This proposal describes a 5 year training program for the development of an academic career as an independent investigator in Pediatric Oncology. The principal investigator (PI) has completed subspecialty training in Pediatric Hematology/Oncology at Children's Hospital of Philadelphia (CHOP). She plans to expand her scientific acumen and master new techniques related to functional genomics to understand the molecular mechanisms that contribute to leukemia and lymphoma pathogenesis and apply this knowledge to designing novel therapeutics to treat these malignancies. She will be mentored by Dr. Garrett Brodeur and co-mentored by Dr. Stephan Grupp, while conducting research in Dr. Grupp's lab. Dr. Brodeur, Professor of Pediatrics at the University of Pennsylvania School of Medicine (U. Penn) and Chief of Oncology at CHOP, is a recognized leader in signal transduction in pediatric malignancies. Dr. Grupp, an Assistant Professor of Pediatrics at U. Penn and Director of the Stem Cell Lab at CHOP, is an accomplished physician-scientist in normal B cell development and the pathogenesis of precursor- B acute lymphoblastic leukemia (pre-B ALL). An advisory committee composed of her mentor, co-mentor, and three other highly-regarded physician-scientists will provide career and scientific guidance. The research will focus on evaluating mTOR inhibitors and the role of IL-7 signaling in B cell malignancies. Pre-B ALL is the most common pediatric cancer. Overall, the prognosis for ALL in children is excellent, but in patients who are at high risk or experience relapse, treatment is often difficult and prognosis dismal. Newer, targeted agents need to be identified and integrated into the present cytotoxic chemotherapy regimens. mTOR inhibitors, such as rapamycin, RAD001, and CCI-779, are potential novel therapeutics for B cell malignancies. mTOR inhibitors have been shown to inhibit growth of mature B cells and to have antineoplastic properties in preclinical models of solid tumors and of mature B cell lymphomas. Our preliminary data suggest that rapamycin and RAD001 inhibit the growth of B precursor ALL lines in vitro, and that this inhibitory effect is reversed by IL-7. These agents also demonstrate in vivo activity in a murine model of leukemia/lymphoma. We hypothesize that mTOR inhibitors will be effective agents in the treatment of leukemia, and that one of the growth signals inhibited by these drugs will be IL-7 mediated. Thus, we will evaluate the activity of mTOR inhibitors alone and in combination with conventional chemotherapeutics using both in vitro studies and mouse models of leukemia/lymphoma. We will also investigate the role of IL-7- mediated signaling in response to mTOR inhibitors. The results from the experiments described herein have immediate clinical relevance. The Oncology Division at CHOP provides an ideal setting for training physician-scientists, given its commitment to pediatric research and making available the diverse resources at both CHOP and U. Penn campus. This environment is one in which the PI will successfully develop into an independent investigator by the end of this 5 year period.
