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Targeting Novel Pediatric-Specific FLT3 Mutations

Institution: 
Fred Hutchinson Cancer Research Center
Researcher(s): 
Soheil Meshinchi, MD,PhD
Grant Type: 
Reach Grants
Year Awarded: 
2015
Type of Childhood Cancer: 
Acute Myelogenous Leukemia (AML), Lymphoma
Project Description: 

Background

Acute myeloid leukemia (AML) remains one of the most difficult challenges in pediatric oncology with more than half of children with AML failing available therapies. Although FLT3 mutations may provide a therapeutic target, these mutations are not common in children. Through genomic sequencing we have discovered 32 different novel mutations in FLT3 gene that are unique to childhood AML and may provide possibility of extending FLT3 inhibitors to a larger cohort of children with AML. Before they can be used as a viable therapeutic target, function of these novel mutations must be established and drugs must be identified that appropriately target these mutations.

Project Goal

We will use molecular cloning techniques developed in our laboratory to engineer cells that express the mutant cells and determine if they can grow without external stimulation. In addition, as each type of mutation may have a different response to different drugs, mutant cells will be tested against a large number of FLT3 inhibitors as well as other targeted agents.

To optimize this analysis, we have developed a robotic high throughput drug-screening platform that can rapidly test multiple cell lines against over 160 drugs and generate a response profile that can be linked to mutation type. This approach will allow identification of precise mutations that would most benefit from the most appropriate drugs. The information from this study will be given to the COG phase III AML trial, which is currently designing the next phase III trial for incorporation.