Characterization of a novel FLT3 tyrosine kinsase inhibitor in AML
Acute myeloid leukemia (AML) is a hematologic malignancy ocurring globally in 200,000 people each year. It is characterized by myeloproliferation and a block in cellular differentiation, leading to infiltration of immature blasts in the bone marrow and peripheral blood. FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expressed in hematopoetic progenitor cells. Approximately 30% of AML cases harbor a mutation in the FLT3 gene leading to constitutive activation of FLT3, which provides a survival and proliferatice advantage to cells. Mutations in FLT3 confer a poor prognosis, and many studies are directed at developing and testing novel FLT3 inhibitors for the treatment of AML.
My project is focused on the characterization of a novel tyrosine kinase inhibitor (TKI) that we hypothesize possesses potent activity against FLT3. I will be working with a panel of AML cell lines, human AML patient samples, and transgenic and xenograft mouse models of AML in order to determine the scope of this compound’s potential application in the treatment of AML patients with FLT3 activating mutations. We are particularly interested in changes in cell viability and signal transduction upon treatment with the inhibitor, as well as perturbation of tumor growth in mice. We are also hoping that these studies will allow us to gain further insight into the development of drug resistance to TKIs, which has been frequently observed with other FLT3 inhibitors in clinical trials. With this information, we can propose combination therapies that will target additional pathways in order to increase the success rate of treatment.