Seclidemstat (SP-2577) Induces Transcriptomic Reprogramming and Cytotoxicity in Multiple Fusion-Positive Sarcomas.

UNLABELLED

Genes encoding the RNA-binding proteins FUS, EWSR1, and TAF15 (FET proteins) are involved in chromosomal translocations in rare sarcomas. The encoded fusion oncoproteins typically include a DNA-binding domain and function as oncogenic transcription factors. FET-rearranged sarcomas are often aggressive malignancies affecting patients of all ages. Oncogenic fusion transcription factors are challenging to target directly, and new therapies are needed. Treatment with the small molecule SP-2509 results in reversal of the transcriptional activity of the FET fusion that causes Ewing sarcoma, EWSR1::FLI1. A similar molecule, seclidemstat (SP-2577), is currently in clinical trials for FET-rearranged sarcomas (NCT03600649), but its pharmacologic activity in FET fusion-positive sarcomas has not been demonstrated. We found potent seclidemstat cytotoxicity against both FET-rearranged and other fusion-positive sarcoma cell lines in vitro, including Ewing sarcoma, desmoplastic small round cell tumor, clear cell sarcoma, myxoid liposarcoma, and fusion-positive rhabdomyosarcoma. We also define transcriptomic effects of seclidemstat with bulk RNA sequencing. Seclidemstat recapitulated much of SP-2509 transcriptional activity in Ewing sarcoma. Widespread transcriptional changes were seen in all tested cell lines after seclidemstat treatment, regardless of the fusion protein expressed. This included reversal of FET fusion transcriptional signatures for EWSR1::WT1, EWSR1::ATF1, and EWSR1::ERG. Though novel inhibitors are unlikely to display single-agent efficacy in the clinic, these data suggest that seclidemstat remains a promising new treatment strategy for patients with FET-rearranged and other fusion-positive sarcomas.

SIGNIFICANCE

In this study, we show seclidemstat has in vitro activity in multiple rare and aggressive sarcomas caused by FET fusion proteins. With 13 RNA sequencing experiments, including multiple FET-rearranged sarcoma cell lines, this dataset is a rich resource for those studying FET-rearranged sarcomas.