Defining fatty acid desaturase 2 (FADS2) as a novel therapeutic target in ewing sarcoma
Active Project Grant Awarded Last action
- Award ID
- F31CA314408
- Recipient
-
Case Western Reserve University UEI HJMKEF7EJW69
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $85,392
Award facts
- Assistance listing
- 93.398 Cancer Research Manpower
- Completion date 0% complete
- Originally
- Place of performance
- Cleveland, OH 44106, USA
Award details come from USAspending.gov.
Description
- Abstract
- 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.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $42,696 | |
| Amendment | $0 | |
| Original award | $42,696 |
Quick answers
Who received award F31CA314408?
F31CA314408 was awarded to Case Western Reserve University by National Cancer Institute (National Institutes of Health) on December 1, 2026.
How much is award F31CA314408 worth?
$85,392 has been obligated on F31CA314408.
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