Osteosarcoma Patient-derived Orthotopic Xenograft (PDOX) Models Used to Identify Novel and Effective Therapeutics: A Review

Abstract

Background/Aim: Recurrent osteosarcoma is recalcitrant with poor response rates to first-line chemotherapy due to heterogeneity and metastatic potential. This disease requires novel drug discovery and precision treatment. Materials and Methods: The osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model mimics the clinical disease and has identified effective clinically-approved drugs and experimental agents, especially drug combinations, that hold much clinical promise. Results: Effective treatment for drugresistant osteosarcoma includes regorafenib, as monotherapy, and temozolomide-irinotecan, trabectedin-irinotecan, sorafenibeverolimus, sorafenib-palbociclib, and olaratumab-doxorubicincisplatinum, as combinations. Conclusion: The PDOX model can be used to improve the outcome of osteosarcoma patients, including individualized, precision therapy. Doxorubicin (DOX), cisplatinum (CDDP), ifosfamide (IFO), and methotrexate (MTX) are first-line therapy for osteosarcoma (1-4). However, osteosarcoma frequently develops resistance to chemotherapy after initial treatment, resulting in tumor recurrence, often metastatic and thereby fatal to the patient (5, 6). Therefore, development of new precision treatment is necessary.The patient-derived orthotopic xenograft (PDOX) model has been developed for sarcoma and mimics the malignant behavior of osteosarcoma due to the natural tumor microenvironment (TME) of the orthotopically-implanted tissue (7-12). Surgical orthotopic implantation (SOI) was used to establish the PDOX models (7-12).The present report reviews the osteosarcoma PDOX models, and their potential to discover effective agents, especially combinations for drug-resistant disease. Patient No. 1. Establishment of a Drug-Resistant Recurrent Osteosarcoma PDOXThe first osteosarcoma PDOX was established from a chondroblastic osteosarcoma of the left distal-femur from a 16-year-old patient who had pre-operative chemotherapy containing CDDP and a limb-salvaging tumor resection with an endoprosthesis (10). One year after the primary surgery, lung metastases were found and metastasectomy was performed. Fresh specimens of the lung metastasis were obtained and immediately taken to our laboratory on wet ice (Figure 1A). The tumor sample was divided into small fragments with surrounding normal tissue in cell-culture medium and subcutaneously implanted on the flank of nude mice (Figure 1B and C). For PDOX establishment, subcutaneous tumors were harvested and divided into 3-4 mm fragments (Figure 1D and E). The vastus-lateralis muscle of the nude mouse was incised and the biceps-femoris muscle was split to expose the distal femur. Subsequently, an incision 5865 This article is freely accessible online.

Review: Precise sarcoma patient-derived orthotopic xenograft (PDOX) mouse models enable identification of novel effective combination therapies with the cyclin-dependent kinase inhibitor palbociclib: A strategy for clinical application

“…Osteosarcoma is the most common malignant primary bone tumor ( 12 ). Resistance to traditional first-line chemotherapy drugs, such as doxorubicin and cisplatinum, leads to local and distance recurrence that is often fatal to patients, which are mostly adolescents and young adults ( 12 ). Osteosarcoma tends to have abnormal cell cycle control regulators, including CDKN2A and CDK4 ( 16 ).…”

“…The osteosarcoma PDOX model was established using SOI by implanting a tumor fragment into a space made by cutting the lateral condyle of the distal femur of nude mice ( Figure 1C ) ( 12 ). The patient tumor used for this osteosarcoma PDOX model was from a fresh biopsy sample of a pelvic osteosarcoma ( 34 ).…”

“…The PDOX models mimic the clinical disease, including the malignant behavior of sarcoma, due to their natural tumor microenvironment ( 7 – 11 ). The PDOX models, established from patients with many cancer types, including sarcoma, have identified effective treatments that hold much clinical promise ( 1 , 12 ). The present report reviews sarcoma PDOX models thus far established and their potential to discover effective combination treatment, based on CDK inhibitors, for recalcitrant sarcoma.…”

Research Status of Mouse Models for Non-Small-Cell Lung Cancer (NSCLC) and Antitumor Therapy of Traditional Chinese Medicine (TCM) in Mouse Models

“…Orthotopic models were established by directly implanting tumor cells or fresh tumor tissues into mice in the anatomical location from which they were originally derived. As a result, the use of orthotopic implantation has resulted in tumor models resembling human cancer with respect to the biology and tumor microenvironment [ 56 , 57 ]. Therefore, orthotopic models allow the evaluation of tumor behavior in an organ-specific microenvironment.…”

MicroRNA34a is associated with chemotherapy resistance, metastasis, recurrence, survival, and prognosis in patient with osteosarcoma

“…[ 1 , 2 ] The potential mechanisms of OS development and progression remain to be elucidated, due to the high complexity of the occurrence and metastasis. [ 3 , 4 ] Clinically, OS is derived from the metastasis of other human cancer, such as breast cancer, gastric cancer, and prostate cancer. [ 5 ] OS is a malignant mesenchymal neoplasm that accounts for ~35% primary bone tumors in human.…”