Our long-term goals are to increase the cure rate and decrease chemotherapy-relate toxicity for patients with leukemia. In particular, we are interested in patients whose leukemias express an activated FLT3 receptor, either as a result of mutation or ligand co-expression. 20% of AML patients have mutations of the FLT3 receptor. These patients have a particularly poor prognosis with almost no one being cured in either the pediatric or adult populations. The mutation of the FLT3 receptor consists of small (18-105 bp) internal tandem duplications (ITDs) which are unique for each patient but all map to the juxtamembrane region of the receptor. These mutations constitutively activate the tyrosine kinase domain of FLT3 receptor which is required for signaling. This makes the development of novel strategies for these patients imperative if we are to effect improvements in their outcome. If FLT3 constitutive activation is contributing to leukemogenesis in these patients, one strategy would be to develop small molecule inhibitors of the kinase domain of the receptor. We therefore propose two major specific aims in this proposal with FLT3 as the novel molecular target for drug discovery. The first id to validate FLT3 as a molecular target by developing several animal models that mimic different ways that the FLT3 can become constitutively activated. We will also introduce second """"""""hits"""""""" that often occur in leukemia to study the spectrum of the hematopoietic disease to which an activated FLT3 can contribute.
The second aim i s to develop assays utilizing cell lines and proteins that can be utilized for high-throughout screening of FLT3 inhibitors. This will enable the discovery of lead compounds that are unable to inhibit FLT3 in a highly potent and specific fashion. We believe that this work will lead to the identification of compounds able to inhibit FLT3 which will ultimately be used as novel therapeutics against leukemia.
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