(P 462) HDAC INHIBITORS AS POTENTIAL SFT THERAPIES

Objective: Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm occurring with an incidence of 1 case/million people/year. Typically, slow growing and asymptomatic, SFT can occur in various anatomical locations. Intrachromosomal rearrangement results in the pathognomonic oncogenic fusion of NGFI-A-binding protein 2 (Nab2) and signal transducer and activator of transcription 6 (Stat6). Based on the different exons of the two genes involved, there are several fusion variants, with the most frequent being Nab2ex4-Stat6ex2 and Nab2ex6-Stat6ex16/ex17. No FDA approved treatments exist to manage SFT. Our study aims to identify potential new therapies to treat SFT and generate new insights into disease mechanisms.

Methods: To identify potential therapeutic vulnerabilities in SFT, we performed a small-molecule screen of 318 compounds inclusive of epigenetic and metabolic compounds in isogenic lung fibroblast cell lines with Nab2ex6-Stat6exex17 fusion (Lf-ns) and without fusion (Lf). LC-MS based targeted metabolomics was performed for mechanistic insights.

Results: The small molecule library screen yielded HDAC inhibitors (HDACi) as top potential candidates. Romidespin, a prodrug activated by reduced glutathione (GSH) was found to be the most potent HDACi with a 5-fold lesser IC50 in Lf-ns cells implicating increased sensitivity to HDACi. Metabolomics revealed increased levels of GSH in Lf-ns cells thus resulting in increased levels of oxidized glutathione (GSSG) after Romidepsin treatment. Therefore, altered metabolism could possibly explain increased sensitivity of N-S expressing cells to Romidepsin.

Conclusion: In conclusion, HDACi Romidepsin shows selective efficacy in Nab2-Stat6 expressing cells, potentially due to metabolic reprogramming. These findings highlight HDAC inhibition as a promising therapeutic strategy for SFT. Building on these findings, the ongoing work explores mechanisms of action and synergistic FDA-approved drug combinations, focused on proteasome inhibitors.