Lgarashi K1,2,3, Murakami T1,2, Kawaguchi K1,2, Kiyuna T1,2, Miyake K1,2, Zhang Y1, Nelson SD4, Dry SM4, Li Y4, Yanagawa J5, Russell TA5, Singh AS6, Tsuchiya H3, Elliott I5, Eilber FC5, Hoffman RM1,2.Author information
1.- AntiCancer, Inc., San Diego, California, USA.
2.- Department of Surgery, University of California, San Diego, California, USA.
3.- Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan.
4.- Department of Pathology, University of California, Los Angeles, California, USA.
5.- Division of Surgical Oncology, University of California, Los Angeles, California, USA.
6.- Division of Hematology-Oncology, University of California, Los Angeles, California, USA.
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 sizes and body weight were measured with calipers and a digital balance 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 precisely maintaining the CDDP resistance of the tumor in the patient, thereby demonstrating the potential of the osteosarcoma PDOX model for precision oncology.