The management of pediatric cancers has seen significant progress in the past two decades, with some cancers (e.g., acute lymphoblastic leukemia) nearing 80-90% cure rates. Long-term survival rates in children with newly diagnosed acute myelogenous leukemia (AML) have recently improved from approximately 50% to 70% at St. Jude Children's Research Hospital. AML, which represents about 15% of all childhood leukemias, is a heterogeneous disease characterized by uncontrolled clonal proliferation of hematopoietic stem/progenitor cells of the myeloid lineage with reduced capacity to differentiate into mature cells. Preclinical research has been supplemented by laboratory studies of human cancer cell lines and xenograft mouse models aimed at identifying therapies. Although this approach has ascertained some novel therapeutics, it is inherently inefficient, often failing to account for the multitude of subtypes and providing little insight into the patients most likely to benefit from each therapy. The goal of this proposal is to address an unmet need to identify effective treatment strategies for children with AML. The underlying hypothesis is that high-throughput screening can predict efficacy and toxicity of novel therapeutics which will be effective for the treatment of childhood AML. To test this hypothesis, we propose the following specific aims: Specific Aim 1: To identify novel therapeutics for the treatment of pediatric AML using a high-throughput screen of over 8000 compounds. Specific Aim 2: To evaluate the efficacy of therapeutic leads identified by high-throughput screen using in vitro and in vivo models of AML in combination with cytarabine. Implementation of acute myeloid leukemia cell lines which represent subtypes with the poorest prognosis, in addition to primary blasts isolated from a c-Myc induced murine model of AML will recapitulate human disease. Furthermore, evaluation of therapeutics leads in combination with standard of care agents is a rational design to accelerate incorporation of new treatment strategies. The long-term goal of this project is to translate our preclinical findings to clinical trials at St. Jude, and ultimately improve the long-term outcome of children with AML.