MBD2 as a Target for Cancer Prevention and Treatment

描述（由申请人提供）：在人类实体器官癌的体细胞基因组改变中，只有DNA甲基化的变化持续发生（约90%的病例），出现较早（首先出现在瘤前病变中），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'转录调控区域，其超甲基化可通过募集5- mcpg结合域（MBD）家族蛋白导致基因转录的抑制。在MBD家族蛋白中，MBD2是一个非常有吸引力的癌症预防和治疗靶点：易于肠道肿瘤发生的Apc Mm/+小鼠，在MBD2 -/-背景下繁殖时，发生肠腺瘤的几率减少了约10倍。本项目探索的治疗策略的特点是选择性靶向MBD2转录抑制途径。为了发现小分子MBD2通路抑制剂，将使用一种新的分阶段“高通量”筛选，以GSTP1的CpG岛为特征，已知GSTP1通过体细胞超甲基化和MBD2介导的抑制在前列腺、乳腺癌和肝癌中“沉默”。然后，新的“先导”化合物将在“沉默”基因再激活方面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进行表征。具体目标是：(i)筛选100,000种化合物，用于从高甲基化GSTP1启动子序列中选择性激活转录，（ii）表征“先导”化合物的分子作用机制，以及（iii）评估小鼠模型的临床前抗癌功效和毒性。

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.