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

Abstract

BackgroundLenvatinib 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.MethodWe 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.ResultLenvatinib 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 significant antitumor activity in KP-1/VEGF and five 5 of 7 different types of human tumor xenograft models at between 1 to 100 mg/kg. We divided 19 human tumor xenograft models into lenvatinib-sensitive (tumor-shrinkage) and relatively resistant (slow-growth) subgroups based on sensitivity to lenvatinib treatments at 100 mg/kg. IHC analysis showed that vascular score was significantly higher in sensitive subgroup than relatively resistant subgroup (p < 0.0004). Among 18 types of human primary tumors, kidney cancer had the highest MVD, while liver cancer had the lowest pericyte coverage, and cancers in Kidney and Stomach had highest vascular score.ConclusionThese results indicated that Lenvatinib inhibited VEGF- and FGF-driven angiogenesis and showed a broad spectrum of antitumor activity with a wide therapeutic window. MVD and pericyte-coverage of tumor vasculature might be biomarkers and suggest cases that would respond for lenvatinib therapy.

Lenvatinib induces early tumor shrinkage in patients with advanced thyroid carcinoma

“…It is an oral multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor (VEGFR)1-3, fibroblast growth factor receptor (FGFR)1-4, platelet-derived growth factor receptor alpha (PDGFR-α), ret proto-oncogene (RET), and KIT proto-oncogene [3][4][5]. In the phase 3 trial, lenvatinib prolonged progression-free survival (PFS; hazard ratio for progression or death, 0.21; 99 %CI, 0.14-0.31, p<0.001) by 14.7 months (lenvatinib median PFS, 8.3 months) compared with placebo (median PFS, 3.6 months) [6].…”

FGFR a promising druggable target in cancer: Molecular biology and new drugs

“…A notable array of compounds have been described in recent years to (partially) inhibit FGFR, next to other Tyrosine Kinase Receptor (TKR), including Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet Derived Growth Factor Receptor (PDGFR), Fms-like tyrosine kinase 3 (FLT-3), c-Kit (c-KIT), Rearranged during transfection (RET) and BCR-ABL. These compounds include Brivatinib (Cai et al, 2008), Lenvatinib (Yamamoto et al, 2014), Regorafenib (Wilhelm et al, 2011), Ponatinib (Gozgit et al, 2012), Dovitininb (Porta et al, 2015), Nintedanib (Dhillon, 2015), Pazopanib (Prince et al, 2009), Orantinib (Ohta et al, 2009), ENMD 2076 (Matulonis et al, 2013), Lucitanib (Bello et al, 2011), PBI 05204 (Hong et al, 2014), Sunitinib (Welti et al, 2011) and Cediranib (Wedge et al, 2005). Although some of them have achieved approval for use against several cancer types, this section only focuses on those multi-target inhibitors that have included a subset of patients with FGFR alterations (Table 1).…”

Lenvatinib in Advanced, Radioactive Iodine–Refractory, Differentiated Thyroid Carcinoma

“…Despite the in vitro studies, lenvatinib showed significant antitumor activity in five DTC xenograft nude mouse models (25). This supports the notion that lenvatinib specifically targets the microvascular environment dependent on angiogenic VEGFR and FGFR signaling pathways rather than tumor proliferation pathways or cell cycle.…”