Our long-term goal is to advance cure rates for children with malignant solid tumors. The program has been reorganized to focus efforts on developmental therapeutics, testing laboratory driven hypotheses in unique preclinical xenograft models of childhood cancers, with subsequent design of clinical trails that simulate schedules and systemic exposures found optimal in these models. Project 1 will study of the role of IGF signaling in mitogenesis and arrested differentiation of rhabdomyosarcoma (RMS). The potential of IGF signaling as a target for new approaches to treatment will be tested in xenograft models using rapamycin analogs which potentialy inhibit this pathway. Project 2 will build on the finding that apoptosis caused by specific agents is dependent on a functional p53 tumor suppressor gene, define classes of cytotoxic agents that are p53-dependent, and whether expression of oncogenes associated with embryonal and alveolar RMS modifies this dependence. P53 is mutated in many rhabdomyosarcoma cell lines, and MDM2 is amplified in approximately 30 percent of RMS biopsies. Work proposed will extend the studies of p53 and MDM2 to additional clinical specimens from patients enrolled in Project 5. Project 3 and 4 have a common focus: anticancer agents that target topoisomerase I. In Project 3 the mechanism by which camptothecin topoisomerase I inhibitors cause cellular redistribution of their target, and its therapeutic significance will be examined in vitro, in xenograft models, and in biopsies of neuroblastoma and RMS from patients enrolled on topotecan studies in Project 5. Project 4 will determine pharmacokinetic and pharmacodynamic relations for camptothecin analogs in different xenograft models to further understand the basis for dramatic schedule-dependency of topotecan, and the enhanced activation of irinotecan in tumor-bearing mice. Studies will be extended to determination of carboxylesterase activities associated with different childhood solid tumors. A non-human primate model will be used to model disposition of camptothecin derivatives in CSF for treatment of leptomeningeal disease. Project 5 comprises Phase I and II clinical trials with topotecan and irinotecan each of which is based on our laboratory and xenograft data. These protocols are supported by pharmacokinetic studies that ensure optimal systemic exposure, and biochemical studies designed to increase our understanding of parameters that determine therapeutic efficacy of camptothecin-based topoisomerase I inhibitors used alone or in combination. We will also evaluate the rapamycin analog (WAY1290327), to test the feasibility of IGF-I targeted therapy, proposed in Project 1.
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