STAT6-targeting Antisense Oligonucleotides against Solitary Fibrous Tumor

Solitary fibrous tumor (SFT) is a rare, non-hereditary soft tissue sarcoma which is thought to originate from fibroblastic mesenchymal stem cells. The etiology of SFT is thought to be due to an environmental intrachromosomal gene fusion between NAB2 and STAT6 genes on chromosome 12. Wherein the activation domain of STAT6 is fused with the DNA-binding domain of NAB2 resulting in the oncogenesis of SFT. All NAB2-STAT6 fusion variations discovered in SFTs contain the C-terminal of STAT6 transcript, and thus can serve as target site for antisense oligonucleotides (ASOs)-based therapies. Indeed, our in vitro studies show the STAT6 3’-untranslated region (UTR)-targeting ASO (ASO 993523) was able to reduce expression of NAB2-STAT6 fusion transcripts in multiple SFT cell models with high efficiency (IC50: 116-300 nM). Encouragingly, In vivo treatment of SFT patient-derived xenograft (PDX) mouse models with ASO 993523 resulted in acceptable tolerability profiles, reduced expression of NAB2-STAT6 fusion transcripts in xenograft tissues (21.9%), and importantly, reduced tumor growth (32.4% decrease in tumor volume compared to the untreated control). Taken together, our study established ASO 993523 as a potential agent for the treatment of SFTs.