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Role of AMPK in melanoma brain metastasis

Award Number: R01CA276448
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Role of AMPK in melanoma brain metastasis - Project Summary: AMP activated protein kinase (AMPK) is a critical evolutionarily conserved energy sensor that regulates energy homeostasis by monitoring changes in the intracellular AMP or ADP to ATP ratios. Mounting evidence supports that the AMPK pathway is one of the major signaling players at the interface of metabolism and cancer. However, the role of AMPK in tumor progression and metastasis remains obscure. Our recent analysis on melanoma cancer genomics data has revealed that the mutations in the PRKAA2 gene, which encodes the alpha 2 catalytic subunit of AMPK, occur in 8-10% of cutaneous melanomas and tend to co-occur with NF1 mutations. In our preliminary studies, we found that knockout of AMPKα2 promoted anchorage-independent growth of mutant NF1-melanoma cells in soft agar assays and their growth as xenografted tumors in nude mice. Importantly, we found that expression of AMPKα2 is significantly downregulated in human melanoma brain metastasis samples compared to patient-matched extracranial metastasis samples. Furthermore, knockout of AMPKα2 promoted brain metastasis of NF1-mutant Mewo melanoma cells in nude mice. Based on these preliminary results, we hypothesize that inactivation of AMPKα2 in melanoma promotes tumor progression to melanoma brain metastasis. In Aim 1, we will establish the role of AMPKα2 in melanoma brain metastasis using mouse models and human samples. We plan to characterize the effects of AMPKα2 loss in both syngeneic and genetically engineered mouse models. Human melanoma brain metastasis samples will be used to explore the contribution of AMPKα2 loss through spatial single cell RNA-seq analyses. In aim 2, we will characterize downstream targets of AMPK involved in the metabolic regulation of melanoma brain metastasis. We will investigate the contribution of a novel putative substrate of AMPKα2 involved in de novo lipogenesis, identified in our preliminary studies, to melanoma brain metastasis, and explore additional new AMPKα2 targets through comprehensive metabolomics and RPPA analyses of tumor samples from mouse models. In aim 3, we will assess the therapeutic effects of metabolic drugs targeting the AMPK pathway on enhancing the efficacies of targeted- and immune- therapies in melanoma brain metastasis using human melanoma xenografts, syngeneic and genetically engineered mouse models. To achieve these aims, we have assembled a team of investigators with various expertise including cancer cell metabolism, melanoma brain metastasis biology, melanoma oncologists/surgeon and computational biology. Our study will not only provide critical insights into the role of AMPK metabolic signaling in melanoma brain metastasis addressing a significant knowledge gap in the field, but also identify novel therapeutic approaches to target melanoma brain metastasis.


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 = $671,615 )
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	004	4	6/3/2025	NON-COMPETING CONTINUATION	$67,161
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	001	4	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	4	1/3/2025	NON-COMPETING CONTINUATION	$604,454
2025	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	003	2	2/14/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$169,206
2025	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Biology Research	002	1	2/14/2025	NEW	-$169,206
														Subtotal = $671,615

Issue Date FY: 2024 ( Subtotal = $637,432 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	003	3	4/16/2024	NON-COMPETING CONTINUATION	$33,551
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	002	3	1/5/2024	NON-COMPETING CONTINUATION	$603,881
2024	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Biology Research	000	1	11/10/2023	NEW	-$188,216
2024	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	001	2	11/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$188,216
														Subtotal = $637,432

Issue Date FY: 2023 ( Subtotal = $687,382 )
2023	2023	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Biology Research	000	1	12/19/2022	NEW	$687,382
														Subtotal = $687,382

Grand Total All Awards = $1,996,429

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Role of AMPK in melanoma brain metastasis

Award Number: R01CA276448

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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