# Overcoming mechanisms of therapeutic resistance in pancreatic ductal adenocarcinoma

> **NIH NIH P01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2024 · $2,922,916

## Abstract

PROJECT SUMMARY – Overall
While mortality rates for many cancers are declining, pancreatic ductal adenocarcinoma (PDA) remains a highly
lethal malignancy with the worst 5-year survival rate of the common malignancies. Unfortunately, current
therapies are largely ineffective in PDA, an outcome attributed in large part to therapeutic resistance. The highly
fibrotic and poorly vascularized tumor microenvironment (TME) restricts both nutrient availability and drug
delivery, and provides pro-survival and immunosuppressive cues. These limitations create energy stresses that
drive metabolic adaptations to support tumor growth and therapeutic resistance. Moreover, the hyperactivation
of pro-survival and resistance pathways in tumor and stromal cell types results in an integrated resistance
network. The induction of these pathways is orchestrated by cell-to-cell communications within the TME,
including aberrant glycosylation (CA-19-9) and the secretion of immunosuppressive and pro-survival paracrine
factors, such as Leukemia Inhibitory Factor (LIF) from cancer-associated fibroblasts (CAFs). In addition, cells
adapt to the hypoxic, nutrient-depleted TME by upregulating cell type-specific survival programs, including
autophagy. Ultimately, to support and respond to these signaling and metabolic programs, both the tumor and
stromal cell epigenomes are reprogrammed, leading to cellular heterogeneity and plasticity that restricts durable
therapy responses. Each of these programs promote resistance to a broad range of therapeutics, including
chemotherapies, targeted therapies, and immune checkpoint inhibitors.
 The central hypothesis of this program is that pancreatic cancer has co-opted an integrated network
of epigenetic programs, paracrine signaling pathways, and metabolic adaptations to promote tumor
survival and therapeutic resistance. Building upon the investigators’ complementary expertise in epigenetics,
cell signaling, and metabolic adaptations, as well as common interests in pancreatic cancer, this program seeks
to understand the interactions that hinder PDA therapeutic responses, with the ultimate goal of identifying
vulnerabilities that can be exploited and targeted to overcome drug resistance. Importantly, the program will
utilize advanced mono- and co-culture organoid systems, cutting-edge mouse models, novel therapeutics,
single-cell approaches, and human clinical specimens to delineate the contributions of both tumor cells and their
stromal support network to therapeutic resistance. Moreover, proposed cooperative and innovative approach will
reveal how these resistance nodes are integrated and can be targeted to improve therapeutic outcomes in PDA.

## Key facts

- **NIH application ID:** 10883558
- **Project number:** 5P01CA265762-02
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** TONY R. HUNTER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,922,916
- **Award type:** 5
- **Project period:** 2023-07-06 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883558

## Citation

> US National Institutes of Health, RePORTER application 10883558, Overcoming mechanisms of therapeutic resistance in pancreatic ductal adenocarcinoma (5P01CA265762-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10883558. Licensed CC0.

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