Validation of Genomic Targets in Melanoma

黑色素瘤基因组靶标的验证

• 批准号: 8691742
• 负责人: MOHAMMED KASHANI-SABET
• 金额: $ 30.53万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691742
• 关键词: Adjuvant Therapy; Alzheimer' s Disease; Award; Biological Assay; Biological Markers; Biology; Catalytic RNA; Complementary DNA; Complex; Correlative Study; Cutaneous Melanoma; Development; Dose; Eastern Cooperative Oncology Group; Enrollment; Factor Analysis; Funding; Gene Expression; Genes; Genomics; Grant; Histology; Human; In Vitro; Interferon-alpha; Laboratories; Mediating; Metastatic Melanoma; MicroRNAs; Microarray Analysis; Modeling; Molecular; Mus; Neoplasm Metastasis; Nevus; Patients; Play; Primary Neoplasm; Prognostic Factor; Prognostic Marker; Public Health; Randomized; Role; Small Interfering RNA; Specimen; Testing; Tissues; Validation; Xenograft Model; base; cDNA Arrays; candidate marker; cohort; fetal; follow-up; high risk; in vivo; melanoma; molecular marker; novel; novel strategies; outcome forecast; overexpression; patient population; prognostic; prospective; small hairpin RNA; therapeutic target; transcriptomics

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.

描述（由申请人提供）：我们实验室的最新研究提出了黑色素瘤进展的新方法，可作为开发黑色素瘤新生物标志物和治疗靶点的基础。在本研究中，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α辅助治疗的随机组间试验（东部协作组试验E1690）。我们的目的是验证多标志物预后测定（在两个不同的队列中具有确认的预后影响）在ECOG队列中的作用。其次，我们的目的是验证胎儿阿尔茨海默病（Fetal Alzheimer，ADZ）基因在小鼠模型中黑色素瘤进展中的功能作用。第三，我们的目标是在一个大的黑色素瘤患者队列中鉴定具有预后意义的microRNAs（miRNAs）。重要的是，这些不同的目标是通过他们的差异表达在相同的组织队列的痣，原发性和转移性黑色素瘤的分析研究。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，我们建议对入组E1690试验的患者人群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化检测的预后作用，并确定其在评估干扰素α辅助治疗获益方面的预测作用。目的2：在小鼠模型中验证P2Z基因在黑色素瘤进展中的作用。我们将通过研究靶向siRNA介导的抑制HLAZ在体内人黑色素瘤进展中的作用来表征HLAZ基因对黑色素瘤进展的功能重要性。目的3：建立microRNA谱在原发性黑色素瘤预后评估中的应用。我们实验室获得的最新结果已经确定了在黑色素瘤进展的已知转变中差异表达的miRNA。我们将在一个大的黑色素瘤患者队列中使用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志物预后测定，牢固地建立了BELZ在促进黑色素瘤转移中的作用，并鉴定了在黑色素瘤中具有预后意义的miRNA。