A patient-derived orthotopic xenograft (PDOX) mouse model of a cisplatinum-resistant osteosarcoma lung metastasis that was sensitive to temozolomide and trabectedin: implications for precision oncology.

Kentaro Igarashi,Takashi Murakami,Sarah M Dry,Tasuku Kiyuna,Kentaro Miyake,Yong Zhang,Scott D Nelson,Fritz C Eilber,Jane Yanagawa,Arun S Singh,Tara A Russell,Robert M Hoffman,Hiroyuki Tsuchiya,Kei Kawaguchi,Irmina Elliott,Yunfeng Li

doi:10.18632/oncotarget.19095

Abstract

In the present study, we evaluated the efficacy of trabectedin (TRAB) and temozolomide (TEM) compared to cisplatinum (CDDP) on a patient-derived orthotopic xenogrraft (PDOX) of a lung-metastasis from an osteosarcoma of a patient who failed CDDP therapy. Osteosarcoma resected from the patient was implanted orthotopically in the distal femur of mice to establish PDOX models which were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal injection, weekly, for 2 weeks); G3, TRAB (0.15 mg/kg, intravenous injection, weekly, for 2 weeks); G4, TEM (25 mg/kg, oral, daily, for 14 days). Tumor size and body weight were measured with calipers and a digital balance, respectively, twice a week. On day 14 after initiation of treatment, TEM and TRAB, but not CDDP, significantly inhibited tumor volume compared to untreated control: control (G1): 814.5±258.8 mm3; CDDP (G2): 608.6±126.9 mm3; TRAB (G3): 286.6±133.0 mm3; TEM (G4): 182.9±69.1 mm3. CDDP vs. control, p=0.07; TRAB vs. control, p=0.0004; TEM vs. control p =0.0002; TRAB vs. CDDP, p =0.0002; TEM vs. CDDP, p =0.00003. The results of the present study show that a PDOX model of an osteosarcoma lung-metastasis that recurred after adjuvant CDDP-treatment has identified potentially, highly-effective drugs for this recalcitrant disease, while accurately maintaining the CDDP resistance of the tumor in the patient, thereby demonstrating the potential of the osteosarcoma PDOX model for precision oncology.

Highlights

Osteosarcoma is a mesenchymal tumor comprising spindle cells and osteoid formation
We evaluated the efficacy of trabectedin (TRAB) and temozolomide (TEM) compared to cisplatinum (CDDP) on a patient-derived orthotopic xenogrraft (PDOX) of a lung-metastasis from an osteosarcoma of a patient who failed CDDP therapy
We previously reported that a subcutaneous transplant nude-mouse model of an ostoeosarcoma lung metastasis that occurred after adjuvant CDDP treatment of the patient, was regressed by tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R)

Summary

Introduction

Osteosarcoma is a mesenchymal tumor comprising spindle cells and osteoid formation. Osteosarcoma first-line therapy is high-dose methotrexate, cisplatinum (CDDP), doxorubicin, and ifosfamide. Temozolomide (TEM) has been used clinically against high-grade glioma [8], melanoma [9], and pediatric rhabdomyosarcomas [10]. TEM has been tested pre-clinically against osteosarcoma cells combined with a molecular targeting drug [11]. TEM has been tested as a single-agent against 6 osteosarcoma xenograft models and achieved complete response in two and stable disease in one [12]. Methylation of the O-6-methylguanineDNA methyltransferase (MGMT) gene is correlated with sensitivity to TEM and may become as a biomarker for TEM. Methylation of the MGMT gene occurred in 23.5% of osteosarcoma patients in one study [13]

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Conclusion