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The antitumor activity of lenvatinib (LEN) in combination with everolimus (EVE) in human renal cell carcinoma (RCC) xenograft models is dependent on VEGFR and FGFR signaling

Date

10 Oct 2016

Session

Poster display

Presenters

Takayuki Kimura

Citation

Annals of Oncology (2016) 27 (6): 1-14. 10.1093/annonc/mdw362

Authors

T. Kimura1, Y. Adachi2, M. Matsuki2, A. Yamaguchi2, Y. Ozawa2, K. Okamoto2, K. Mitsuhashi2, T. Hoshi2, O. Tohyama2, K. Tai2, M. Ogo2, J. Matsui2, Y. Funahashi2

Author affiliations

  • 1 Eisai Co., Ltd., 3003635 - Ibaraki/JP
  • 2 Eisai Co., Ltd., Ibaraki/JP
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Resources

Abstract 1284

Background

LEN mesylate is an oral multikinase inhibitor that selectively inhibits angiogenic or oncogenic kinase activities of vascular endothelial growth factor receptors (VEGFR)1–3, fibroblast growth factor receptors (FGFR) 1–4, platelet-derived growth factor receptor–α, and KIT and RET proto-oncogenes. We previously reported that LEN + EVE showed significantly greater antitumor activity in human RCC xenograft models compared with each monotherapy. LEN + EVE inhibited in vitro angiogenesis driven by VEGF and FGF in an additive and a synergistic manner, respectively. Here, we examined FGFR and VEGFR signaling pathway participation in tumor growth and angiogenesis in human RCC xenografts treated with LEN + EVE.

Methods

Antitumor activity was evaluated in 2 human RCC xenograft models (A–498 and Caki–1). To assess dependence of in vivo growth of RCC xenografts on FGFR signaling, nude mice with RCC xenografts were treated daily with the selective FGFR inhibitor PD173074 (50 mg/kg, orally [p.o.]). To evaluate antiangiogenic activity, mice were treated daily with LEN (10 mg/kg, p.o.), EVE (30 mg/kg, p.o.) or LEN + EVE (10 + 30 mg/kg p.o.). Microvessel density (MVD) was evaluated by immunohistochemistry using an α-CD31 antibody.

Results

PD173074 inhibited in vivo growth of RCC xenografts. In the Caki-1 model, administration of LEN or EVE decreased MVD in tumor tissues, with significantly reduced MVD observed with LEN + EVE (P 

Conclusions

The combined activity of LEN + EVE was therefore based on 1) enhanced inhibition of VEGF- and FGF-driven angiogenesis and 2) the combination of the antiangiogenic activity of LEN and antiproliferative activity of EVE. These data demonstrate that both FGFR and VEGFR pathways are necessary for the LEN + EVE combined activity in RCC xenograft models.

Clinical trial identification

Legal entity responsible for the study

Eisai Co., Ltd

Funding

This study was funded by Eisai Co., Ltd

Disclosure

All authors are employees of Eisai Co., Ltd, Tsukuba, Ibaraki, Japan.

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