Defining fatty acid desaturase 2 (FADS2) as a novel therapeutic target in Ewing sarcoma

About This Grant

Project Summary: Ewing sarcoma is a devastating pediatric malignancy characterized by pathological EWSR1-ETS fusion transcription factors and remains devoid of molecularly targeted therapies. Through unbiased small molecule screening, transcript-level correlational analyses, and mechanistic validation, I have identified a class of compounds—FADS2-dependent cytotoxins (FDCs)—that selectively kill Ewing sarcoma cells by co-opting the oxidative catalytic activity of fatty acid desaturase 2 (FADS2). Mechanistic studies suggest these agents act as non-native substrates that induce a gain-of-toxic-function effect on FADS2, leveraging its catalytic activity to generate superoxide and drive redox collapse. There is a direct positive correlation between FADS2 expression level and increased toxicity to FDCs. Notably, Ewing sarcoma exhibits uniquely and consistently high FADS2 expression across established cancer cell lines and patient-derived tumors, with comparably low expression in non-diseased tissue—suggesting an exploitable therapeutic window. Yet, the mechanistic underpinnings of FDC- induced cytotoxicity and their translational potential in Ewing sarcoma remain uncharacterized. This proposal tests the central hypothesis that aberrantly high FADS2 expression creates a lineage-specific vulnerability that can be pharmacologically exploited with FDCs. In Aim 1, I will define the requirement of FADS2 expression in mediating FDC toxicity using genetic loss-of-function. In Aim 2, I will define the oxidative intermediates formed in response to FDC treatment in a FADS2-dependent manner. In Aim 3, I will evaluate the in vivo efficacy of FDCs in Ewing sarcoma orthotopic xenograft models. Together, these studies will establish a mechanistic framework for FADS2-dependent cytotoxicity, provide preclinical rationale for targeting this metabolic liability in Ewing sarcoma, and advance a novel therapeutic strategy for a disease with urgent unmet clinical need.