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Engrailed-1 and Epigenetic Vulnerabilities in Metastatic Pancreatic Cancer

Award Number: R37CA249007
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2028

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Engrailed-1 and Epigenetic Vulnerabilities in Metastatic Pancreatic Cancer - Abstract Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers, largely due to its aggressive nature and resistance to therapies. Our research focuses on the transcription factor EN1, a key regulator of the epigenome in PDA. During the R37 grant period, we made significant progress in understanding EN1's role in pancreatic cancer, including the establishment of PDA patient-derived organoids (PDOs), characterization of En1-deficient pancreatic cancer mouse models, and detailed investigation of the pancreatic epigenome upon EN1 perturbations. In the proposed 2-year extension period, we aim to expand our investigation into EN1's role in PDA through two new sub-aims. Aim 1D will explore the role of EN1 in topologically associating domains (TADs) during PDA progression. We hypothesize that EN1 modulates promoter-enhancer (PE) loop formations, impacting chromatin architecture and gene expression. To test this, we will profile tumor- and metastasis-derived organoids using Hi-C sequencing and perform genetic perturbation experiments to assess the effects of EN1 on TAD structures. This study will provide insights into how EN1-mediated changes in chromatin organization contribute to PDA progression and metastasis. Aim 2D seeks to identify and understand the roles of EN1- interacting partners in gene regulation. Preliminary IP-MS data have identified several negative regulators of transcription as EN1-interacting partners, including EZH2. We will validate these interactions through co- immunoprecipitation and investigate their functional roles using genetic and pharmacological perturbations. The proposed research aims to deepen our understanding of EN1's role in PDA by investigating its impact on TAD structures and its interactions with other transcriptional regulators. The outcomes of this study have the potential to uncover novel mechanisms driving PDA progression and identify new targets for therapeutic intervention, ultimately contributing to the development of more effective treatments for this aggressive cancer.


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 = $357,267 )
2026	2026	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Biology Research	000	6	3/4/2026	EXTENSION WITH OR WITHOUT FUNDS	$357,267
														Subtotal = $357,267

Issue Date FY: 2025 ( Subtotal = $354,974 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Biology Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$35,497
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Biology Research	000	5	2/12/2025	NON-COMPETING CONTINUATION	$319,477
														Subtotal = $354,974

Issue Date FY: 2024 ( Subtotal = $337,341 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Biology Research	000	4	2/8/2024	NON-COMPETING CONTINUATION	$319,585
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Biology Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$17,756
														Subtotal = $337,341

Issue Date FY: 2023 ( Subtotal = $348,109 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Biology Research	000	3	2/24/2023	NON-COMPETING CONTINUATION	$348,109
														Subtotal = $348,109

Issue Date FY: 2022 ( Subtotal = $355,328 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Biology Research	001	2	5/3/2022	NON-COMPETING CONTINUATION	$35,533
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Biology Research	000	2	2/21/2022	NON-COMPETING CONTINUATION	$319,795
														Subtotal = $355,328

Issue Date FY: 2021 ( Subtotal = $346,099 )
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Biology Research	000	1	3/8/2021	NEW	$346,099
														Subtotal = $346,099

Grand Total All Awards = $2,099,118

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Engrailed-1 and Epigenetic Vulnerabilities in Metastatic Pancreatic Cancer

Award Number: R37CA249007

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2028

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