Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage

作者：Yuji Yamamoto, Junji Matsui, Tomohiro Matsushima, Hiroshi Obaishi, Kazuki Miyazaki, Katsuji Nakamura, Osamu Tohyama, Taro Semba, Atsumi Yamaguchi, Sachi Hoshi, Fusayo Mimura, Toru Haneda, Yoshio Fukuda, Junichi Kamata, Keiko Takahashi, Masayuki Matsukura, Toshiaki WAKABAYASHI, Makoto Asada, K. Nomoto, Tatsuo Watanabe, Zoltán Dezső, Kentaro Yoshimatsu, Yasuhiro Funahashi, Akihiko Tsuruoka · 发表于：Vascular Cell · 年份：2014 · DOI：10.1186/2045-824x-6-18 · 被引用次数：504 · 研究领域：Fibroblast Growth Factor Research、Angiogenesis and VEGF in Cancer、MRI in cancer diagnosis

BACKGROUND: Lenvatinib is an oral inhibitor of multiple receptor tyrosine kinases (RTKs) targeting vascular endothelial growth factor receptor (VEGFR1-3), fibroblast growth factor receptor (FGFR1-4), platelet growth factor receptor α (PDGFR α), RET and KIT. Antiangiogenesis activity of lenvatinib in VEGF- and FGF-driven angiogenesis models in both in vitro and in vivo was determined. Roles of tumor vasculature (microvessel density (MVD) and pericyte coverage) as biomarkers for lenvatinib were also examined in this study. METHOD: We evaluated antiangiogenesis activity of lenvatinib against VEGF- and FGF-driven proliferation and tube formation of HUVECs in vitro. Effects of lenvatinib on in vivo angiogenesis, which was enhanced by overexpressed VEGF or FGF in human pancreatic cancer KP-1 cells, were examined in the mouse dorsal air sac assay. We determined antitumor activity of lenvatinib in a broad panel of human tumor xenograft models to test if vascular score, which consisted of high MVD and low pericyte coverage, was associated with sensitivity to lenvatinib treatment. Vascular score was also analyzed using human tumor specimens with 18 different types of human primary tumors. RESULT: Lenvatinib inhibited VEGF- and FGF-driven proliferation and tube formation of HUVECs in vitro. In vivo angiogenesis induced by overexpressed VEGF (KP-1/VEGF transfectants) or FGF (KP-1/FGF transfectants) was significantly suppressed with oral treatments of lenvatinib. Lenvatinib showed signifi...