Osteosarcoma is a disease in which the recent lack of progress in improving patient survival strongly suggests the need for novel treatment approaches. A panel of well characterized osteosarcoma patient derived xenografts with genetic changes recapitulating the disease, have been tested by our laboratory as part of the Pediatric Preclinical Testing Program. These efforts thus far have been highly successful in identifying several drugs which are currently being or about to be tested in osteosarcoma clinical trials conducted by the Children’s Oncology Group – specifically eribulin and glembatumumab vedotin. Numerous additional osteosarcoma patient derived xenograft models have been developed potentially permitting expansion of the panel of tumors assessed. In this proposal exploration of using a more efficient approach to screen for drug activity in the established models may permit utilization of a broader panel of osteosarcoma patient derived xenografts. In this proposal eltrombopag will be explored for activity in the treatment of osteosarcoma based on promising in vitro data. Building on prior findings, eribulin will be tested for additive activity with agents routinely used in the treatment of osteosarcoma including cisplatin, cyclophosphamide and etoposide. Finally, a novel ALK inhibitor that also has IGF-1R inhibitory activity, certinib, will be tested as a single agent and in combination with rapamycin for activity in the osteosarcoma patient derived xenografts. These results can be informative for future osteosarcoma clinical trials development as well as potentially identify novel agents that can be considered for clinical trials.