Abstract 3980: Targeting Ewing sarcoma based on RNA expression

Abstract

Abstract Purpose: Ewing sarcoma (ES) is the second most common malignant bone sarcoma in children and young adults. Current treatment for Ewing sarcoma includes a combination of cytotoxic chemotherapeutic agents and local control with radiation and/or surgery. The survival rate of those with Ewing sarcoma has seen very little improvement over the past several decades and remains dismal for those with recurrent or metastatic disease. The purpose of this study is to identify novel agents currently available for use in Ewing sarcoma. Methods: Novel targeted approaches for the treatment of ES were identified using RNA sequencing performed on 15 ES patient derived cell lines with bioinformatic analysis of gene expression. Targeted agents were tested on patient cell lines at escalating doses. At 48 hours cell viability was assessed with CellTiter-Glo 2.0 and analyzed with GraphPad Prism to determine the IC50. At 24- and 48-hours western blot analysis was performed to evaluate the effect on cell cycle and apoptosis. Combination studies with standard chemotherapy were performed to evaluate for synergy using SynergyFinder 2.0. Results: RNA analysis identified HDAC2, ALK and JAK1 as a potential therapeutic targets. The pan-HDAC inhibitor, Panobinostat, was cytotoxic to all Ewing sarcoma cell lines tested with clinically relevant IC50s (≤200nM) and repressed expression of Cyclin D1 and pRB. ALK inhibition was cytotoxic at doses slightly higher than that of clinical relevance. HDAC and ALK expression levels correlated to cell sensitivity. JAK1 inhibition does not appear to have efficacy at clinically relevant dosing. Panobinostat synergizes with Doxorubicin at clinically relevant doses. Conclusion: This work highlights that RNA expression may identify potential targets which could be effective in treating Ewing sarcoma or potentially improve the efficacy of standard of care drugs. HDAC and ALK inhibition show a decrease in cell viability in ES cell line models. Future studies of HDAC and ALK inhibitors will aim to determine efficacy in xenograft models. Citation Format: Kaitlyn Smith, Divya Gandra, Kimberly McKinney, Karl Dykema, Abhinav Nagulapally, Giselle S. Sholler, Javier Oesterheld, Erin Trovillion. Targeting Ewing sarcoma based on RNA expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3980.