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Reprogramming inflammatory fibroblasts to overcome therapeutic resistance in pancreatic adenocarcinoma

Award Number: R37CA311069
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/05/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Reprogramming inflammatory fibroblasts to overcome therapeutic resistance in pancreatic adenocarcinoma - Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is an exceptionally deadly cancer with few available treatment options. The lack of treatment options and poor treatment outcomes is associated with its extensive fibrosis, which contributes to therapeutic resistance. Cancer-associated fibroblasts (CAFs) mediate local tissue remodeling and are implicated in PDAC’s extensive fibrosis. However, therapies targeting CAF development and activation have paradoxically led to worsening tumor growth and metastasis in PDAC. Recent analyses at the single cell resolution have identified a unique subpopulation of inflammatory CAFs in PDAC. Our preliminary work has focused on understanding CAF phenotypes, determining the factors that promote differentiation to inflammatory CAFs, and the influence of CAF phenotypes on the tumor microenvironment. Using primary human cell models, we have demonstrated that inflammatory CAF differentiation occurs in response to exposure to interleukin 1 (IL-1), lipopolysaccharide (LPS), or PDAC cell conditioned media and is dependent on intact fibroblast myeloid differentiation factor 88 (MyD88) signaling. Furthermore, inflammatory CAFs generated in this manner are potent suppressors of T cell activation, interferon-γ production, and cytotoxic T cell function. This revelatory preliminary work suggests that aberrant MyD88 signaling is responsible for tumor progression, which explains the poor outcomes associated with previous therapies. MyD88 presents a promising new therapeutic target for the treatment of PDAC. We will first assess whether inflammatory CAF differentiation can be suppressed by MyD88 inhibition in mouse models of PDAC. This work will elucidate the factors that control the inflammatory CAF phenotype in PDAC, the influence of the inflammatory CAF phenotype on the tumor microenvironment, and the resultant impact on tumor growth and disease progression. Next, we will determine the mechanism of T cell suppression in PDAC through identification of the secreted factors from inflammatory CAFs responsible for this activity using primary human cell models of patient-derived CAFs. These secreted factors present valuable targets for treatments that specifically prevent T cell suppression from inflammatory CAFs, likely to be more valuable for treatment than global suppression of MyD88 signaling. Third, we will explore a novel treatment regimen which leverages MyD88 pathway inhibition in PDAC in combination with immune checkpoint blockade. This work will utilize a currently available MyD88 pathway inhibitor which has not previously been investigated for efficacy in combination with immune checkpoint blockade. These experiments will solidify a novel relationship between inflammatory CAFs, MyD88 signaling, and T cell suppression. In addition to providing mechanistic insights into CAF differentiation in the development of PDAC, we propose to complete the preclinical work necessary to combine immune checkpoint blockade and MyD88 pathway inhibition in a clinical trial for PDAC.


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 = $357,370 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	000	1	5/7/2026	NEW	$357,370
														Subtotal = $357,370

Grand Total All Awards = $357,370

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Reprogramming inflammatory fibroblasts to overcome therapeutic resistance in pancreatic adenocarcinoma

Award Number: R37CA311069

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/05/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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