Lenvatinib Suppresses Angiogenesis through the Inhibition of both the VEGFR and FGFR Signaling Pathways
Journal Title: Global Journal of Cancer Therapy - Year 2016, Vol 2, Issue 1
Abstract
Lenvatinib mesilate (lenvatinib) is an oral multiple-receptor tyrosine kinase inhibitor that selectively inhibits the kinase activities of Vascular Endothelial Growth Factor Receptor (VEGFR) 1-3, Fibroblast Growth Factor Receptor (FGFR) 1-4, Platelet-Derived Growth Factor Receptor (PDGFR) α, KIT, and RET. The VEGFR and FGFR signaling pathways are the master regulators of normal and tumor angiogenesis. Lenvatinib showed significant activity in patients with radioiodine-refractory thyroid cancer in a Phase III study and is used in the United States, the European Union, and Japan. Moreover, based on Phase II study, lenvatinib has been approved in the United States for the treatment of patients with advanced renal cell carcinoma in combination with everolimus. In addition, the efficacy of lenvatinib is being evaluated in other cancers, including hepatocellular carcinoma and endometrial cancer. The purpose of this study was to elucidate the mechanism underlying the clinical activities of lenvatinib by using in vitro and in vivo angiogenesis models. First, we established an in vitro tube formation system, in which capillary-like structures formed on basement membrane extract in response to pro-angiogenic factors. Lenvatinib suppressed tube formation induced by bFGF alone and by bFGF plus VEGF. Furthermore, plasma levels of VEGF and FGF23, pharmacodynamic biomarkers of inhibition of the VEGFR and FGFR signaling pathways, respectively, were up-regulated after the administration of lenvatinib to mice. By contrast, the administration of another VEGFR inhibitor, sorafenib tosylate (sorafenib), up-regulated plasma levels of VEGF but not FGF23. Finally, lenvatinib suppressed bFGF-driven angiogenesis in Matrigel plug assays at low dosage (3 mg/kg), whereas sorafenib did so only at a higher dose (30 mg/kg). These results indicate that lenvatinib inhibits both VEGFR and FGFR in vitro and in vivo. This combined inhibition of both VEGFR and FGFR may lead significant clinical activities.
Authors and Affiliations
Ichikawa Kenji, Miyano Saori Watanabe, Adachi Yusuke, Matsuki Masahiro, Okamoto Kiyoshi, Matsui Junji
Keywords
Related Articles
- EP ID EP352858
- DOI 10.17352/2581-5407.000009
- Views 102
- Downloads 0
The Paradoxes of Neoantigenes in Predicting Better Prognosis of Cancer Patients
Increased neoantigens of cancer generated by mutations are reported to be associated with favorable prognosis of cancer patients. The interesting findings contradict the notions that cancers were caused by accumulation o...
Financial Crisis and Health
The financial crisis has a dramatic impact on social life, since reduced or even non-existent incomes affect people’s well-being and push big parts of the population to poverty. The individuals’ financial status affects...
Video Endoscopic Inguinal Lymphadenectomy: Refining surgical technique after ten years experience
Penile carcinoma is a rare malignant disease with a significantly higher incidence in some areas of under- developed countries [1]. Inguinal nodal involvement is found in 20% to 40% of cases at diagnosis and nodal metast...
A Novel Small-Molecule Integrin Antagonist Inhibits Cells Adhesion Followed By Anoikis in Endothelial Cells - A Comparative Analysis with Cilengitide
Background: Despite the crucial role of integrin receptors in cancer pathogenesis and massive efforts towards establishing clinically relevant drugs, to the present no effective integrin antagonist for the treatment of m...
Identification of Combinatorial Drugs that Synergistically Kill both Eribulin-Sensitive and Eribulin-Insensitive Tumor Cells
Eribulin sensitivity was examined in a panel of twenty-five human cancer cell lines representing a variety of tumor types, with a preponderance of breast and lung cancer cell lines. As expected, the cell lines vary in se...