Abstract 1374: Lenvatinib, tri-specific targeted therapy to VEGFR/FGFR/RET, suppresses angiogenesis through the inhibition of both VEGFR and FGFR signaling pathways
Authors: Ichikawa Kenji , Miyano Saori Watanabe , Adachi Yusuke , Yamamoto Yuji , Ozawa Yoichi , Funahashi Yasuhiro , Okamoto Kiyoshi , Nomoto Kenichi , Matsui Junji 
Published: August 2015

Abstract
Lenvatinib mesilate (lenvatinib) is an oral multiple receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor receptors (VEGFR1-3), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor receptors (FGFR1-4), the platelet-derived growth factor receptor (PDGFR) α, KIT, and RET. Recently, lenvatinib showed a highly statistically significant improvement of progression free survival compared to placebo control in subjects with radioiodine-refractory differentiated thyroid cancer in a Phase 3 trial. To elucidate the mechanism of action in anti-tumor effect by lenvatinib, we examined the antiangiogenic activity of lenvatinib in the VEGF and FGF driven angiogenesis models both in vitro and in vivo.
First, in in vitro angiogenesis model, lenvatinib inhibits both VEGF-driven and FGF-driven tube formation of HUVEC at almost similar dose (IC50 values are 2.1 nmol/L and 7.3 nmol/L, respectively). Next, the 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. In vivo angiogenesis induced by overexpressed VEGF (KP-1/VEGF transfectants) or FGF (KP-1/FGF4 transfectants) was significantly suppressed with oral treatments of lenvatinib at 10 and 30 mg/kg. In addtion, lenvatinib significantly inhibited bFGF-induced angiogenesis in matrigel plug assay, which is driven by recombinant human bFGF and stromal-derived mouse VEGF, at even 3 mg/kg. Increase of plasma FGF23 level is PD biomarker for an inhibition of FGFR1 signaling and it has been known that plasma FGF23 level is up-regulated by administration of FGFR inhibitors in mice. Lenvatinib at 10 mg/kg significantly elevated mice FGF23 levels 24 hours after lenvatinib treatment in a dose dependent manner.
In conclusion, lenvatinib has potent both VEGF and FGF driven-antiangiogenic activity in vitro and in vivo. Inhibition of FGFR signaling pathway with lenvatinib was also supported by increase of plasma FGF23 levels at the same dose to show an inhibition in FGF-driven in vivo angiogenesis model. Therefore, the significant clinical outcome might be based on the unique antiangiogenesis activity of lenvatinib, in particular VEGFR and FGFR inhibition, which should be further investigated.
Citation Format: Kenji Ichikawa, Saori Watanabe Miyano, Yusuke Adachi, Yuji Yamamoto, Yoichi Ozawa, Yasuhiro Funahashi, Kiyoshi Okamoto, Kenichi Nomoto, Junji Matsui. Lenvatinib, tri-specific targeted therapy to VEGFR/FGFR/RET, suppresses angiogenesis through the inhibition of both VEGFR and FGFR signaling pathways. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1374. doi:10.1158/1538-7445.AM2015-1374