The long-term goals of this PPG are to understand the pathogenesis of myeloid leukemias andmyeloproliferative disorders (MPDs) and use this information to develop novel and effective therapies. It isproposed that the ideal targets for therapy are the protein products of the oncogenes that cause acute orchronic myeloid diseases, and this proposal will continue to focus on tyrosine kinases. In the last cycle of thisgrant, this project focused on understanding the role that mutations in FLT3 play in causing AML and ontesting the concept that mutant FLT3 was a valid target for drug therapy. The hypothesis was that inhibitionof FLT3 tyrosine kinase activity would be cytotoxic for AML cells and would therefore potentially be ofsignificant therapeutic benefit. We were instrumental in bringing two FLT3 inhibitors to clinical trials, andearly phase studies were sufficiently encouraging that at least one of these agents will undergo phase IIItesting in induction therapy of patients with AML and mutated FLT3 in a cooperative group setting (seeproject 5). Here, we propose to continue our efforts to understand how to optimally target mutant FLT3, andin addition, propose to initiate specific, focused projects on two other tyrosine kinases mutated in myeloidleukemias, KIT and JAK2.The major focus of the proposal remains on FLT3, The proposed studies are aimed at testing thehypothesis that 'combination targeted therapy' for AML has more therapeutic value than use of a kinaseinhibitor alone. For example, we predict that targeting both a mutant oncogene, such as FLT3-ITD, and acritical downstream pathway mediating enhanced viability of leukemic cells, such as PI3K, is highly likely tobe synergistic. We will also develop higher affinity inhibitors and carefully study resistance mechanisms. Ifsuccessful, we hope to have a much better understanding of how to design the next generation of FLT3kinase inhibitor trials in AML.In two other, smaller, specific aims, we propose some focused studies on two other tyrosine kinases thatare mutated in either AML (KIT) or Polycythemia Vera (JAK2). These studies will explore therapeutictargeting of these kinases in preclinical models, with the goal of developing clinical trials that can later beconducted in Project 5.
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