# Intratumoral Metabolic Crosstalk Promotes Therapeutic Resistance in Pancreatic Cancer

> **NIH NIH R37** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $373,469

## Abstract

ABSTRACT
Pancreatic cancer is a devastating disease with a five-year survival rate below 10%. One of the main factors
underscoring this low survival rate is the lack of effective clinical treatments. The chemotherapy gemcitabine is
the most widely used agent for pancreatic cancer due to its well tolerated profile, even though treatment only
marginally extends survival. In other cancers, gemcitabine can be very effective. The limited utility of
gemcitabine in pancreatic cancer is thought to result from non-cancerous cells in the tumor creating a physical
barrier limiting drug delivery. According to this model, chemotherapeutic agents are unable to penetrate the
tumor and reach the cancer cells. We found that tumor associated macrophages (TAMs), a non-cancerous
immune cell type, abundantly secrete the nucleoside deoxycytidine (dC), and this directly inhibits the cytotoxic
activity of gemcitabine. In this research proposal, we will define how dC is made and released by TAMs and
how dC is obtained and utilized by pancreatic cancer cells to promote gemcitabine resistance. We will also test
the hypothesis that dC release is a TAM property that can be reversed by reprogramming the TAM phenotype.
These studies will be accomplished using metabolomics techniques in combination with inhibitors of
metabolism and signal transduction. In parallel, we will disrupt TAM-pancreatic cancer dC crosstalk in human
patient-derived microtumor models and in syngeneic mouse models to determine the translation value. The
clinical application of insights from these studies could have an immediate impact on patients. A means to
predict gemcitabine response based on TAM properties and/or to enhance gemcitabine efficacy by targeting
the TAM phenotype would increase the utility of this well-tolerated, mainstay treatment option for patients with
pancreatic cancer.

## Key facts

- **NIH application ID:** 10305594
- **Project number:** 5R37CA237421-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Costas Andreas Lyssiotis
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $373,469
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10305594

## Citation

> US National Institutes of Health, RePORTER application 10305594, Intratumoral Metabolic Crosstalk Promotes Therapeutic Resistance in Pancreatic Cancer (5R37CA237421-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10305594. Licensed CC0.

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