Thursday, January 8, 2026 1/8/2026

Targeting HNF1A-mediated therapeutic resistance in pancreatic ductal adenocarcinoma

Award Number: R37CA275961
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/03/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Targeting HNF1A-mediated therapeutic resistance in pancreatic ductal adenocarcinoma - Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers with a survival rate of 11% due to its aggressive nature and resistance to therapies. While nearly all PDA cases are driven by mutations in the KRAS gene, efforts to target KRAS or its effectors (e.g., MEK and ERK) are met with adaptive resistance. Pancreatic cancer stem cells (PCSCs), a subpopulation of transcriptionally-plastic cancer cells that are especially drug resistant and particularly tumorigenic, are a critical component of the aggressive and therapy- resistant nature of PDA. There are currently no strategies to target PCSCs, as well as a lack of information regarding their drivers. We previously identified HNF1A, a gastrointestinal-lineage transcription factor, as a novel master regulator of the PCSC state. Our preliminary data show that HNF1A expression can be potently blocked by BET-inhibitors (BETi), a class of drugs which inhibit the epigenetic reader protein BRD4. Interestingly, re-expression of HNF1A rescues cell cycle progression and PCSC-properties in BETi-treated PDA cells, suggesting that HNF1A is a novel and critical target for these drugs. We have also found that HNF1A is a novel driver of resistance to targeting KRAS and downstream MEK/ERK-signaling. Importantly, the use of BETi in combination with MEK- and ERK-inhibitors (MEKi/ERKi) increases growth arrest and cell death in an HNF1A-dependent manner. We hypothesize that HNF1A is directly regulated by BRD4, and is therefore targetable with BETi, and that the inhibition of HNF1A expression with BETi will nullify HNF1A-dependent PCSCs and adaptive resistance to KRAS-ablation. In this proposal, we aim to characterize the regulation of HNF1A and its role in therapeutic response and resistance. In Specific Aim 1, we will characterize the regulation of HNF1A by BETi-target BRD4. Specific Aim 1 will combine genetic manipulation of BRD4, ChIP- PCR, and reporter assays to demonstrate regulation of HNF1A by BRD4. Re-expression of HNF1A in BRD4- depleted cells will 1) define the role of HNF1A in BRD4-mediated cell growth and survival in vitro and in vivo, as well as 2) determine the contribution of HNF1A to the BRD4 transcriptome using RNA-seq/ChIP-seq to identify how HNF1A determines response to BETi. In Specific Aim 2, we will establish BETi as a means to overcome HNF1A-mediated resistance to KRAS-ablation. Specific Aim 2 will use PDA cells with and without ectopic HNF1A expression to examine the contribution of HNF1A to BETi and KRAS-pathway inhibitor activity; we will utilize in vitro and in vivo assays to examine how these drugs affect PCSCs and use RNA-seq/ChIP- seq to determine how HNF1A promotes resistance to targeting KRAS-signaling. Both aims will utilize next- generation bromodomain-selective inhibitors that have not been explored in PDA or combinatorial therapies. The completion of the above studies will dramatically improve our understanding of PDA biology and uncover novel therapeutic targets. By improving our understanding of resistance to KRAS suppression and expanding the therapeutic spectrum of PDA to include PCSCs, more effective treatment of PDA can be achieved.


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 = $470,879 )
2026	2026	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Treatment Research	000	4	12/17/2025	NON-COMPETING CONTINUATION	$470,879
														Subtotal = $470,879

Issue Date FY: 2025 ( Subtotal = $518,878 )
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Treatment Research	000	3	11/27/2024	NON-COMPETING CONTINUATION	$466,991
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Treatment Research	001	3	6/11/2025	NON-COMPETING CONTINUATION	$51,887
														Subtotal = $518,878

Issue Date FY: 2024 ( Subtotal = $449,607 )
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Treatment Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$23,664
2024	2024	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Treatment Research	000	2	1/9/2024	NON-COMPETING CONTINUATION	$425,943
														Subtotal = $449,607

Issue Date FY: 2023 ( Subtotal = $473,270 )
2023	2023	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Treatment Research	001	1	7/28/2023	NEW	$0
2023	2023	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Treatment Research	000	1	2/3/2023	NEW	$473,270
														Subtotal = $473,270

Grand Total All Awards = $1,912,634

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Targeting HNF1A-mediated therapeutic resistance in pancreatic ductal adenocarcinoma

Award Number: R37CA275961

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/03/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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