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Characterization and targeting of the epigenetic state underlying uveal melanoma liver metastasis

Award Number: R01CA256193
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/09/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Characterization and targeting of the epigenetic state underlying uveal melanoma liver metastasis - Uveal melanoma (UM) is a highly aggressive and frequently fatal cancer of the eye. While only 2-4% of patients will have detectable metastases at diagnosis, up to 50% of patients later develop metastatic disease, overwhelmingly localized to the liver. Gene expression profiling separates UM to into two sub-groups, low risk Class 1 UM and high risk Class 2 UM. Almost all UMs harbor an initiating mutation in the Gαq signaling pathway, most commonly in GNAQ. Class 2 UMs harbor “progression mutations” in one of several genes that drive tumor progression, the most common being BAP1. Previous studies from our group identified biallelic inactivation of BAP1 as the strongest predictor of liver metastasis in UM. However, the cellular and molecular mechanisms underlying liver metastasis in UM remain undetermined. This gap in our knowledge limits our ability to develop effective adjuvant treatment for high risk patients and systemic treatments for disseminated disease. Gαq signaling activates the MAPK pathway in UM cells, and our preliminary single cell data show that Gαq- mutant UMs are enriched for FOS/JUN transcriptional states. Loss of BAP1 function was associated with escape from senescence, and a de-differentiated phenotype in UM cells that allowed their interaction with hepatic stellate cells, leading to progression of liver metastases and drug resistance. The dedifferentiated state of UM cells was specifically dependent on HDAC1, with HDAC inhibition restoring the differentiated state of UM cells, and increasing the efficacy of MEK inhibition in UM liver metastasis models. The overarching goal of this grant is to define the mechanism by which mutant Gαq and BAP1 loss co-operate to drive UM liver metastasis development. In Aim 1 we will define how BAP1 loss alters the signaling, transcriptional and epigenetic state of Gαq-mutant UM cells to allow senescence to be overcome. In Aim 2, we will address how the cellular state of Gαq-mutant/BAP1-loss UM activates hepatic stellate cells to generate a pro-survival niche in the liver through increased angiogenesis and upregulation of MAPK signaling. In Aim 3, we will explore the HDAC1 dependency of the Gαq-BAP1 loss UM cell state and will validate hits from recent CRISPR screens to identify novel therapeutic approaches to treat UM liver metastases, that we will validate in animal models. At completion of this study, we expect to have defined new approaches to prevent and treat UM liver metastases, that we will explore in clinical trials.


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 = $651,147 )
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	5	8/11/2025	NON-COMPETING CONTINUATION	$651,147
														Subtotal = $651,147

Issue Date FY: 2024 ( Subtotal = $618,592 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	4	8/16/2024	NON-COMPETING CONTINUATION	$618,592
														Subtotal = $618,592

Issue Date FY: 2023 ( Subtotal = $638,384 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	3	7/27/2023	NON-COMPETING CONTINUATION	$638,384
														Subtotal = $638,384

Issue Date FY: 2022 ( Subtotal = $638,640 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	2	8/1/2022	NON-COMPETING CONTINUATION	$638,640
														Subtotal = $638,640

Issue Date FY: 2021 ( Subtotal = $684,278 )
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	1	8/9/2021	NEW	$684,278
														Subtotal = $684,278

Grand Total All Awards = $3,231,041

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Characterization and targeting of the epigenetic state underlying uveal melanoma liver metastasis

Award Number: R01CA256193

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/09/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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