# Rational targeting of Cdc42 to benefit immunotherapy

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $594,402

## Abstract

ABSTRACT
T cells play important role in cancer cell immunosuppression. Cancer cells can interact with immune
checkpoint proteins expressed on effector T cells to cause T cell exhaustion and facilitate regulatory T
(Treg) cell suppression of effector T cells. Understanding T cell immunity is an important goal in cancer
immunotherapy. Although immune checkpoint inhibitors and CAR-T cell therapies have shown
tremendous promise, current immunotherapies only benefit a fraction of cancer patients, and new
approaches from mechanism-driven immune modulations are needed to broaden the therapeutic benefits
to less responsive patients. Targeting Treg cells to activate effector T cells to combat cancer is an
emerging concept in cancer immunotherapy. While systemic depletion of Treg cells can cause excessive
T cell activation leading to autoimmunity, proper induction of Treg cell instability without side effects of
autoimmune responses may open a new avenue for immune modulation. In preliminary studies, we have
found that heterozygous deletion of the Rho GTPase Cdc42 in Treg cells did not affect Treg cell
homeostasis nor result in autoimmune response but caused a destabilization of Treg cells that elicited
an anti-tumor immunity. Pharmacological targeting of Cdc42 with a small molecule inhibitor, CASIN,
mimicked Cdc42 heterozygous deletion in destabilizing Treg cells and in gaining an anti-tumor T cell
immunity. CASIN potentiated the effects of immune checkpoint inhibitors in tumor suppression without
detectable autoimmunity in mice. This project hypothesizes that the rational designed small molecules
targeting Cdc42 activity can destabilize Treg cells and modulate anti-cancer immunotherapy without
inflammatory side effects. In Aim 1, to determine the molecular pharmacology of CASIN action we will
define the mechanism of action of CASIN and improve CASIN efficacy. We will carry out further medicinal
chemistry studies, validate CASIN derivatives for proper target engagement, and examine potential
toxicity in T cells and other cell types. In Aim 2 we will demonstrate a proof of concept for CASIN or its
derivatives in targeting of Cdc42 in mouse models to trigger anti-tumor T cell immunity. We will determine
the toxicity, pharmacokinetics and pharmacodynamics of CASIN and its derivatives, and examine their
preclinical efficacies in destabilizing Treg cells to elicit anti-tumor T cell immunity, alone or in combination
with immune checkpoint inhibitors. Overall, our work will establish a novel concept and present a useful
approach for anti-cancer immunomodulation.

## Key facts

- **NIH application ID:** 10793036
- **Project number:** 1R01CA278756-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Fukun Guo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $594,402
- **Award type:** 1
- **Project period:** 2023-12-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10793036

## Citation

> US National Institutes of Health, RePORTER application 10793036, Rational targeting of Cdc42 to benefit immunotherapy (1R01CA278756-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10793036. Licensed CC0.

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