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Defining the Role of Renal Gluconeogenesis in Renal Cell Carcinoma

Award Number: R37CA258261
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/12/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026
AWARD TERMINATION DATE: 04/25/2025

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Defining the Role of Renal Gluconeogenesis in Renal Cell Carcinoma - Project Summary Renal cell carcinoma is the most common primary kidney cancer, representing 90-95% of primary renal neoplasms. Obesity and diabetes are associated with an increased risk of renal cell carcinoma, but the mechanisms by which systemic metabolic changes promote tumor progression are unknown. Although its reputation as a glucose-producing organ has been dwarfed by that of the liver over the years, the kidney possesses the same complement of gluconeogenic enzymes as the liver – with a higher concentration of gluconeogenic proteins per gram of tissue in the kidney, suggesting that its gluconeogenic capacity may even exceed the liver's. Glucose is well-known to be a crucial substrate for tumor growth; given the gluconeogenic activity of the kidney, it is likely that increased renal gluconeogenesis may fuel tumor growth. However, this phenomenon, and its mechanistic explanation, remains to be explored. We have recently found that fibroblast growth factor-21 (FGF-21) promotes renal gluconeogenesis during starvation by activating intrarenal lipolysis through a 2-adrenergic pathway, thereby activating pyruvate carboxylase flux in healthy rodents. Therefore, this proposal will test the Overarching Hypothesis that in renal cell carcinoma, increased FGF-21 acts through a similar mechanism to promote intrarenal lipolysis, pyruvate carboxylase activity, and as a result, gluconeogenesis, and that this increased renal glucose supply fuels tumor growth. We will also examine the utility of an FGF-21 neutralizing antibody against mice genetically prone to renal cell carcinoma, which we anticipate will reduce renal gluconeogenesis and renal cell carcinoma progression. If the hypotheses are confirmed, these data would identify FGF-21 – which is already being targeted in advanced clinical trials for metabolism- and diabetes-related indications – as a potential therapeutic target in renal cell carcinoma.


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 = $400,213 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Biology Research	000	5	1/16/2026	NON-COMPETING CONTINUATION	$400,213
														Subtotal = $400,213

Issue Date FY: 2025 ( Subtotal = $444,681 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Biology Research	000	4	2/13/2025	NON-COMPETING CONTINUATION	$400,213
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Biology Research	001	4	3/14/2025	NON-COMPETING CONTINUATION	$0
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Biology Research	004	4	6/10/2025	NON-COMPETING CONTINUATION	$44,468
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Biology Research	003	4	4/25/2025	NON-COMPETING CONTINUATION	$0
2025	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Biology Research	002	3	4/24/2025	TERMINATION	$0
														Subtotal = $444,681

Issue Date FY: 2024 ( Subtotal = $469,368 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Biology Research	001	3	4/16/2024	NON-COMPETING CONTINUATION	$22,234
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Biology Research	002	3	9/4/2024	SUPPLEMENT FOR EXPANSION	$46,921
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Biology Research	000	3	1/12/2024	NON-COMPETING CONTINUATION	$400,213
														Subtotal = $469,368

Issue Date FY: 2023 ( Subtotal = $435,786 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Biology Research	000	2	12/8/2022	NON-COMPETING CONTINUATION	$400,213
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Biology Research	001	2	3/14/2023	NON-COMPETING CONTINUATION	$35,573
														Subtotal = $435,786

Issue Date FY: 2022 ( Subtotal = $444,681 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Biology Research	000	1	1/12/2022	NEW	$444,681
														Subtotal = $444,681

Grand Total All Awards = $2,194,729

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Defining the Role of Renal Gluconeogenesis in Renal Cell Carcinoma

Award Number: R37CA258261

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/12/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

AWARD TERMINATION DATE: 04/25/2025

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