Osteosarcoma patient-derived orthotopic xenograft (PDOX) models for identification of novel and effective therapeutics.

228 Background: Osteosarcoma is the most common malignant primary tumor of bone and mainly occurs in young generations. Due to the heterogeneity, rarity, poor response rate to systemic therapy, and metastatic potential of osteosarcoma, individualized precision medicine and novel drug discovery are greatly needed. Toward this goal, we have established the patient-derived orthotopic xenograft (PDOX) mouse model with surgical orthotopic implantation for all major cancers. The PDOX models recapitulate human tumors better than subcutaneous-transplanted xenografts including patient-derived xenograft (PDX). Metastasis is observed to a greater extent in PDOX models due to the intact histology and correct-organ tumor micro-environment of the orthotopically implanted tissue. Therefore, the PDOX model is highly predictive of drug efficacy and useful for identifying effective drugs for tumors in which new drugs are difficult to develop. Methods: We have reported 18 osteosarcoma PDOX studies evaluating approved and experimental drugs since 2017. The present report reviews our research group’s experience with the osteosarcoma-PDOX model, and the power of the PDOX models to identify effective therapeutics. Results: Effective treatment for drug-resistant osteosarcoma includes regorafenib, as monotherapy, and temozolomide-irinotecan, trabectedin-irinotecan, sorafenib-everolimus, sorafenib-palbociclib, and olaratumab-doxorubicin-cisplatin, as combinations. Experimental therapy with recombinant methioninase, tumor-targeting S. typhimurium A1-R, or combinations of these agents and other drugs have shown surprising efficacy in the recalcitrant-osteosarcoma PDOX models. Conclusions: Owing to the high concordance of drug efficacy between patients and their corresponding PDOX models, these models provide improved and personalized treatment options for patients with osteosarcoma. The patient does not need to suffer from the potential drug toxicity and morbidity of ineffective chemotherapies. In an era of growing promise of new treatment and precision medicine, PDOX models can offer a unique opportunity to provide specific and individualized therapy and novel therapeutic options for osteosarcoma patients.