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A High-Throughput Model for Human Melanoma

Award Number: R01CA121118
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/13/2007
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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A High-Throughput Model for Human Melanoma - Significant advances in melanoma research have resulted in new therapies that have remarkably improved the management and overall survival of melanoma. However, many patients still succumb to the disease and more than half of all melanoma deaths are due to brain metastases. As a means to overcome this challenge, we developed a novel mouse model that allows postnatal delivery of genes of interest to melanocytes. Using genomic and proteomic data from human melanoma samples, we tested several gene combinations for their ability to induce metastatic melanoma in vivo. Hyperactivation of the PI3K/AKT pathway in the context of mutant BRAF and CDKN2A loss resulted in the development of spontaneous melanoma with full penetrance and a mean survival of only 6 weeks. The majority of these mice also developed multiple metastases to the lungs and brain. This model mimics the human disease genetically, histologically, and by sites of metastasis. Importantly, this model system provides a powerful platform to further study the mechanisms of melanoma metastasis. Elucidation of this network will allow the identification of key pathway nodes that represent potential therapeutic targets to disrupt this process. We used next generation sequencing and proteomics analysis of non-metastatic and metastatic tumor samples to identify downstream targets of AKT1 implicated in melanoma brain metastasis. Our data showed that tumors expressing activated AKT1 displayed elevated levels of focal adhesion (FA) factors and phosphorylated focal adhesion kinase (P-FAK). In addition, mutant AKT1 expression increased invasion and this was reduced by pharmacological inhibition of either AKT or FAK. Moreover, loss of PTEN, which also results in increased FAK activity, cooperated with activated AKT1 to further enhance brain metastasis in vivo. Despite these promising preliminary findings, a critical gap still remains in understanding whether and how FAK promotes melanoma brain metastasis, and whether the AKT1-FAK-PTEN axis can be exploited as a therapeutic target in this disease. Our long-term goal is to use this knowledge to develop novel melanoma therapies and improve patient outcomes. Pursuant to this goal, we have generated a diverse collection of state-of-the-art research tools and assembled a talented team of scientists and clinicians with a track record of productive collaboration to carry out and critically evaluate the results of the proposed aims. Using these unique resources, we propose to test the following hypotheses: 1) AKT1→ FAK signaling is essential for the development of melanoma brain metastases; 2) Combined inhibition of BRAFV600E, MEK, and FAK is superior to standard of care targeted therapy and; 3) Loss of PTEN expression results in sustained FAK phosphorylation, which enhances the development of melanoma brain metastases. Successful completion of the aims in this proposal will significantly impact the field by laying the groundwork for translation into clinical trials, leading to new and better treatments for patients with brain metastases and those who are at high risk of developing brain metastases.


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 = $289,750 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	15	11/7/2024	NON-COMPETING CONTINUATION	$260,775
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	001	15	6/3/2025	NON-COMPETING CONTINUATION	$28,975
														Subtotal = $289,750

Issue Date FY: 2024 ( Subtotal = $275,263 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	14	11/6/2023	NON-COMPETING CONTINUATION	$260,775
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	001	14	4/16/2024	NON-COMPETING CONTINUATION	$14,488
														Subtotal = $275,263

Issue Date FY: 2023 ( Subtotal = $289,750 )
2023	2023	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	13	12/1/2022	NON-COMPETING CONTINUATION	$260,775
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	002	13	9/18/2023	NON-COMPETING CONTINUATION	$5,795
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	001	13	3/15/2023	NON-COMPETING CONTINUATION	$23,180
														Subtotal = $289,750

Issue Date FY: 2022 ( Subtotal = $283,955 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	001	12	5/20/2022	NON-COMPETING CONTINUATION	$23,180
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	12	11/25/2021	NON-COMPETING CONTINUATION	$260,775
														Subtotal = $283,955

Issue Date FY: 2021 ( Subtotal = $414,750 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	001	11	11/23/2020	COMPETING CONTINUATION	$289,750
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	003	11	6/15/2021	SUPPLEMENT FOR EXPANSION	$125,000
2021	2018	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	002	10	3/24/2021	NON-COMPETING CONTINUATION	$0
2021	2018	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	10	11/23/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $414,750

