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Targeting mechanisms of chromatin plasticity to improve the efficacy of epigenetic solid tumor therapy

Award Number: F99CA305570
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 09/01/2027

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Targeting mechanisms of chromatin plasticity to improve the efficacy of epigenetic solid tumor therapy - PROJECT SUMMARY Aberrant DNA methylation is a hallmark of nearly all human cancers, driving oncogenesis through abnormal gene expression. DNA methyltransferase (DNMT) inhibitors hold promise for reversing these abnormal DNA methylation patterns and act as “priming agents” to enhance immunotherapy in hematological cancers. However, DNMT inhibitors as single-agent therapies have yielded limited clinical benefit in solid tumors due to insufficient DNA demethylation and poorly understood resistance mechanisms. The overarching goal of my F99 training phase is to potentiate the efficacy of DNMT inhibitors for treating solid tumors. Preliminary studies from my dissertation research have demonstrated that DNMT inhibitor treatment elevates UHRF1-dependent histone H3 lysine 18 ubiquitination (H3K18ub), which stimulates the SUV39H1/H2 methyltransferase activity to establish transcriptionally repressive histone H3 lysine 9 tri-methylation (H3K9me3) at tumor suppressor gene (TSG) promoters in colon cancer cells. Disrupting this H3K18ub-directed SUV39H1 activity through loss-of-function mutations in SUV39H1 ubiquitin interaction motif (UIM) enhanced the DNMT inhibitor-mediated TSG reactivations, innate immune response gene upregulations, and anti-proliferation effect in colon cancer cells. I hypothesize that this H3K18ub-H3K9me3 crosstalk is a targetable mechanism that limits DNMT inhibitor efficacy in solid tumors. In Aim 1 (F99 Phase), I will determine the effects of combined SUV39H1 UIM disruption and DNMT inhibition on anti-tumor efficacy and immunotherapy responses using syngeneic colon cancer models. I will also utilize machine learning-based protein design tools to develop SUV39H1 UIM protein/peptide antagonists that might become lead compounds for potential therapeutic development. In Aim 2 (K00 Phase), I will extend these chromatin plasticity insights to improve Chimeric Antigen Receptor (CAR) T cell therapy in solid tumors, leveraging epigenetic modulation to enhance T cell persistence and reduce exhaustion. DNMT3A depletion has been shown to enhance CAR T cell memory and resistance to exhaustion, while it is unclear whether compensatory chromatin modifications in DNMT3A-depleted T cells may limit their therapeutic efficacy in solid tumors. Using a CRISPR screen targeting epigenetic regulators in DNMT3A-depleted CAR T cells, I will identify key factors that synergize with DNMT3A to strengthen CAR T cell function. I will validate top candidates for their effects on T cell persistence, memory formation, and antitumor activity in vitro, and I will assess their potential to sustain durable antitumor responses in vivo. Overall, this project aims to overcome key barriers to DNMT inhibitor and CAR T cell therapies in solid tumors by identifying novel epigenetic vulnerabilities. By bridging fundamental epigenetic research with translational cancer therapy, this project will advance therapeutic strategies for solid tumors and support my development into an independent translational research scientist.


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: 2026 ( Subtotal = $0 )
2026	2025	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Research Manpower	000	1	12/10/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $50,038 )
2025	2025	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Research Manpower	001	1	9/10/2025	NEW	$0
2025	2025	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Research Manpower	000	1	7/29/2025	NEW	$50,038
														Subtotal = $50,038

Grand Total All Awards = $50,038

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Targeting mechanisms of chromatin plasticity to improve the efficacy of epigenetic solid tumor therapy

Award Number: F99CA305570

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 09/01/2027

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