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.

由于染色质重塑而导致的基因活性异常变化在癌细胞中很常见。他们涉及 启动子区域中富含胞嘧啶-鸟嘌呤 (CpG) 的岛的胞嘧啶甲基化/去甲基化 组蛋白的转录后修饰（乙酰化/甲基化）。 DNA 的异常获得或丢失 甲基化导致参与肿瘤发生和恶性细胞维持的基因表达改变 表型包括肿瘤抑制因子、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治疗的基本原理 DNA去甲基化剂5-Aza-2'-脱氧胞苷（5-Aza-CdR，也称为 地西他滨）、其类似物 5-氮杂胞苷和组蛋白脱乙酰酶 (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相关的表观基因组标记。这些标记可以是 预测反应和使用表观遗传修饰剂调整治疗反应的测定的基础 患者。在目标 1 中，我们将评估敏感人群中地西他滨响应的基因表达的整体变化。 和耐药黑色素瘤细胞，并确定可以预测生长抑制的基因表达谱。 在目标 2 中，我们将探究敏感细胞中 DNA 启动子甲基化模式的全基因组变化。 和耐药黑色素瘤细胞对 5-Aza-CdR 的反应，并将其与受影响基因的概况相关联 目标 1 中揭示。我们还将确定黑色素瘤肿瘤中 DNA 甲基化的整体变化 从接受 5-氮杂胞苷治疗的患者身上切除，并将其与培养中的黑色素瘤细胞进行比较。 在目标 3 中，我们将验证 5-Aza-CdRresponsive 调控区域的表观遗传修饰（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 对来自染色质修饰和基因的信息进行数据挖掘和整合 表达式数组数据。我们预计这些信息将有助于设计一种具有成本效益的表观遗传修饰剂 可以预测黑色素瘤患者对此类药物的疗效并监测治疗反应的测试。 该项目包括 5-氮杂胞苷的 I 期试验，是多学科的，涉及多个学科的共同努力 基础科学家、分子生物学家、生物信息学和临床肿瘤学家。