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Therapeutic Targeting of LARG-RhoA Signaling Axis in Childhood Leukemia

Cincinnati Children's Hospital Medical Center
Yi Zheng, PhD
Grant Type: 
Innovation Grants
Year Awarded: 
Type of Childhood Cancer: 
Acute Myeloid Leukemia (AML)
Project Description: 

The overall outcome of acute myeloid leukemia (AML) remains unacceptable. AML1-ETO (AE), the product of chromosome translocation 8;21, is the most frequently observed fusion gene in childhood acute myeloid leukemia. As a transcription factor, AML1-ETO interferes with normal blood production by disturbing gene expression normally regulated by the AML1 protein. There are currently no targeted therapies available for AML1-ETO-expressing AML.

Project Goal
Our goal is to identify new small molecule drug candidates based on novel molecular mechanisms driving blood malignancies that are amenable to targeted therapy. In particular, we seek to discover lead small molecular inhibitors targeting one of the key components of the AML1-ETO induced malignancy, the newly identified target gene product, LARG (which stands for Leukemia-Associate Rho Guanine Nucleotide Exchange Factor), that is a druggable enzyme useful for eradication of AML.

Our previous work has provided a rationale of LARG serving as a useful target in AML1-ETO expressing leukemia and discovered lead chemical inhibitors specific for LARG, a high throughput screening assay platform, and a humanized AML mouse model. Through the Alex's Lemonade Stand Foundation support, our studies may implicate, for the first time, a druggable target of AML1-ETO and demonstrate a novel targeted therapeutic principle. Further, our work may produce a preclinical lead drug for AML after a rigorous medicinal chemistry optimization of our identified hits for which we own the intellectual property.