Development of targeted therapies against FET oncogene sarcomas

Abstract

FET oncogene sarcomas are fusion-driven malignancies characterized by gene fusions involving one of the genes FUS, EWSR1 or TAF15, fused to a transcription factor partner. FET oncogene sarcomas comprise more than ten different sarcoma entities, with myxoid liposarcoma (MLS) and Ewing sarcoma (EWS) being the most prevalent. Current treatments for advanced disease in MLS and EWS rely on chemotherapy, but outcomes remain poor. New therapies and improved methods to assess treatment efficacy are urgently needed. The aim of this project was to explore potential targeted therapies in preclinical models of MLS and EWS. Initially, we analyzed receptor tyrosine kinase (RTK) signaling in MLS and tested the efficacy of targeted RTK inhibitors. Overall, they showed limited therapeutic benefit, likely due to compensatory crosstalk between different RTKs facilitated by the chaperone protein HSP90. We subsequently evaluated the HSP90 inhibitor 17-DMAG in both MLS cell lines and a patient-derived xenograft (PDX) model of MLS, observing potent anti-tumor effect. Various HSP90 inhibitors then demonstrated comparable efficacy in vitro, while the in vivo effects varied significantly between inhibitors. Next, we investigated tumor vessel formation in MLS and found that the tumor vasculature was enriched with pericytes. Additionally, we observed increased PDGFB-PDGFRB signaling, suggesting the presence of an autocrine loop that may influence both cell survival and vascular architecture. Targeting PDGFRB with the multi-RTK inhibitor imatinib caused tumor regression in vivo, though it did not noticeably alter the vascular morphology. We then pursued another treatment strategy targeting epigenetic dysregulation caused by the FET fusion oncoproteins. Combined inhibition of BRD4 and histone deacetylases, both epigenetic proteins, resulted in synergistic effects in vitro and significant tumor regression in vivo. Finally, we explored the use of circulating tumor DNA and inflammatory protein profiles as informative blood-based biomarkers for treatment monitoring. We demonstrated that simultaneous ctDNA and inflammatory protein quantification can be used to monitor treatment response and provide complementary tumor-related data in a patient with metastatic undifferentiated pleomorphic sarcoma. In conclusion, our findings add to the understanding of dysregulated signaling pathways in FET oncogene sarcomas and potential targeted therapies to be further evaluated in clinical trials. Furthermore, incorporating quantification of novel blood-based biomarkers may enhance the precision and adaptability of future clinical trials, ultimately improving patient outcomes through real-time response assessment.