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 89
- Downloads 0
MEK Inhibitors in Combination with Immune Checkpoint Inhibition: Should we be Chasing Colorectal Cancer or the KRAS Mutant Cancer
In the past few years, immunotherapy, particularly immune checkpoint inhibitors, have redefined standard of care cancer treatment for numerous malignancies. However, despite the wealth of promising data and great enthusi...
Novel Strategies to Improve Rituximab Efficacy in Non-Hodgkin’s Lymphomas
Non-Hodgkin’s lymphomas (NHLs) are the second fastest growing cancer in terms of incidence and deaths in the United States and Europe. NHLs are a heterogeneous cancer group including several haematological neoplasias wit...
Total Oncology is necessary for Japanese new era
Still in Japan, medical oncologists need to play a main role and work a lot of tasks by themselves in cancer chemotherapy. The situation of cancer chemotherapy has progressed day by day and considering the current enviro...
Angiosarcoma of the Scalp and Face: A Hard to Treat Tumor
Cutaneous angiosarcoma is a rare and aggressive malignant tumor of vascular origin. Multimodality treatment including surgery, radiotherapy and chemotherapy should be used according to age and local spread. Prognosis is...
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...