E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models
- 14 February 2011
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 71 (4), 1396-1405
- https://doi.org/10.1158/0008-5472.can-10-2700
Abstract
Tumor angiogenesis is a degenerate process regulated by a complex network of proangiogenic factors. Existing antiangiogenic drugs used in clinic are characterized by selectivity for specific factors. Antiangiogenic properties might be improved in drugs that target multiple factors and thereby address the inherent mechanistic degeneracy in angiogenesis. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) family members and their cognate receptors are key players in promoting tumor angiogenesis. Here we report the pharmacologic profile of E-3810, a novel dual inhibitor of the VEGF and FGF receptors. E-3810 potently and selectively inhibited VEGF receptor (VEGFR)-1, -2, and -3 and FGF receptor (FGFR)-1 and -2 kinases in the nanomolar range. Ligand-dependent phosphorylation of VEGFR-2 and FGFR-1 was suppressed along with human vascular endothelial cell growth at nanomolar concentrations. In contrast, E-3810 lacked cytotoxic effects on cancer cell lines under millimolar concentrations. In a variety of tumor xenograft models, including early- or late-stage subcutaneous and orthotopic models, E-3810 exhibited striking antitumor properties at well-tolerated oral doses administered daily. We found that E-3810 remained active in tumors rendered nonresponsive to the general kinase inhibitor sunitinib resulting from a previous cycle of sunitinib treatment. In Matrigel plug assays performed in nude mice, E-3810 inhibited basic FGF-induced angiogenesis and reduced blood vessel density as assessed by histologic analysis. Dynamic contrast-enhanced magnetic resonance imaging analysis confirmed that E-3810 reduced the distribution of angiogenesis-sensitive contrast agents after only 5 days of treatment. Taken together, our findings identify E-3810 as a potent antiangiogenic small molecule with a favorable pharmacokinetic profile and broad spectrum antitumor activity, providing a strong rationale for its clinical evaluation.Keywords
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This publication has 44 references indexed in Scilit:
- Fibroblast Growth Factor Receptor Signaling Dramatically Accelerates Tumorigenesis and Enhances Oncoprotein Translation in the Mouse Mammary Tumor Virus–Wnt-1 Mouse Model of Breast CancerCancer Research, 2010
- Molecular Mechanisms of Resistance to Tumour Anti-Angiogenic StrategiesJournal of Oncology, 2010
- The FGF family: biology, pathophysiology and therapyNature Reviews Drug Discovery, 2009
- Combination of antiangiogenesis with chemotherapy for more effective cancer treatmentMolecular Cancer Therapeutics, 2008
- Modes of resistance to anti-angiogenic therapyNature Reviews Cancer, 2008
- FGFR1 amplification in breast carcinomas: a chromogenic in situhybridisation analysisBreast Cancer Research, 2007
- AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma PatientsCancer Cell, 2007
- Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3bCarcinogenesis: Integrative Cancer Research, 2005
- Tumour-educated macrophages promote tumour progression and metastasisNature Reviews Cancer, 2004
- The Hallmarks of CancerCell, 2000