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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Genes encoding FET proteins (FUS, EWSR1, TAF15) drive rare, aggressive sarcomas via fusion oncoproteins.
• Oncogenic transcription factors (TFs) are difficult to target directly, necessitating new therapeutic strategies.
• Seclidemstat (SP-2577) is a small molecule in clinical trials for FET-rearranged sarcomas, but its activity requires demonstration.

Purpose of the Study:

• To evaluate the pharmacological activity and cytotoxicity of seclidemstat in various FET-rearranged and fusion-positive sarcoma cell lines.
• To define the transcriptomic effects of seclidemstat treatment using bulk RNA sequencing.
• To assess seclidemstat's potential as a novel therapeutic agent for fusion-driven sarcomas.

Main Methods:

• In vitro cytotoxicity assays on multiple sarcoma cell lines.
• Bulk RNA sequencing to analyze transcriptomic changes after seclidemstat treatment.
• Comparison of seclidemstat's transcriptional effects with SP-2509 in Ewing sarcoma.

Main Results:

• Seclidemstat demonstrated potent cytotoxicity against FET-rearranged and other fusion-positive sarcoma cell lines.
• Transcriptomic analysis revealed widespread transcriptional changes induced by seclidemstat across all tested cell lines.
• Seclidemstat reversed FET-fusion transcriptional signatures, including EWSR1::WT1, EWSR1::ATF1, and EWSR1::ERG, and recapitulated SP-2509 activity in Ewing sarcoma.

Conclusions:

• Seclidemstat exhibits significant anti-cancer activity and reverses oncogenic transcriptional programs in diverse fusion-positive sarcomas.
• Despite challenges with single-agent efficacy, seclidemstat represents a promising therapeutic strategy for patients with FET-rearranged and other fusion-driven sarcomas.