# Targeted Inhibition in Leukemia

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $465,554

## Abstract

ABSTRACT
We have identified the first in vivo and in vitro small molecule inhibitor of Vav3, a signaling hub that is overex-
pressed in many cancers and an activator of the small GTPase Rac. Rac is a major mediator of oncogenic and
non-oncogenic addiction in cancer stem/progenitor cells. At low dose, our inhibitor eliminates TKI-resistance in
vivo, prolongs the survival of a mouse model of pre-B-ALL, and eradicates cancer stem cell propagation in a
model of mouse serial transplantation. It induces apoptosis of primary pediatric Philadelphia-positive (Ph+) and
Ph-like B-ALL and chemotherapy-resistant RAM immunophenotype primary pediatric AML cells. It specifically
targets leukemic cells while sparing normal hematopoiesis in vivo and shows no toxicity. In addition, it is active
in oncogenic Ras xenografts mouse models of human solid tumors. Given this broad activity and the wide in-
volvement of Vav3 and Rac in human disease, it is likely that our inhibitor will be efficacious in several human
cancers resistant to current therapies.
Even though we focus on Ph+ B-cell acute lymphoblastic leukemia (Ph+ B-ALL) as a simpler cancer model to
validate the mechanism of action of our inhibitor, we will test its efficacy in models of pediatric TKI-resistant B-
ALL and AML. Despite the introduction of ABL tyrosine kinase inhibitor (TKI) therapy and more recently highly-
toxic immunotherapies, Ph+ B-ALL and AML remain poor prognosis diseases, especially in adults, as a result of
frequent relapse and resistance to current therapies. The long-term goal of this grant application is a multidrug
approach consisting of a TKI and our drug or an optimized derivative as a new therapy for ALL and AML without
the toxicity associated with current salvage therapy approaches. We postulate that multitarget approaches in
ALL and AML are necessary to prevent resistance to single-agent TKI therapy.
Based on our preliminary data, we hypothesize that our drug increases death of leukemia initiating and propa-
gating cells and overcomes TKI-resistance by targeting Vav3. The goal of the proposed research is to (1) validate
the Vav3/Rac signaling axis as our drug’s target using biochemical and genetic approaches and determine in
vivo implications; (2) to identify our drug’s binding site on Vav3 using biophysical, structural, and genetic ap-
proaches, and validate the site using site-directed mutagenesis. Finally, (3) we will take advantage of the
CCHMC Oncology Leukemia/Solid Tumor Repository to test our drug’s efficacy in PDX models of chemotherapy-
resistant pediatric ALL and AML alone and in combination with existing TKI approaches and validate metallothi-
onein as a biomarker. If successful, we would like to see our drug, or a more potent analog, move into pre-clinical
safety analysis and potentially into a Phase I clinical trial in ALL and AML resistant to TKI therapies. Allosteric
targeting of the Vav3 autoinhibited conformation as proposed here could be generalized to other ‘u...

## Key facts

- **NIH application ID:** 10212981
- **Project number:** 5R01CA237016-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Jose A. Cancelas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $465,554
- **Award type:** 5
- **Project period:** 2020-07-08 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212981

## Citation

> US National Institutes of Health, RePORTER application 10212981, Targeted Inhibition in Leukemia (5R01CA237016-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10212981. Licensed CC0.

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