# Targeting Focal Adhesion Kinase to Improve RT-inducted Tumor Immunity

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $412,324

## Abstract

PROJECT SUMMARY
The resistance of PDAC to multiple agents, has been linked in part to its unique tumor microenvironment
(TME), which is characterized by a desmoplastic stroma composed of dense collagen-rich extracellular matrix
(ECM), abundant and diverse populations of cancer associated fibroblasts (CAFs), and resultant tumor cell
hypoxia. PDAC’s fibrotic stroma contributes to poor drug delivery, and deprived infiltration and function of anti-
tumor immune cells. These three aspects have been linked to PDAC resistance to both chemo- and
immunotherapy. However, it is not clear how the PDAC-associated desmoplasia and fibrosis might impact
resistance to RT. Historical studies have focused on radation therapy (RT) as a direct mechanism to damage
proliferating tumor cells leading to the accumulation of double-strand DNA breaks and cell death. It is also
appreciated that RT can prime anti-tumor immunity by releasing tumor-derived antigens and danger signals,
and that this likely plays a critical role in RT efficacy in multiple cancer types. However, it is unclear if these
immune priming functions of RT are intact in a highly fibrotic and immunosupressive cancers like PDAC.
Previous work from our lab demonstrated that inhibition of Focal Adhesion Kinase (FAK), which is hyper
activated in PDAC, reduced tumor-associated fibrosis and thus improves responses to chemo- and checkpoint
immunotherapies14,15. These studies have moved to clinical trials with promising early results. However, our
recent data suggest FAK can synergize even more effectively with RT plus T cell checkpoint combinations.
Based on these data, we hypothesize that fibrotic stroma contributes to PDAC resistance to RT and RT-
induction of tumor immunity. To test this we will:
Aim 1. Determine the mechanism(s) by which fibrosis impairs RT efficacy and how FAK inhibition overcomes
this.
Aim 2: Determine if FAK inhibition enhances RT-induced anti-tumor immunity and disease control in locally
advanced PDAC patients.
Aim 3: Determine the mechanism(s) by which inhibition of FAK signaling improves RT-induced checkpoint
immunotherapy response.
Impact: Studying how fibrosis negatively impacts RT efficacy in PDAC will further our understanding of how to
integrate a stromal targeted agents into current RT regimens with the ultimate goal of improving efficacy of RT.

## Key facts

- **NIH application ID:** 10836419
- **Project number:** 5R01CA248917-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** David G DeNardo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $412,324
- **Award type:** 5
- **Project period:** 2020-04-14 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10836419

## Citation

> US National Institutes of Health, RePORTER application 10836419, Targeting Focal Adhesion Kinase to Improve RT-inducted Tumor Immunity (5R01CA248917-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10836419. Licensed CC0.

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