My long-term career goals are to develop better therapies, improve cure rates, and minimize toxicities for children with high-risk leukemias. My clinical experiences as a pediatric oncologist inspire the bench-based laboratory studies that will help me to achieve these goals. This mentored career development award (CDA) proposal is designed to facilitate my development as an independent translational physician-scientist via acquisition of critical laboratory skills in human leukemia xenograft models and preclinical signal transduction inhibitor testing, as well as to pursue additional didactic training in oncogenic signl transduction, cell death, pharmacology, and early phase clinical trial design and biostatistics. I will conduct the proposed studies under the outstanding mentorship of Dr. Stephan Grupp and Dr. Martin Carroll, both international leaders in translational leukemia research and experienced CDA mentors, and my multi-disciplinary Advisory Committee comprised of senior faculty with scientific and clinical expertise in hematologic malignancies. The resource-rich environment of the Children's Hospital of Philadelphia and the University of Pennsylvania provides an ideal setting in which to conduct these patient-oriented laboratory studies. We have focused upon the Philadelphia chromosome-like (Ph-like) subset of acute lymphoblastic leukemia (ALL), which comprises ?15% of childhood and adult ALL and is associated with extremely high relapse rates and dismal long-term survival. We and others have observed constitutive activation of oncogenic cytokine receptor signaling in earlier studies of Ph- like ALL, particularly of the JAK/STAT and PI3K/Akt/mTOR pathways. While preclinical and early clinical studies of JAK inhibition in ALL are underway, therapeutic disruption of aberrant PI3K pathway signaling has not been specifically investigated in Ph-like ALL. We hypothesize that we can efficiently individualize high-risk ALL therapy by reliably identifying the Ph-like ALL phenotype by phosphoflow cytometry and can use these data for rational selection of signal transduction inhibitors for effective combinatorial therapy. During the next five years, I propose (1) to define the Ph-like ALL phosphosignature and to predict responses to signal transduction inhibitors, (2) to discover the most potent PI3K pathway signal transduction inhibitor in Ph-like ALL and to identify compensatory upregulation of signaling proteins as a potential mechanism of treatment failure, and (3) to determine the chemosensitization potential of PI3K pathway signal transduction inhibitor treatment in Ph-like ALL. Successful development of these laboratory and clinical research strategies will ultimately allow me to lead a translational research program in developmental therapeutics for children with clinically high-risk leukemias.