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The Role of HIF2 in Pancreatic Ductal Adenocarcinoma

Award Number: R01CA269565
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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The Role of HIF2 in Pancreatic Ductal Adenocarcinoma - PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) contains a desmoplastic stroma that limits blood perfusion and thus the delivery of nutrients, oxygen, and therapeutics, creating a hypoxic microenvironment that is able to resist nearly all forms of treatment, including immunomodulating therapy. Cancer-associated fibroblasts (CAFs) are the main components and producers of stroma in PDAC. The hypoxia-inducible factors-1 (HIF1) and -2 (HIF2) are stabilized in low oxygen and have been hypothesized to mediate therapeutic resistance and aggressive growth of PDAC, but deletion of HIF1 or HIF2 in the pancreatic epithelial compartment produced no obvious phenotype in PDAC. Thus, we reasoned that HIF may instead be supporting PDAC pathobiology through its functions in cancer-associated fibroblasts (CAFs), which are the other major cellular component in pancreatic tumors. Since little was known about the role of HIF in the stromal compartment, we created a mouse model that exploits two recombinases enabling us complete spatiotemporal control of tumor growth and HIF ablation in CAFs. Using this model, we found that the abrogation of HIF2 in CAFs decreased tumor growth and doubled the median survival of animals with pancreatic cancer. The loss of HIF2 in CAFs correlated with fewer intratumoral M2 macrophages and regulatory T cells. Furthermore, conditioned media from hypoxic CAFs produced similar effects in ex vivo assays even after boiling. These preliminary data suggested a HIF2- dependent crosstalk between CAF and the immune compartment that may be critical to the ability of PDAC to evade the immune system. Building on this preliminary data, we propose to identify the molecular mechanisms that allow hypoxic CAFs to modulate the immune microenvironment of pancreatic cancer through three aims. In Aim 1, we will determine the molecular mediators of HIF2-dependent crosstalk between CAFs and macrophages. We will use mass spectrometry to identify the HIF2 dependent factor secreted from CAFs capable of inducing M2 polarization in macrophages and determine how this factor is produce in CAFs and how it alters macrophage function. Aim 2 will define the HIF2-dependent relationships between CAFs and T lymphocytes. We will explore how CD8+ suppression and Treg conversion is regulated by HIF2 signaling in CAFs using mouse models and co-culture methods. Lastly, in Aim 3, we will repurpose HIF2 inhibitors from their current indications in renal cell carcinoma to pancreatic cancer as a drug to enhance immunotherapy responses. The proposed research is significant because pancreatic cancer does not respond to immunotherapy, and our data suggests that HIF2 inhibition may greatly improve immune responses. This research is innovative because we will provide the first description of the immune-targeting molecular pathways activated by hypoxic microenvironment in PDAC. Further, we will offer the first mechanistic evaluation of a potential therapeutic combination using a HIF2 inhibitor along with immune checkpoint blockade as the first steps towards clinical translation.


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 = $515,400 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	12/15/2025	NON-COMPETING CONTINUATION	$515,400
														Subtotal = $515,400

Issue Date FY: 2025 ( Subtotal = $609,668 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	12/17/2024	NON-COMPETING CONTINUATION	$515,400
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	3	9/17/2025	NON-COMPETING CONTINUATION	$57,267
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	003	3	9/17/2025	SUPPLEMENT FOR EXPANSION	$3,700
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	3	1/14/2025	SUPPLEMENT FOR EXPANSION	$33,301
														Subtotal = $609,668

Issue Date FY: 2024 ( Subtotal = $609,720 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	2	4/17/2024	NON-COMPETING CONTINUATION	$28,635
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	003	2	4/22/2024	SUPPLEMENT FOR EXPANSION	$3,458
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	2/6/2024	NON-COMPETING CONTINUATION	$515,400
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	2	2/9/2024	SUPPLEMENT FOR EXPANSION	$62,227
														Subtotal = $609,720

Issue Date FY: 2023 ( Subtotal = $609,668 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	1	7/28/2023	SUPPLEMENT FOR EXPANSION	$37,001
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	12/29/2022	NEW	$572,667
														Subtotal = $609,668

Grand Total All Awards = $2,344,456

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The Role of HIF2 in Pancreatic Ductal Adenocarcinoma

Award Number: R01CA269565

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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