Abstract LB-248: Chemically distinct class I HDAC inhibitors synergize to inhibit global lipid metabolism in cancer

Abstract

Abstract An increased rate of lipid production is a hallmark metabolic feature in cancer cells, which provides energy supplies, building blocks for membrane biogenesis, and signaling molecules for increased cancer cell proliferation. Current chemotherapeutic strategies targeting lipid metabolism have shown significant limitations, and as such, there is great interest in discovering novel therapies that effectively inhibit lipid production in cancer cells. Class I histone deacetylases (HDACs 1-3) are a key component of the epigenetic machinery regulating gene expression, and behave as oncogenes in several cancer types, spurring the development of HDAC inhibitors (HDACi) as novel anticancer drugs. Interestingly, HDAC inhibitors (HDACi) have been shown to decrease lipid production in different cells by modulating key genes in cholesterol synthesis, uptake, and efflux. However, effects of HDACi in lipid biosynthesis of cancer remains poorly studied. We have discovered a novel class of HDACi with a previously undescribed benzoylhydrazide scaffold. These new inhibitors are highly selective and potent to the class I HDACs (HDAC1, HDAC2, and HDAC3). Using global lipidomics approach by Ultra High-Performance Liquid Chromatography coupled High-Resolution Mass Spectrometry (UHPLC-HRMS), we found that a novel optimized analog, SR-4370, exhibits potent inhibition of lipid production in cells of diverse cancer types. Strikingly, SR-4370 in combination with entinostat, a benzamide analog of class I HDAC inhibitor currently in multiple clinical trials for treating breast cancer and other types of solid tumors, exhibits synergistic effects on inhibition of lipid production in cancer cells. We will present lipidomic profiling data from cells and xenograft tumors after treatment with SR-4370/entinostat, and discuss mechanisms of action for these distinct HDACi in inhibiting lipid production. In summary, our findings provide a rationale for inhibiting lipogenesis using isoform-selective HDACi in cancer therapy. Citation Format: Iqbal Mahmud, Timothy J. Garrett, Ryan Stowe, William R. Roush, Daiqing Liao. Chemically distinct class I HDAC inhibitors synergize to inhibit global lipid metabolism in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-248.