Core E

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The Preclinical Testing Core (PTC) will validate the activity of agents against newly identified targets in _anels of developmental solid tumor cell lines and xenografts. Specific aims of the core include: 1) maintaining and developing a representative panel of pediatric solid tumor cell lines and xenografts, 2) rapid in vitro screening of potential new agents in a representative panel of pediatric solid tumor cell lines (Level 1), 3) in vivo testing of potential new agents at the murine MTD to identiy those agent appropriate for advanced evaluation (Level 2), and 4) advanced in vivo evaluation of selected agents (Level 3). Level 1 testing will include the in vitro analysis of new targeted therapies against a panel of cell lines including OS, ESFT, RMS, DSRCT and NB. Those agents that demonstrate in vitro cytotoxic effects at concentrations that can be achieved in humans or for agents without a known MTD by comparison with related chemotherapeutic agents will be advanced to Level 2 testing. Level 2 testing includes the determination of the murine species-specific MTD for the compound, and the evaluation of the anti-tumor effect of the new agent at that MTD in tumor-bearing mice. Those agents that demonstrate promising activity will be advanced to Level 3 testing. For non-cytotoxic agents, biologic endpoints, such as target binding or inhibition, will be evaluated. Level 3 testing includes the determination of a dose-response relationship for the new compound, the in vivo pharmacokinetics and the potential interaction of the new compound in combination with rationally chosen known chemotherapeutic agents. Alternative models including immune intact or heterotopic/metastatic tumors will be considered. The PTC will facilitate rapid advances in specific projects by 1) identifying those agents with activity against a comprehensive panel of pediatric tumors in vitro, 2) providing an efficient means of evaluating new agents in xenograft models of pediatric tumors and 3) providing a standardized system of preclinical testing and prioritization of new agents for clinical studies.