Reverse the Epigenetic Suppression of BRM through High Throughput Screening

描述(申请人提供)：这一转化研究计划的长期目标是开发针对癌症发生过程的药物。细胞利用基因表达的表观遗传沉默来调节分化和发育。在癌症的发展过程中，表观遗传沉默可能会被异常激活，导致关键的细胞基因不适当地沉默。然而，这些基因并不是不可逆转的改变。识别特定逆转这一过程并恢复沉默基因表达的化合物是开发针对癌症的靶向基因疗法的重要策略。我们已经发现，基本染色质重塑复合体SWI/SNF的一个亚基BRM没有突变，而是表观遗传沉默。BRM缺失发生在20%-30%与二手烟有关的肿瘤类型中，包括肺癌、结肠癌和膀胱癌。在BRM缺陷的细胞系中，BRM的表达可以用小分子抑制剂丁酸盐或曲古菌素恢复。然而，值得注意的是，目前可用的小分子抑制剂，包括我们研究的那些，是广泛作用的，影响许多蛋白质。因此，这些化合物干扰了所需的细胞内过程，增加了它们的副作用，并降低了它们作为临床药物的效用。事实上，我们已经发现，各种这些抑制剂，虽然有效地恢复BRM的表达，但干扰SWI/SNF功能的多个其他方面。因此，它们缺乏特异性，从而阻断了恢复BRM和其他此类蛋白质表达的有益效果，从而否定了它们大部分潜在的抗癌作用。为了弥补这一缺陷，我们建议通过高通量药物筛选来寻找新的化合物，这些化合物可以靶向并选择性地拮抗BRM异常沉默的机制。我们还将确定每种化合物的作用部位。这些化合物不仅将通过恢复BRM而在临床上有益于癌症患者，而且它们还可能逆转许多其他被这一机制抑制的重要抗癌基因的沉默。我们有一支独一无二地准备完成这项研究的团队：一名在肿瘤学方面有专长的临床科学家，一名在药物开发方面有经验的转化研究人员，一名专业药物化学家，以及密歇根大学生命科学研究所药物筛选设施以及密歇根高通量中心。我们开发修复BRM的化合物的工作是将基础科学发现转化为可直接使患者受益的疗法的重要第一步，因此有很大潜力造福于与烟草烟雾暴露相关的癌症患者。 公共卫生相关性：传统化疗影响细胞周期，因此不是非常特异或有效。新化合物的发现将有助于抗癌，因为这些药物具有高度的特异性，毒性要小得多。

DESCRIPTION (provided by applicant): The long-term goal of this translational research program is to develop drugs that target the process of tumorigenesis in cancers Epigenetic silencing of gene expression is used by cells to regulate differentiation and development. During cancer development, epigenetic silencing can be aberrantly activated, causing key cellular genes to be inappropriately silenced. These genes are not irreversibly altered, however. Identifying compounds that specifically reverse this process and restore expression of silenced genes is an important strategy for developing targeted gene therapies for cancer. We have found that BRM, a subunit of the essential chromatin remodeling complex SWI/SNF, is not mutated but epigenetically silenced. BRM loss occurs in 20- 30% of tumor types related to secondhand smoke, including lung, colon, and bladder cancers. In BRM- deficient cell lines, BRM expression can be restored with the small molecule inhibitors butyrate or trichostatin. Significantly, however, currently available small molecular inhibitors, including those in our studies, are broad- acting, affecting many proteins. These compounds thus interfere with required intracellular processes, contributing to their side-effect profile and diminishing their utility as clinical agents. Indeed, we have found that a variety of these inhibitors, while effective in restoring BRM expression, interfere with multiple other aspects of SWI/SNF function. Their lack of specificity hence negates much of their potential anticancer effects by blocking the beneficial effects of restoring the expression of BRM and other such proteins. To remedy this drawback, we propose to identify novel compounds using high-throughput drug screening that can target and selectively antagonize the mechanism underlying the aberrant silencing of BRM. We will also identify the site of action of each of these compounds. Such compounds will not only be clinically beneficial for cancer patients by restoring BRM, but they will also likely reverse the silencing of many other important anticancer genes suppressed by this mechanism. We have a team that is uniquely poised to accomplish this research: a clinical scientist with expertise in oncology, translational researchers with experience in drug development, an expert medicinal chemist, and the Life Science Institute drug screen facility at the University of Michigan as well as the Michigan High Throughput Center. Our work in developing compounds that restore BRM is an important first step in translating basic science discoveries into therapies that can directly benefit patients-and thus has strong potential for benefiting patients with cancers related to tobacco smoke exposure. PUBLIC HEALTH RELEVANCE: Traditional chemotherapy affects the cell cycle and hence is not very specific nor effective. The discovery of new compounds which the genesis of cancer will aid in fight against cancer as these drugs will be highly specific and much less toxicity.