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Using dietary glutamine supplementation for melanoma prevention and targeted therapy

Award Number: R01CA244360
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Using dietary glutamine supplementation for melanoma prevention and targeted therapy - PROJECT SUMMARY Despite recent advances in cancer metabolism, whether and how nutritional interventions affect tumor development, metastasis and therapeutic response are still poorly understood. Thus, the goal of this study is to elucidate the effect of glutamine supplementation on tumor development and therapeutic responses, and eventually provide molecular evidence that nutritional interventions on cancer patients can inhibit tumor growth and sensitize tumors to treatments. Using metabolomic analysis, we and others have found that, compared to other amino acids, many solid tumor cells are situated in a glutamine poor environment in vivo. Interestingly, we found that glutamine deficiency in melanoma tumors resulted in cancer cell de-differentiation and resistance to treatment due to increased histone methylation levels. This finding further prompted us to test if increases in glutamine levels through dietary supplementation can be detrimental to tumor cells that have been well adapted to a low glutamine environment. Our preliminary data demonstrated that supplementation of glutamine in the diet is sufficient to increase tumoral α-ketoglutarate levels and leads to decreased histone methylation in melanoma patient-derived xenograft (PDX) tumors. Importantly, we found that high glutamine diet significantly hinders tumor growth and decreases expression of melanoma-associated oncogenes compared to control diet. In support with this, accumulating evidence from in vivo experiments demonstrate that glutamine is not an essential nutritional source to support TCA cycle and tumor growth. Thus, we hypothesize that dietary glutamine supplementation inhibits melanoma tumor growth and sensitizes tumor cells to current treatments via epigenetic reprogramming. In this proposal, we will 1) determine the effect of dietary glutamine supplementation on melanoma tumor growth, metabolism and oncogene expression in vivo; 2) determine the molecular mechanisms by which glutamine supplementation inhibits tumor growth; 3) investigate the effect of glutamine supplementation in response to BRAF/MEK inhibitors and immunotherapy for melanoma treatment. Despite many proven clinical benefits of glutamine supplementation to cancer patients, recent in vitro studies showing that tumor cells are avid glutamine consumers led to cautionary usage of dietary glutamine on cancer patients. Completion of the proposed studies will provide insight into glutamine driven epigenetic regulation and its effect on tumor growth. The results of these studies will reveal a novel therapeutic direction for using dietary glutamine supplementation to prevent tumor growth and enhance therapeutic responses without detrimental side effects.


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 = $424,991 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Cause and Prevention Research	000	5	8/5/2025	NON-COMPETING CONTINUATION	$424,991
														Subtotal = $424,991

Issue Date FY: 2024 ( Subtotal = $403,742 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Cause and Prevention Research	000	4	6/12/2024	NON-COMPETING CONTINUATION	$403,742
														Subtotal = $403,742

Issue Date FY: 2023 ( Subtotal = $410,444 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Cause and Prevention Research	000	3	7/4/2023	NON-COMPETING CONTINUATION	$410,444
														Subtotal = $410,444

Issue Date FY: 2022 ( Subtotal = $419,220 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Cause and Prevention Research	000	2	7/1/2022	NON-COMPETING CONTINUATION	$419,220
														Subtotal = $419,220

Issue Date FY: 2021 ( Subtotal = $436,727 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Cause and Prevention Research	000	1	3/15/2021	NEW	$436,727
														Subtotal = $436,727

Grand Total All Awards = $2,095,124

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Using dietary glutamine supplementation for melanoma prevention and targeted therapy

Award Number: R01CA244360

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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