Abstract 2088: Targeting transcriptional factor IWS1 as a potential treatment of advanced dedifferentiated liposarcoma

Abstract Introduction. Surgery remains the only curative treatment for patients with liposarcoma (LPS). The translation of novel therapies has been hampered, and there has been no significant improvement in prognosis for 30 years. Our recent findings demonstrate that IWS1, a transcription elongation and alternative splicing factor, is elevated in dedifferentiated LPS (ddLPS) patient tumor samples and is associated with worse survival and a shorter time to relapse in ddLPS. In this study, we present preliminary results on a novel treatment for advanced ddLPS: an IWS1 inhibitor, serving as a way to discover a spliceosome as a novel therapeutic target. Methods. Utilizing computer-aided, structure-based virtual screening approaches, we identified a class of compounds that exhibited inhibitory potential. A subset of FDA-approved drugs was evaluated by molecular docking calculations, and compounds with the highest calculated theoretical potency were selected for further analysis. To assess the ability of specific compounds to disrupt IWS1/Spt6 binding, Co-immunoprecipitation (Co-IP) experiments on ddLPS cell line Lipo863 were conducted. Transwell invasion and migration assays were performed to evaluate the effect of the drug candidate on the metastatic potential of cells. Additionally, to evaluate the impact of IWS1 inhibition on spheroid formation, a matrigel extracellular matrix scaffold was employed. Results. Through virtual screening, we identified a class of compounds characterized by a specific chemical pattern featuring a tricyclic fused-ring structure. This class of compounds includes the well-known FDA-approved drug Ketotifen, an antihistamine and mast cell stabilizer. Co-immunoprecipitation of IWS1/Spt6 complex after 48-hour treatment with Ketotifen showed a decrease of over 50% of the isolated complex. Migration and invasion of the ddLPS cell line, Lipo863, were reduced in a dose-dependent manner by 18-44% and 17-52%, respectively, when treated with Ketotifen, without affecting cell viability. In a 3D model, a 14-day treatment of Ketotifen significantly reduced spheroid formation, confirming its impact on tumor growth and cell proliferation. Conclusion. Ketotifen effectively disrupted IWS1/Spt6 complex in vitro. Importantly, it did not affect cell viability while reducing the migratory and invasive potential of ddLPS. The dose-dependent effect of Ketotifen suggests that there may be an optimal in vivo concentration to prevent cells from invading nearby structures and/or metastasizing. We are currently testing the ability of these compounds in preclinical mouse models of ddLPS. Citation Format: Marina Goryunova, Yiran He, Nipin Sp, Elizaveta K. Titerina, Sayumi Tahara, Carson Karakis, Alessandro La Ferlita, Michael Sorkin, Alex Kim, Hua Zhu, Christopher M. Hadad, Raphael E. Pollock, Joal D. Beane. Targeting transcriptional factor IWS1 as a potential treatment of advanced dedifferentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2088.