Abstract 3266: Antitumor activity of a combination of lenvatinib mesilate, ifosfamide, and etoposide against human pediatric osteosarcoma cell lines

Abstract

Lenvatinib mesilate (lenvatinib) is an orally administered molecular targeted agent that selectively inhibits several receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), platelet-derived growth factor receptor (PDGFR) α, RET, and KIT. Lenvatinib has been marketed for the treatment of advanced or differentiated thyroid cancer refractory to radioactive iodine. Lenvatinib showed antitumor activity against various tumor types mainly through its potent inhibition of angiogenesis. In this study we evaluated the antitumor activities of lenvatinib in combination with ifosfamide and etoposide against human pediatric osteosarcoma cell lines. Five human pediatric osteosarcoma cell lines (143B, G-292 clone A141B1, HOS, HuO9, and Saos-2) were used. Antiproliferative activity of lenvatinb and etoposide was evaluated in WST-8-based colorimetric proliferation assay or in soft agar colony formation assay. To evaluate the in vivo antitumor activity, lenvatinib alone, the combination of etoposide and ifosfamide, and the combination of these 3 drugs were administered to mice bearing the human osteosarcoma xenografts. Etoposide inhibited cell proliferation with IC50 values of a range within 0.31 - 4.1 μmol/L. G-292 clone A141B1 (G-292) had the lowest sensitivity to etoposide. Four human osteosarcoma cell lines out of five were not sensitive to lenvatinib in proliferation assay (IC50 values >10 μmol/L), and only G-292 was susceptible to lenvatinib with IC50 values of 1.3 and 0.059 μmol/L in proliferation assay or soft agar colony formation assay, respectively. G-292 has been reported to have FGFR1 amplification and shows high transcript expression of FGFR1, suggesting that the antiproliferative activity of lenvatinib could be mediated by the FGFR1 blockade. In all xenograft models, tumor volumes with the triple combination treatment were significantly lower than that with vehicle treatment on Day 8. Antitumor effect of the triple combination was significantly more potent than that of lenvatinib alone and the ifosfamide-etoposide combination in 143B, G-292, and HOS, and more potent than that of lenvatinib alone in HuO9 and Saos-2 xenograft models. The triple combination of lenvatinib, ifosfamide, and etoposide was active against all examined human pediatric osteosarcoma xenografts in mice, and lenvatinib enhanced antitumor activity of the ifosfamide-etoposide combination in 3 out of 5 models. These results support further investigation of the combination of lenvatinib with ifosfamide and etoposide in osteosarcoma. In addition, direct antitumor activity of lenvatinib against the osteosarcoma cells harboring FGFR1 amplification warrants further investigation. Citation Format: Masahiro Matsuki, Kiyoshi Okamoto, Zoltan Dezso, Sergei I. Agoulnik, Yasuhiro Funahashi, Junji Matsui. Antitumor activity of a combination of lenvatinib mesilate, ifosfamide, and etoposide against human pediatric osteosarcoma cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3266.