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	10	4/24/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $247,340 )
2018	2018	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	10	4/23/2018	NON-COMPETING CONTINUATION	$247,340
														Subtotal = $247,340

Issue Date FY: 2017 ( Subtotal = $247,340 )
2017	2017	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	9	5/19/2017	NON-COMPETING CONTINUATION	$247,340
														Subtotal = $247,340

Issue Date FY: 2016 ( Subtotal = $247,340 )
2016	2016	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	8	5/3/2016	NON-COMPETING CONTINUATION	$247,340
														Subtotal = $247,340

Issue Date FY: 2015 ( Subtotal = $250,535 )
2015	2015	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	7	5/12/2015	NON-COMPETING CONTINUATION	$250,535
														Subtotal = $250,535

Issue Date FY: 2014 ( Subtotal = $250,535 )
2014	2014	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	6	5/22/2014	COMPETING CONTINUATION	$250,535
2014	2010	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	001	5	9/19/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $250,535

Issue Date FY: 2013 ( Subtotal = $59,552 )
2013	2013	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	5	9/12/2013	SUPPLEMENT FOR EXPANSION	$59,552
														Subtotal = $59,552

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2010	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	001	5	12/20/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$179,400
2012	2010	NEVADA CANCER INSTITUTE	1000 WEST CHARLESTON BOULEVARD	LAS VEGAS	NV	89135	CLARK	USA	Cancer Biology Research	000	4	12/20/2011	NON-COMPETING CONTINUATION	-$179,400
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $189,600 )
2010	2010	NEVADA CANCER INSTITUTE	1000 WEST CHARLESTON BOULEVARD	LAS VEGAS	NV	89135	CLARK	USA	Cancer Biology Research	000	4	1/21/2010	NON-COMPETING CONTINUATION	$189,600
														Subtotal = $189,600

Issue Date FY: 2009 ( Subtotal = $911,204 )
2009	2009	NEVADA CANCER INSTITUTE	1000 WEST CHARLESTON BOULEVARD	LAS VEGAS	NV	89135	CLARK	USA	Cancer Biology Research	000	3	1/16/2009	NON-COMPETING CONTINUATION	$170,640
2009	2009	NEVADA CANCER INSTITUTE	1000 WEST CHARLESTON BOULEVARD	LAS VEGAS	NV	89135	CLARK	USA	Trans-NIH Recovery Act Research Support	003	3	5/29/2009	SUPPLEMENT FOR EXPANSION	$208,080
2009	2009	Nevada Cancer Institute	STE 260	IAS VEGAS	NV	89135		USA	Trans-NIH Recovery Act Research Support	002	3	9/18/2009	SUPPLEMENT FOR EXPANSION	$513,524
2009	2009	NEVADA CANCER INSTITUTE	1000 WEST CHARLESTON BOULEVARD	LAS VEGAS	NV	89135	CLARK	USA	Cancer Biology Research	001	3	3/20/2009	NON-COMPETING CONTINUATION	$18,960
														Subtotal = $911,204

Issue Date FY: 2008 ( Subtotal = $189,600 )
2008	2008	NEVADA CANCER INSTITUTE	1000 WEST CHARLESTON BOULEVARD	LAS VEGAS	NV	89135	CLARK	USA	Cancer Biology Research	000	2	1/28/2008	NON-COMPETING CONTINUATION	$189,600
														Subtotal = $189,600

Issue Date FY: 2007 ( Subtotal = $229,100 )
2007	2007	NEVADA CANCER INSTITUTE	1000 WEST CHARLESTON BOULEVARD	LAS VEGAS	NV	89135	CLARK	USA	Cancer Biology Research	000	1	4/13/2007	NEW	$229,100
														Subtotal = $229,100

Grand Total All Awards = $4,375,614

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A High-Throughput Model for Human Melanoma

Award Number: R01CA121118

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/13/2007

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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