title: Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage.
abstract: 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Matsui
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsushima
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Obaishi
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Miyazaki
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Katsuji
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Biomarkers and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Tohyama
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Semba
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Atsumi
authors.initials: A
authors.lastname: Yamaguchi
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Sachi Suzuki
authors.initials: SS
authors.lastname: Hoshi
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Fusayo
authors.initials: F
authors.lastname: Mimura
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Haneda
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fukuda
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Kamata
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsukura
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Wakabayashi
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Asada
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Nomoto
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Biomarkers and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810, U.S.A.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Dezso
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshimatsu
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.|Biomarkers and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810, U.S.A.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Funahashi
authors.affiliation: Oncology Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tsuruoka
keywords: FGFR kinase inhibitor; Lenvatinib; Microvessel density; Pericyte coverage; VEGFR2 kinase inhibitor