Discovery of BRM Targeted Therapies: Novel Reactivation of an Anticancer Gene

Sarah      Gramling; David      Reisman

Abstract

Drug discovery in the field of oncology has been advanced mainly through the targeting of receptor tyrosine kinases. Both antibodies and small molecule inhibitors have been found to have successful applications in blocking the proliferative functions of these cell surface receptors. Based on these early successes, additional kinases within the cytoplasm have been found to promote cancer and, as such, have been recognized as feasible targets for additional modes of therapies. Unlike these oncogene targets, most tumor suppressors are irreversibly altered during cancer progression and therefore are not feasible targets for therapy. However, a subset of these genes is reversibly epigenetically suppressed. One such gene is BRM, and when it is re-expressed in cancer cells, this gene halts their growth. Moreover, as the key catalytic subunit of the SWI/SNF complex, BRM is centrally important to a host of anticancer pathways and cellular mechanisms, and its status may serve as a biomarker. Restoring its expression will both reconnect a number of growthcontrolling pathways and affect cellular adhesion, DNA repair, and immune functions. For these reasons, restoring BRM expression is not only feasible, but potentially a potent form of anticancer therapy. To identify BRM-restoring compounds, we developed a cell-based luciferase assay. In this review, we discuss some of the challenges we encountered, issues related to this type of drug discovery, and our future ambitions. We hope this review will provide insight to this type of endeavor and lead to more investigations pursuing this type of drug research.

Keywords: Brahma, Anticancer, Tumor suppressor, Epigenetic suppression, SWI/SNF, High throughput screening, Drug, receptor tyrosine kinases, biomarker, cellular adhesion, DNA repair, oncogenes, BRM, HDAC, BGR1, phenotype, mitotic nuclei, carcinogens, IDP, MEF2, BRM-negative cell lines, polymorphisms, genotyping, BRM Assay, MMTV, density, PCR, RH, GK, MGR13, sRNAi, cancer