PREDICTIVE AND THERAPEUTIC UTILITIES OF EPIGENETIC CHANGES IN CHROMATIN IN MELANO

黑色素染色质表观遗传变化的预测和治疗用途

• 批准号: 7147298
• 负责人: SHERMAN Morton WEISSMAN
• 金额: $ 17.97万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147298
• 关键词: DNA; DNA methylation; bioinformatics; chromatin; clinical research; epigenetics; gene expression; genes; melanoma; methylation; neoplasm /cancer

Aberrant changes in gene activity due to chromatin remodeling are frequent in cancer cells. They involve methylation/demethylation of cytosine at cytosine-guanine (CpG) pair rich islands in promoter regions and post-transcriptional modifications (acetylation/methylation) of histones. Aberrant gain or loss of DNA methylation causes altered expression of genes involved in tumorigenesis and maintenance of the malignant phenotype including tumor suppressors, apoptotic factors, DNA repair enzymes, adhesion molecules, and immunomodulators. The reversible nature of epigenetic changes in chromatin is the rationale for clinical development of the DNA demethylation agents 5-Aza-2'-deoxy-cytidine (5-Aza-CdR, also known as decitabine), its analogue 5-azacytidine, and the histone deacetylase (HDAC) inhibitors. Our goal is to identify epigenomic markers associated with growth arrest of melanoma cells and tumors. These markers can be the basis for an assay for predicting responses and tailoring treatment with epigenetic modifiers to responsive patients. In Aim 1 we will assess global changes in gene expression in response to decitabine in sensitive and resistant melanoma cells and determine gene-expression profiles that can predict growth suppression. In Aim 2 we will interrogate genome-wide changes in the patterns of DNA promoter methylation in sensitive and resistant melanoma cells in response to 5-Aza-CdR, and correlate it to the profiles of affected genes revealed in Aim 1. We will also determine the global changes in DNA methylation in melanoma tumors excised from patients undergoing treatment with 5-azacytidine and compare it to melanoma cells in culture. In Aim 3 we will verify the epigenetic modification (DNA methylation) in regulatory regions of 5-Aza-CdRresponsive genes deemed critical to inducing growth arrest. We will employ multiple bioinformatics methods to perform data mining and integration of the information derived from the chromatin modification and gene expression array data. We foresee that the information will help devise a cost-effective epigenetic-modifier test that can predict efficacy and monitor therapeutic responses to this class of agents in melanoma patients. This project includes a Phase I trial with 5-azacytidine, is multidisciplinary, involving the concerted efforts of basic scientists, molecular biologists, bioinformatics and clinical oncologists.

癌细胞中染色质重塑引起的基因活性的异常变化。他们涉及 胞嘧啶 - 瓜氨酸（CPG）在启动子区域和 组蛋白的转录后修饰（乙酰化/甲基化）。 DNA的异常增益或损失 甲基化会导致涉及肿瘤发生和维持恶性肿瘤的基因表达的改变 表型包括肿瘤抑制剂，凋亡因子，DNA修复酶，粘附分子和 免疫调节剂。染色质表观遗传变化的可逆性是临床的理由 DNA脱甲基化剂的开发5-aza-2'-脱氧 - 酪氨酸（5-aza-cdr，也称为 ），其类似物5-氮杂丁胺和组蛋白脱乙酰基酶（HDAC）抑制剂。我们的目标是确定 与黑色素瘤细胞和肿瘤生长停滞有关的表观基因组标记。这些标记可以是 基于预测反应和用表观遗传修饰剂来量身定制治疗的分析的基础 患者。在AIM 1中，我们将评估敏感敏感性依次的基因表达的全局变化 和抗性黑色素瘤细胞并确定可以预测生长抑制的基因表达谱。 在AIM 2中，我们将询问全基因组在敏感的DNA启动子甲基化模式中的变化 对5-aza-CDR响应的抗性黑色素瘤细胞，并将其与受影响基因的谱相关 在AIM 1中揭示。我们还将确定黑色素瘤肿瘤中DNA甲基化的全局变化 从接受5-氮杂丁胺治疗的患者中切除，并将其与培养中的黑色素瘤细胞进行比较。 在AIM 3中，我们将验证5-Za-CrESS的调节区域中的表观遗传修饰（DNA甲基化） 被认为对诱导生长停滞至关重要的基因。我们将采用多种生物信息学方法 进行数据挖掘和从染色质修饰和基因得出的信息的集成 表达数组数据。我们预见到这些信息将有助于设计一种经济高效的表观遗传模型 可以预测黑色素瘤患者对该类药物的治疗反应的测试。 该项目包括与5-azacytidine的I期试验，是多学科的，涉及 基础科学家，分子生物学家，生物信息学和临床肿瘤学家。