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Rational targeting of Cdc42 to benefit immunotherapy

Award Number: R01CA278756
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Rational targeting of Cdc42 to benefit immunotherapy - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $594,402 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Treatment Research	001	2	6/2/2025	NON-COMPETING CONTINUATION	$59,440
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Treatment Research	000	2	11/27/2024	NON-COMPETING CONTINUATION	$534,962
														Subtotal = $594,402

Issue Date FY: 2024 ( Subtotal = $594,402 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Treatment Research	000	1	11/22/2023	NEW	$594,402
														Subtotal = $594,402

Grand Total All Awards = $1,188,804

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Rational targeting of Cdc42 to benefit immunotherapy

Award Number: R01CA278756

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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