Wednesday, August 20, 2025 8/20/2025

Defining and targeting epigenetic plasticity-driven drug resistance and immune escape in melanoma

Award Number: R01CA262483
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Defining and targeting epigenetic plasticity-driven drug resistance and immune escape in melanoma - Project summary Melanoma is a heterogeneous tumor, with a high degree of phenotypic plasticity that allows for rapid adaptation to BRAF-MEK inhibitor therapy. Initial therapeutic responses are typically followed by a period of quiescence in which signaling is rewired to evade therapy, followed by the emergence of a bona fide resistant state. Little is known about how the initial persister cell state transitions to an irreversibly resistant state, the role of the immune system in the emergence of these lineages, and whether this resistant state can be targeted. In preliminary studies we identified the type I histone deacetylase HDAC8 as a master regulator of a lineage switch to a resistance-associated melanoma cell state. Activation of HDAC8 alters the phenotype of melanoma cells with loss of function of lineage identity genes such as MITF, increased activity of AP-1/TEAD transcription factors and resistance to therapy. The resistant cell state persisted even after removal of targeted therapy, and was associated with increased mutational load. HDAC8 overexpression also led to the reduced expression of melanoma antigens, increased levels of the immune checkpoint proteins and reduced T cell infiltration. We believe the stability of this state may be at least in part be epigenetic due to altered acetylation and function of transcription factors, cofactors as well as altered function of the cohesin complex involved in chromatin looping, and gene expression. We hypothesize that HDAC8 is a master regulator of a resistance-associated melanoma cell state and represents a target for the prevention of lineage switching. In this proposal, we will use multi-omics approaches (ATAC-Seq, scRNA-Seq, Hi-C, proteomics) to define the mechanisms by which HDAC8 reprograms melanoma cells, and will determine if HDAC8 affects the cohesin complex, leading to fixed resistance-conferring genetic or epigenetic changes. We will utilize a mouse model of BRAF/PTEN-HDAC8-driven melanoma and single cell RNA-Seq to investigate how the HDAC8 modulates the immune microenvironment leading to the emergence of drug resistant melanoma lineages. We will specifically determine whether HDAC8 drives a transcriptional program associated with decreased MHC class I and antigen expression leading to decreased tumor-T cell recognition. Further studies will define whether JUN-mediated transcription of IL-11 reprograms the myeloid compartment leading to a suppressive melanoma immune environment that eradicates tumor-reactive CD8 T cells. CRISPR screens will be performed to identify targets to prevent the emergence of drug resistant lineages in mouse models. We will then evaluate these targets and HDAC8 inhibitors as strategies to improve therapeutic responses to BRAF-MEK inhibitor and immune checkpoint inhibitor therapy in syngeneic mouse melanoma models. We expect that new insights into the mechanisms underpinning the emergence and maintenance of drug resistant lineages in melanoma will lead to the development of new therapeutic strategies to improve the depth and duration of responses to immunotherapy and targeted therapy in melanoma. Our findings will have important implications across multiple cancer types and many different therapies.


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 = $485,968 )
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	4	6/25/2025	NON-COMPETING CONTINUATION	$485,968
														Subtotal = $485,968

Issue Date FY: 2024 ( Subtotal = $463,483 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	3	7/9/2024	NON-COMPETING CONTINUATION	$463,483
														Subtotal = $463,483

Issue Date FY: 2023 ( Subtotal = $478,486 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	2	7/6/2023	NON-COMPETING CONTINUATION	$478,486
														Subtotal = $478,486

Issue Date FY: 2022 ( Subtotal = $498,307 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	1	7/15/2022	NEW	$498,307
														Subtotal = $498,307

Grand Total All Awards = $1,926,244

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Defining and targeting epigenetic plasticity-driven drug resistance and immune escape in melanoma

Award Number: R01CA262483

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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