MBD2 as a Target for Cancer Prevention and Treatment

MBD2作为癌症预防和治疗的靶点

• 批准号: 6899546
• 负责人: WILLIAM George NELSON
• 金额: $ 28.95万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899546
• 关键词: CpG islands; DNA methylation; breast neoplasms; cancer prevention; chemical registry /resource; chemoprevention; combinatorial chemistry; disease /disorder model; drug discovery /isolation; drug screening /evaluation; gene induction /repression; genetic promoter element; genetic transcription; genetically modified animals; high throughput technology; inhibitor /antagonist; laboratory mouse; liver neoplasms; molecular genetics; neoplasm /cancer; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; prostate neoplasms; small molecule

DESCRIPTION (provided by applicant): Of somatic genome alterations in human solid organ cancers, only changes in DNA methylation occur consistently (>90% of cases), arise early (first appearing in preneoplastic lesions), and can be reversed (the DNA sequence remains intact). Hypermethylation of CpG island sequences, which encompass the 5' transcriptional regulatory regions of many genes, can lead to repression of gene transcription via the recruitment of 5-mCpG-binding domain (MBD) family proteins. Of the MBD family proteins, MBD2 is a very attractive target for cancer prevention and treatment: Apc Mm/+ mice, prone to intestinal tumorigenesis, develop some 10-fold fewer intestinal adenomas when bred to an Mbd2 -/- background. The therapeutic strategy to be explored in this Project features the selective targeting of the MBD2 transcriptional repression pathway. To discover small molecule MBD2 pathway inhibitors, a novel staged "highthroughput" screen will be used, featuring the CpG island of GSTP1, known to be "silenced" in prostate, breast, and liver cancers via somatic hypermethylation and MBD2-mediated repression. New "lead" compounds will then be characterized for potency and efficacy at "silenced" gene reactivation, and for therapeutic index in animal model studies of cancer prevention and treatment. The Specific Aims to be pursued are: (i) the screening of 100,000 compounds for selective activation of transcription from hypermethylated GSTP1 promoter sequences, (ii) the characterization of "lead" compounds for molecular mechanisms of action, and (iii) the evaluation of preclinical anti-cancer efficacy and toxicity in mouse models.

描述（由申请人提供）：在人类实体器官癌症的体细胞基因组改变中，只有DNA甲基化的变化持续发生（>90%的病例）、早期出现（首先出现在肿瘤前病变中）并且可以逆转（DNA序列保持完整）。 CpG 岛序列（包含许多基因的 5' 转录调控区）的超甲基化可通过招募 5-mCpG 结合域 (MBD) 家族蛋白来抑制基因转录。在 MBD 家族蛋白中，MBD2 是癌症预防和治疗的一个非常有吸引力的靶标：容易发生肠道肿瘤的 Apc Mm/+ 小鼠，当在 Mbd2 -/- 背景下饲养时，发生肠道腺瘤的数量会减少 10 倍。本项目探索的治疗策略以选择性靶向 MBD2 转录抑制途径为特色。为了发现小分子 MBD2 通路抑制剂，将使用一种新颖的分阶段“高通量”筛选，其特征是 GSTP1 的 CpG 岛，已知该岛通过体细胞高甲基化和 MBD2 介导的抑制在前列腺癌、乳腺癌和肝癌中“沉默”。然后，新的“先导”化合物将被表征为“沉默”基因重新激活的效力和功效，以及癌症预防和治疗的动物模型研究中的治疗指数。所要追求的具体目标是：(i) 筛选 100,000 种用于选择性激活高甲基化 GSTP1 启动子序列转录的化合物，(ii) 表征“先导”化合物的分子作用机制，以及 (iii) 评估小鼠模型中的临床前抗癌功效和毒性。