Abstract
Ewing Sarcoma (ES) is characterized by recurrent translocations between EWSR1 and members of the ETS family of transcription factors. The transcriptional activity of the fusion oncoprotein is dependent on interaction with the nucleosome remodeling and deactylase (NuRD) co-repressor complex. While inhibitors of both histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1) subunits of the NuRD complex demonstrate single agent activity in preclinical models, combination strategies have not been investigated. We selected 7 clinically utilized chemotherapy agents, or active metabolites thereof, for experimentation: doxorubicin, cyclophosphamide, vincristine, etoposide and irinotecan as well as the HDAC inhibitor romidepsin and the reversible LSD1 inhibitor SP2509. All agents were tested at clinically achievable concentrations in 4 ES cell lines. All possible 2 drug combinations were then tested for potential synergy. Order of addition of second-line conventional combination therapy agents was tested with the addition of SP2509. In two drug experiments, synergy was observed with several combinations, including when SP2509 was paired with topoisomerase inhibitors or romidepsin. Addition of SP2509 after treatment with second-line combination therapy agents enhanced treatment effect. Our findings suggest promising combination treatment strategies that utilize epigenetic agents in ES.
Highlights
Ewing sarcoma (ES) is the second most common bone sarcoma affecting children and adolescents
The half maximal inhibitory concentrations (IC50s), simulated maximal plasma concentrations (Cmax), and area under the curves (AUC) were within clinically achievable levels for all drugs selected in most contexts (Fig 1, Table 1, Table 2)
Some variability between cell lines was observed with A673 and TC-71 demonstrating a trend towards tolerance relative to RD-ES and TC32; cell line drug sensitivities were mostly uniform across the cell lines and were uniform for vincristine
Summary
Our aim was to evaluate the inclusion of romidepsin and SP2509, both NuRD complex-directed therapeutics, with agents currently utilized in the treatment of ES
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