In order to identify more effective
therapy for recalcitrant
osteosarcoma, we evaluated the efficacy of an mTOR-VEGFR inhibitor combination on
tumor growth in a unique
osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model derived from the lung
metastasis of an
osteosarcoma patient who failed
doxorubicin therapy. We also determined the efficacy of this inhibitor combination on angiogenesis using an in vivo
Gelfoam fluorescence angiogenesis mouse model implanted with
osteosarcoma patient-derived cells (OS-PDCs). PDOX models were randomly divided into five groups of seven nude mice. Group 1, control; Group 2,
doxorubicin (DOX); Group 3,
everolimus (EVE, an mTOR and
VEGF inhibitor); Group 4,
pazopanib (PAZ, a VEGFR inhibitor); Group 5, EVE-PAZ combination.
Tumor volume and
body weight were monitored 2 times a week. The in vivo
Gelfoam fluorescence angiogenesis assay was performed with implanted OS-PDCs. The nude mice with implanted
Gelfoam and OSPDCs also were divided into the four therapeutic groups and vessel length was monitored once a week. The EVE-PAZ combination suppressed
tumor growth in the
osteosarcoma PDOX model and decreased the vessel length ratio in the in vivo
Gelfoam fluorescent angiogenesis model, compared with all other groups (p < 0.05). There was no significant
body-weight loss in any group. Only the EVE-PAZ combination caused
tumor necrosis. The present study demonstrates that a combination of an mTOR-
VEGF inhibitor and a VEGFR inhibitor was effective for a DOX-resistant lung-metastatic
osteosarcoma PDOX mouse model, at least in part due to strong anti-angiogenesis efficacy of the combination.