Leukemia remains a deadly disease in both adults and children. The majority of patients still die, and new treatments are urgently needed. There is now substantial data indicating that the receptor tyrosine kinase FLT3 plays a role in a significant fraction of leukemias. FLT3, which is expressed in most cases of acute myeloid and acute lymphocytic leukemia (AML and ALL), is constitutively activated by internal tandem duplication (ITD) mutations of the juxtamembrane region, by point mutations in the kinase domain, and by co-expression of FLT3 ligand (FL). 30% or more of AML cases harbor an activating mutation of FLT3, and this subset of patients has been shown to have a worse prognosis. Preliminary data presented here provides evidence that a FLT3 tyrosine kinase inhibitor is specifically cytotoxic to AML cells harboring FLT3 activating mutations. This proposal's scientific objective is the development of a FLT3 tyrosine kinase inhibitor for use in the treatment of leukemia. The immediate goal is to characterize the responses of different types of leukemias to the inhibitors in order to predict which patients may benefit from this therapy.
The specific aims will be to test human leukemia cell lines and primary leukemic blasts for cytotoxic response to FLT3 inhibitors, with and without chemotherapy, and to correlate this cytotoxic response with changes in downstream signaling proteins and gene expression. Similar correlative studies will be performed on samples from patients receiving the inhibitor as part of a clinical trial. A FLT3 inhibitor has tremendous potential as an alternative or adjunct to conventional therapy for acute leukemias. This proposal has two goals. The first is to address the urgent need for new leukemia therapies. The second is to allow the principal investigator, Dr. Mark Levis, to develop into a laboratory-based researcher whose focus is to translate basic science research into clinical applications. With the guidance of a mentor who has expertise in the pathogenesis of leukemia, along with a structured educational program and a supportive academic environment, the principal investigator will use the support provided by this award to complete the transition to independent clinician scientist. ? ?
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