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Targeting Rheostatic Mechanisms of Melanoma Progression

Award Number: R37CA230630
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Targeting Rheostatic Mechanisms of Melanoma Progression - Cutaneous melanoma is highly lethal and the fifth most common cancer in the U.S. Peak incidence is in middle age adults but the elderly, young adults and even children are affected. Among all cancer types, melanoma is one of the most aggressive in its propensity for extremely early metastasis. Metastatic melanoma is difficult to eradicate and new therapies are urgently needed to limit disease progression. Genetic causes of melanoma align along a continuum of RAS protein signaling whereby BRAFV600E mutation is the most common driver. The mutant BRAFV600E protein depends on MAPK signaling for both initiation and maintenance of tumor growth. Targeting this abnormally-activated pathway with RAF and MEK inhibitors have had limited success in treating this disease due to MAPK signaling reactivation, causing drug resistance. Thus, more mechanistic insights are needed in order to develop combination therapies that can circumvent resistance. We reported that aberrant activation of the small GTPase ARF6, a protein that controls intracellular trafficking, accelerates metastasis of BRAFV600E melanoma. Prior to metastasis, our unpublished data reveal that the protein ARF6 is also required for efficient tumor development and growth in mice with BRAFV600E melanoma. This positions ARF6 as a key regulator at multiple points in disease progression. Indeed, our preliminary data suggest a novel role for ARF6 in MAPK signaling by regulating the nuclear localization of activated, phospho-ERK, a key effector protein for BRAF. Thus, we hypothesize that ARF6 modulates BRAFV600E-mediated tumor progression, controlling MAPK signaling and providing a vulnerable node for pharmacologic inhibition of both tumor growth and metastasis. Using genetic and pharmacologic approaches, including our unique mouse models and a specific ARF6 inhibitor that we helped develop, our goals are to dissect the roles of ARF6 in MAPK signaling, discover new role(s) for ARF6 in tumor cell function, and test the efficacy of ARF6 inhibitors in restricting tumor progression. Pursuant to these goals, we will: 1) Test the hypothesis that ARF6 controls MAPK signaling in BRAFV600E-melanoma; 2) Test the hypothesis that ARF6 is critical for proliferation and survival of BRAFV600E melanoma; 3) Test the hypothesis that pharmacologic inhibition of ARF6 has therapeutic efficacy in BRAFV600E melanoma patient-derived xenografts (MPDX). Successful completion of the aims in this proposal will identify new mechanisms of melanoma progression that are amenable to therapeutic intervention and may position ARF6 as a potential therapeutic target in RAS-mutant cancers.


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 = -$331,402 )
2025	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	001	5	7/21/2025	NON-COMPETING CONTINUATION	-$329,285
2025	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	5	4/22/2025	NON-COMPETING CONTINUATION	-$331,402
2025	2024	PROVIDENCE HEALTH & SERVICES - OREGON	1801 LIND AVE SW STE 9016	RENTON	WA	98057	KING	USA	Cancer Biology Research	002	6	7/21/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$329,285
														Subtotal = -$331,402

Issue Date FY: 2024 ( Subtotal = $331,402 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	5	7/2/2024	NON-COMPETING CONTINUATION	$331,402
														Subtotal = $331,402

Issue Date FY: 2023 ( Subtotal = $341,867 )
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	4	7/6/2023	NON-COMPETING CONTINUATION	$341,867
														Subtotal = $341,867

Issue Date FY: 2022 ( Subtotal = $348,844 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	3	6/23/2022	NON-COMPETING CONTINUATION	$348,844
														Subtotal = $348,844

Issue Date FY: 2021 ( Subtotal = $348,844 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	2	6/30/2021	NON-COMPETING CONTINUATION	$348,844
														Subtotal = $348,844

Issue Date FY: 2020 ( Subtotal = $348,844 )
2020	2020	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	1	5/21/2020	NEW	$348,844
														Subtotal = $348,844

Grand Total All Awards = $1,388,399

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Targeting Rheostatic Mechanisms of Melanoma Progression

Award Number: R37CA230630

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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