# Anti-tumor efficacy of novel cGAS-STING pathway agonists

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $214,767

## Abstract

PROJECT SUMMARY
The goal of this proposal is a molecular and immunological examination of novel compounds that activate innate
immune signaling mediated by the proteins cyclic GMP-AMP (cGAMP) synthase (cGAS) and Stimulator of
Interferon Genes (STING). Innate immunity is initiated following engagement of pattern recognition receptors by
molecules indicative of microbial infection or dying cells. These lead to the orchestration of adaptive immune
responses that subsequently eliminate cancerous or infected tissues. cGAMP is the primary activating ligand of
STING and its synthesis is triggered by contact between cGAS and cytosolic DNA. Macrophages, dendritic cells
(DCs), and endothelial cells are exposed to cytosolic DNA following phagocytosis of material from apoptotic cells
including those in the tumor microenvironment. STING-mediated signaling leads to secretion of type I interferons
(IFN-I) and proinflammatory cytokines that then activate antigen-presenting cells (APCs), thereby facilitating
antigen-directed T-cell killing. STING is, in fact, required for initiating immune responses capable of clearing
tumor cells. Intriguingly, pharmacologic activation of STING-dependent processes can lead to spontaneous
tumor clearance and even tumor antigen-derived protective immunity in murine models. Numerous efforts are
thus focused on understanding the molecular and immunological bases of STING-mediated therapeutic
outcomes as well as identifying new molecular entities that can safely elicit these. Our work has identified six
small molecular analogs that induce cGAS-mediated synthesis of cGAMP without affecting cytosolic DNA levels.
These directly activate STING-dependent phenotypes in both human and murine cells. Moreover, intratumoral
administration of the original parent molecule in mouse models of cancer led to impaired tumor growth and
prolonged animal survival. We hypothesize that our improved analogs, when paired with formulations optimized
for in vivo use, will exhibit enhanced antitumor activity. To our knowledge these represent the first synthetic direct
inducers of cGAS-mediated signaling yet described. As such, they are uniquely positioned to establish cGAS
(and perhaps STING regulatory proteins in general) as a viable drug target and also reveal new insights into the
role of cGAS-STING in antitumor immunity. We thus propose to undertake a penetrative and comparative
characterization of the immunological and molecular responses, anti-tumor capacities, and potential adverse
effects of our novel cGAS agonist formulations in murine models of cancer. Results will allow a mechanistic
assessment to be made of their immunotherapeutic utility, especially in comparison to clinically pursued
molecules and in therapies involving combination with checkpoint inhibitors. Our historically collaborative group
possesses expertise in innate immunity, molecular biology, T cell immunology, and cancer immunotherapy and
is thus well positioned to execute these studi...

## Key facts

- **NIH application ID:** 10430274
- **Project number:** 5R21CA256295-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** VICTOR Robert DEFILIPPIS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $214,767
- **Award type:** 5
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430274

## Citation

> US National Institutes of Health, RePORTER application 10430274, Anti-tumor efficacy of novel cGAS-STING pathway agonists (5R21CA256295-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10430274. Licensed CC0.

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