# Combining Immunotherapy with Urolithin A to Improve Pancreatic Cancer Survival

> **NIH NIH R03** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $76,750

## Abstract

PROJECT SUMMARY/ABSTRACT:
 Pancreatic ductal adenocarcinoma (PDAC) remains a major therapeutic challenge due to its innate and acquired
chemoresistance. To date, the addition of targeted molecular therapies to cytotoxic compounds has failed to show any
significant improvement in increasing overall survival in PDAC. Hence, there is a desperate need to develop novel
therapeutic approaches that both reduce the PDAC tumor burden and improve overall survival without producing
significant off-target effects. We have shown that Urolithin A (Uro A), a novel natural dietary microflora-derived
metabolite, mediates its anti-tumor activities by inhibiting immunosuppressive cells. A Phase I clinical trial of Uro A
demonstrates that it is well-tolerated with good bioavailability. The relative superiority of Uro A to cytotoxic
chemotherapy in our preclinical study highlights the need to study Uro A as a chemopreventive agent. Uro A treatment
alone increased T-cell infiltration to the tumor while decreasing the overall number of intratumoral myeloid derived
suppressor cells and immunosuppressive regulatory T cells. Tumor suppressive effect of Uro A is T cell dependent and is
accompanied by sustained PD-L1/PD-1 expression. Immune therapies targeting the checkpoint inhibitors (CPI) such as
PD-1 and/or CTLA-4 can enhance the T cell response to tumors and these inhibitors have shown great success in clinic.
Therefore, we hypothesize that the addition of an anti-PD1 and/or anti-CTLA-4 therapy to Uro A combination will
allow assessment of its effects on the tumor microenvironment and overall response rate. We further hypothesized
that CPI unmasks clinical responses to Uro A and that enhanced T cell responses with this regimen may ultimately be
limited by the increased activity of immune TME. We will test these hypotheses in two aims with pre-clinical murine
models. Aim 1: Evaluate the impact of combined Uro A treatment and checkpoint inhibition on stromal and
immune microenvironment in PDAC in vivo. We will determine the immune predictors of responses and profile the
phenotypes of various immune cell subsets from treatment groups. Aim 2: Determine if checkpoint inhibition together
with Uro A will improve survival in mouse model of PDAC. Genetic mice will be treated with Uro A followed by anti-
PD1 and/or anti-CTLA-4 antibodies to determine efficacy of the treatment response. This project will elucidate a
mechanistic understanding of the impact of a chemopreventive agent and CPI on PDAC, facilitating the development of
optimal combinatorial therapy for PDAC. Success in these pre-clinical models would then facilitate rapid translation of
this work into clinical trials.

## Key facts

- **NIH application ID:** 10134289
- **Project number:** 5R03CA249401-02
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Nagaraj S. Nagathihalli
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $76,750
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134289

## Citation

> US National Institutes of Health, RePORTER application 10134289, Combining Immunotherapy with Urolithin A to Improve Pancreatic Cancer Survival (5R03CA249401-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134289. Licensed CC0.

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