# Causes and Consequences of Adenosine Signaling in Pancreatic Cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $653,452

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of cancer, known for its
profound immune suppression and resistance to most therapies. One strategy to overcome these barriers is to
leverage the effects of standard-of-care chemotherapy to increase extracellular ATP and promote anti-tumor
inflammation. However, PDACs express high levels of ectonucleotidases ENPP1, CD39, and CD73 that
quickly convert extracellular ATP released by dying tumor cells to immunosuppressive adenosine. In a recent
Phase IA/1B clinical trial at UCLA for patients with Borderline Resectable PDAC (NCT03970252), neoadjuvant
FOLFIRINOX chemotherapy and PD-1 inhibition produced changes of a more permissive anti-tumor immune
microenvironment (TME) and was associated with excellent overall survival. However, compensatory
adenosine signaling increased in post-treatment tumors, potentially hindering anti-tumor immunity. To
strategically address this problem, a follow-up Phase 1/2 trial (NCT05688215) was initiated at UCLA in
collaboration with Arcus Biosciences that introduces a small molecule inhibitor of CD73 to neoadjuvant
FOLFIRINOX and PD-1 inhibition to limit adenosine in the PDAC TME. This proposal aims to extensively
evaluate pre- and post-treatment patient specimens from this trial to define the impact of CD73 inhibition on
tumor adenosine metabolism, signaling and -mediated immunosuppression (Aim 1). Predictors of response
and resistance to CD73 inhibition will be identified. In Aim 2, autochthonous tumor models, implantable models
of metastasis and human tumor explants will be used to define the roles of ENPP1 and CD39 as regulators of
ATP breakdown and whether they cooperate with CD73 to generate adenosine. In addition to ATP, the
ectonucleotidase ENPP1 degrades the natural STING ligand cGAMP, also released by tumor cells after DNA
damaging chemotherapy, to further reduce anti-tumor inflammation. Therefore, the proposed studies in Aim 3
will build on novel preliminary data showing that adenosine directly inhibits STING activation in myeloid cells
and will explore whether ENPP1 inhibition cooperates with CD73 inhibitor-mediated adenosine depletion to
enhance STING signaling in the TME. These experiments will draw on a newly developed anti-human ENPP1
antibody and ENPP1 humanized mouse model. A transdisciplinary team with expertise in PDAC biology, tumor
immunology, clinical trials, bioinformatics, biostatistics and mass spectrometry with a strong track record of
working together has been assembled to complete the proposed studies. This project not only will provide a
comprehensive understanding of ATP and adenosine metabolism in the PDAC TME but also identify the
immunologic consequences of these changes. Overall, it has the potential to advance treatment outcomes for
patients with this challenging cancer type by effectively reversing adenosine-mediated immunosuppression to
unleash the full potency of chemo-immunotherapy.

## Key facts

- **NIH application ID:** 10999892
- **Project number:** 1R01CA290888-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Timothy R Donahue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $653,452
- **Award type:** 1
- **Project period:** 2024-06-26 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999892

## Citation

> US National Institutes of Health, RePORTER application 10999892, Causes and Consequences of Adenosine Signaling in Pancreatic Cancer (1R01CA290888-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10999892. Licensed CC0.

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