# Explore the therapeutic potential of small-molecule immune modulators

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $387,977

## Abstract

The overarching goal of our research program is to facilitate the development small-molecule drugs. The focus
of this study is to explore the therapeutic potential of the cyclic dinucleotide class of immunopotentiators in
cancer. Cancer is the second leading cause of death, contributing to 22.5% of total deaths in the US. Recently,
immune checkpoint blockade has emerged as a powerful treatment modality for cancer, showing remarkable
efficacy and response rate. Unlike the traditional radiation or chemotherapies, it utilizes our bodies’ own
immune system to fight cancer. However, many patients do not have sufficient immunity to benefit from this
new treatment strategy. Our team has recently identified cGAMP to be the endogenous small-molecule that
activates the innate immune system and demonstrated its antitumor activity in mice. Based on this work,
several synthetic analogs have been developed by pharmaceutical companies to mimic this natural
immunopotentiator. The accumulated effort has led to two Phase I clinical trials to evaluate the safety and
tolerance of cGAMP analogs in human. Despite the rapid progress, the full functional profile of cGAMP is still
not clear. In this project, we will establish a proteomic approach to extensively map drug-protein interactions for
cGAMP and its metabolically stable analogs including the investigational drug MIW815. This work will help
shed lights on the potential new functions of cGAMP and the potential off-target effects of synthetic cyclic
dinucleotides. Additionally, we believe that selective activation of a specific group of dendritic cells by cGAMP
or its analogs will help reduce the risk of systemic inflammation, the major concern of the immune stimulation
therapies. We will thus develop a conjugation strategy for site-specific delivery of cGAMP to improve efficacy,
reduce toxicity, and help understand the roles of dendritic cells at different sites in anticancer immunity. Overall,
the results of this study will inform future development of cGAMP analogs for their safe use in human and
provide information on the role of innate immunity in cancer.

## Key facts

- **NIH application ID:** 9817682
- **Project number:** 5R01CA226419-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** CHUO CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,977
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9817682

## Citation

> US National Institutes of Health, RePORTER application 9817682, Explore the therapeutic potential of small-molecule immune modulators (5R01CA226419-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9817682. Licensed CC0.

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