Reverse the Epigenetic Suppression of BRM through High Throughput Screening

University Of Florida, Gainesville FL

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Abstract

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.