Chemotherapy response is the primary determinant of long term survival for patients with osteosarcoma (OS), where patients who are resistant to chemotherapy are considered incurable. The ultimate goal of this study is to identify the molecular pathways controlling chemotherapy resistance in OS. To achieve this goal, we will develop a novel transposon-mutagenesis mouse model to evaluate chemotherapy resistance and utilize transposon insertion sites identify which genes confer chemotherapy resistance. The results of this study may identify novel prognostic biomarkers and reveal new drug targets to overcome chemoresistance in osteosarcoma,
The Sleeping Beauty (SB) transposon system can generate mouse OS with a diverse array of genetic mutations (Moriarity et. al. 2015). In this study, primary cell lines from these tumors will be transplanted into immunodeficient mice and animals will be treated with combination chemotherapy. RNA-sequencing analysis and transposon mapping will specifically identify genes mutated in chemotherapy resistant tumors. Candidate genes will be validated in human OS tissues and functional characterization of these genes will be performed in vitro and in vivo. Furthermore, pharmacological therapies to target chemoresistance mechanisms will also be evaluated in vitro and in animal models. Together these studies will provide insight into the genetic basis of chemoresistant OS.