Reverse the Epigenetic Suppression of BRM through High Throughput Screening

通过高通量筛选逆转 BRM 的表观遗传抑制

• 批准号: 7761456
• 负责人: DAVID N REISMAN
• 金额: $ 2.91万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761456
• 关键词: ATP phosphohydrolase; Adverse effects; Affect; Basic Science; Biological Assay; Biological Sciences; Bladder; Breast; Butyrates; Cancer Cell Growth; Cancer Patient; Cancer cell line; Cell Adhesion; Cell Cycle; Cell Line; Cells; Cervix Uteri; Chromatin Remodeling Factor; Clinical; Colon; Complex; DNA Repair; Data; Development; Dose; Drug Delivery Systems; Epigenetic Process; Gene Expression; Gene Silencing; Genes; Goals; Growth; HDAC3 gene; Head and neck structure; Histone Deacetylase Inhibitor; Institutes; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Methods; Michigan; Molecular; Mutate; Ovary; Patients; Pharmaceutical Preparations; Preclinical Drug Evaluation; Process; Proteins; Recruitment Activity; Regulation; Regulator Genes; Research; Research Personnel; SMARCA4 gene; SMARCB1 gene; Scientist; Series; Signal Transduction Pathway; Site; Smoke; Specificity; Testing; Tobacco smoke; Toxic effect; Translating; Translational Research; Tumor Suppressor Proteins; Universities; Work; chemotherapy; drug development; experience; fight against; gene therapy; high throughput screening; in vitro Assay; inhibitor/antagonist; novel; oncology; programs; public health relevance; response; small molecule; transcription factor; tumor; tumor progression; tumorigenesis; tumorigenic

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.

描述（由申请人提供）：该转化研究计划的长期目标是开发靶向癌症肿瘤发生过程的药物。细胞使用基因表达的表观遗传沉默来调节分化和发育。在癌症发展过程中，表观遗传沉默可能被异常激活，导致关键细胞基因被不适当地沉默。然而，这些基因并不是不可逆地改变的。鉴定特异性逆转这一过程并恢复沉默基因表达的化合物是开发癌症靶向基因疗法的重要策略。我们已经发现，BRM，一个亚基的基本染色质重塑复合物SWI/SNF，没有突变，但表观遗传沉默。BRM损失发生在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缺陷细胞系中，BRM表达可以用小分子抑制剂丁酸盐或阿司他汀恢复。然而，值得注意的是，目前可用的小分子抑制剂，包括我们研究中的那些，是广泛作用的，影响许多蛋白质。因此，这些化合物干扰所需的细胞内过程，导致其副作用特征并降低其作为临床药剂的效用。事实上，我们已经发现，多种这些抑制剂，而有效地恢复BRM表达，干扰多个其他方面的SWI/SNF功能。因此，它们缺乏特异性，通过阻断恢复BRM和其他此类蛋白质表达的有益作用而否定了它们的大部分潜在抗癌作用。为了弥补这一缺陷，我们提出使用高通量药物筛选来鉴定新的化合物，其可以靶向并选择性地拮抗BRM异常沉默的机制。我们还将确定这些化合物中每一种的作用部位。这些化合物不仅通过恢复BRM对癌症患者有临床益处，而且它们还可能逆转由这种机制抑制的许多其他重要抗癌基因的沉默。我们有一个独特的团队来完成这项研究：具有肿瘤学专业知识的临床科学家，具有药物开发经验的转化研究人员，专家药物化学家，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州高风险中心。我们在开发恢复BRM的化合物方面的工作是将基础科学发现转化为可以直接使患者受益的疗法的重要的第一步，因此具有使与烟草烟雾暴露相关的癌症患者受益的强大潜力。 公共卫生相关性：传统化疗会影响细胞周期，因此不是很特异也不是很有效。发现新的化合物，癌症的起源将有助于对抗癌症，因为这些药物将是高度特异性和毒性小得多。