PATIENT-DERIVED TUMOR XENOGRAFT MODELS AS A PLATFORM FOR INVESTIGATING MULTIDRUG RESISTANCE IN OSTEOSARCOMA

INTRODUCTION AND OBJECTIVES: Osteosarcoma (OS) is the most common malignant bone neoplasm in children and young people. The survival of patients with metastatic disease is still low and the percentage of “poor responders” is between 47% to 71%. One of the mechanisms that may be associated with the poor response is the multidrug resistance (MDR) phenotype, and the expression of ABC superfamily transmembrane proteins. The difficulty of relevant clinical trials for a disease considered orphan from a commercial point of view is evident. Patient-derived xenograft (PDX) model is reproducible for several types of sarcomas and, in addition to recapitulating the phenotypic characteristics of the primary OS. This study aims to validate the OS PDX model, which has already been established by our group, as a tool for evaluating MDR by mapping the expression profile of ABC transporters. MATERIAL AND METHODS: The study was approved by human (CAAE: 69859417.20000.5273) and animal (014/2022) ethics committees. Tumor tissue samples were collected at the time of biopsy or surgical resection avoiding necrotic areas. After sectioning, fragments were stored in RNA later® and maintained in culture medium at 4oC until implantation. Fragments were implanted in the subcutaneous tissue of NOD scid gamma (NSG™) mice. Tumor growth was monitored once a week and when the tumor size reached the approximate volume of 1500 mm3, it was transplanted to the next generation (P2) and processed for histological analysis and RNA extraction. RESULTS AND CONCLUSION: Over a period of four months, samples were collected from six patients, average age of 31 years, with histopathological diagnosis of osteosarcoma. Two samples were collected at biopsy and four at resection/disarticulation surgeries. We observed tumor growth in four out of six samples (66% engraftment rate). Two samples reached the second passage (P1) and none reached P2 after four months. The mean growth period of the samples that achieved P1 was 122.8 ± 17.6 days with a mean volume of 958.1 ± 638.1 mm3. Also, our preliminary results confirmed the histological consistency with the corresponding parental osteosarcoma. Therefore, we consider the PDX a suitable model for preclinical tests and a promising tool to investigate and address several unanswered issues in clinical oncology.