Tuesday, September 16, 2025 9/16/2025

Targeting Lipid Metabolism in Colorectal Cancer

Award Number: R01CA249734
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Targeting Lipid Metabolism in Colorectal Cancer - PROJECT SUMMARY Metastasis is the main cause of death from solid tumors including colorectal cancer (CRC). Our long-term goal is to develop more selective therapeutic options to prevent or reduce the incidence of CRC metastasis by understanding how changes in fatty acid metabolism contribute to metastatic disease. Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated and activated in CRC, and its activity is associated with poor prognosis, higher risk of disease recurrence, and death. We identified FASN as a potential target for advanced CRC and showed that upregulation of this enzyme is a key mechanism supporting metastasis in CRC. However, the underlying mechanisms of FASN regulation of metastasis and potential mechanism of resistance to FASN inhibition are not understood. The current application proposes a comprehensive research plan to study novel mechanisms of regulation of CRC metastasis by lipid metabolism. Our preliminary data suggest that the primary product of de novo fatty acid synthesis, palmitate, is selectively used for sphingolipid synthesis. Overexpression of FASN selectively regulates activity of SphK1 and SphK2 and increases the level of sphingosine-1-phosphate (S1P), a bioactive sphingolipid implicated in metastasis. Therefore, in Aim 1, we will test the hypothesis that FASN enhances metastasis by upregulating the SphK/S1P axis and we will determine the contributions of SphK1 and SphK2 to CRC metastasis. Furthermore, our preliminary studies show a correlation between expression of FASN and CD36, a fatty acid translocase responsible for exogenous FA uptake. Our data show that inhibition of FASN leads to upregulation of CD36 and it can be a potential mechanism of resistance to novel FASN inhibitors that are currently being tested in Phase II clinical trials. Therefore, in Aim 2, we will elucidate how FASN regulates CD36 and determine molecular mechanisms by which upregulation of CD36 contributes to CRC metastasis including the effect of CD36 upregulation on sphingolipid metabolism and S1P synthesis. In Aim 3, we will test whether inhibition of FA uptake via CD36 will increase efficacy of a novel FASN inhibitor TVB-3664 in CRC. We will utilize biological samples from patients, human primary CRC cells, tumor organoids established from genetically modified mice and CRC metastasis models, which are the most advanced models for pre-clinical target and drug evaluations. These models will be used in conjunction with state-of-the-art approaches, including targeted and stable isotope-resolved metabolomics (SIRM), to evaluate the effect of alteration in lipid synthesis and FA uptake on cancer cell metabolism. These studies have a high translational impact since CD36 and FASN inhibitors are currently tested in multiple pre-clinical studies and Phase I-II clinical trials and there is urgent need for more research and knowledge on their effects in CRC. Beside validation of FASN, SphKs and CD36 as therapeutic targets in CRC, the comprehensive analysis of metabolic and signaling pathways proposed in the current application also have the potential to identify new druggable targets and therapeutic strategies for CRC.


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: 2025 ( Subtotal = $346,432 )
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cancer Biology Research	000	5	3/6/2025	NON-COMPETING CONTINUATION	$311,789
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cancer Biology Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$34,643
														Subtotal = $346,432

Issue Date FY: 2024 ( Subtotal = $329,272 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cancer Biology Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$17,331
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cancer Biology Research	000	4	3/25/2024	NON-COMPETING CONTINUATION	$311,941
														Subtotal = $329,272

Issue Date FY: 2023 ( Subtotal = $339,827 )
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cancer Biology Research	000	3	2/28/2023	NON-COMPETING CONTINUATION	$339,827
														Subtotal = $339,827

Issue Date FY: 2022 ( Subtotal = $346,916 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cancer Biology Research	000	2	3/18/2022	NON-COMPETING CONTINUATION	$312,224
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cancer Biology Research	001	2	5/17/2022	NON-COMPETING CONTINUATION	$34,692
														Subtotal = $346,916

Issue Date FY: 2021 ( Subtotal = $347,063 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cancer Biology Research	000	1	3/17/2021	NEW	$347,063
														Subtotal = $347,063

Grand Total All Awards = $1,709,510

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Targeting Lipid Metabolism in Colorectal Cancer

Award Number: R01CA249734

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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