成功，这些研究将验证黑色素瘤的多标记预后分析，牢固地确立FALZ在促进黑色素瘤转移中的作用，并确定在黑色素瘤中具有预后意义的mirna。

DESCRIPTION (provided by applicant): Recent studies in our laboratory have suggested novel approaches to melanoma progression that could serve as the basis for the development of novel biomarkers and therapeutic targets for melanoma. In this proposal, we aim to conduct a biomarker analysis in a prospective cohort, the randomized intergroup trial of adjuvant therapy with high-dose interferon alpha (Eastern Cooperative Group trial E1690). We aim to validate the role of a multi-marker prognostic assay (with confirmed prognostic impact in two distinct cohorts) in the ECOG cohort. Secondly, we aim to validate the functional role of the fetal Alzheimer (FALZ) gene in the progression of melanoma in murine models. Third, we aim to identify microRNAs (miRNAs) with prognostic significance in a large cohort of melanoma patients. Importantly, these diverse targets were identified by virtue of their differential expression in profiling studies of the same tissue cohort of nevi, primary and metastatic melanomas. Our three specific aims are: Aim 1: To perform a molecular prognostic factor analysis on the E1690 cohort. In this aim, we propose correlative studies on tissues from the patient population enrolled in the E1690 trial. We propose to validate the prognostic role of a multi-marker immunohistochemical assay in the E1690 cohort, and to determine its predictive role in assessing benefit to adjuvant therapy with interferon alpha. Aim 2: To validate the role of the FALZ gene in melanoma progression in murine models. We will characterize the functional importance of the FALZ gene on the progression of melanoma by examining the role of targeted siRNA-mediated suppression of FALZ in the progression of human melanoma in vivo. Aim 3: To develop microRNA profiles in the prognostic assessment of primary melanoma. Recent results obtained in our laboratory have identified differentially expressed miRNAs in the known transitions in melanoma progression. We will examine the prognostic role of ten miRNAs using TaqMan analysis in a large cohort of melanoma patients. If successful, these studies will validate a multi-marker prognostic assay for melanoma, firmly establish a role for FALZ in promoting melanoma metastasis, and identify miRNAs with prognostic significance in melanoma.