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

Award Number: F31CA314408
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $42,696 )
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Research Manpower	001	1	5/19/2026	NEW	$0
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Research Manpower	000	1	5/19/2026	NEW	$42,696
														Subtotal = $42,696

Grand Total All Awards = $42,696

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

Award Number: F31CA314408

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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