Cabozantinib, a Multityrosine Kinase Inhibitor of MET and VEGF Receptors Which Suppresses Mouse Laser-Induced Choroidal Neovascularization

Abstract

Choroidal neovascularization (CNV) is a leading cause of blindness in the elderly in developed countries and is particularly associated with age-related macular degeneration (AMD). Cabozantinib (CBZ) hinders the activation of multiple receptor tyrosine kinases involved in tumor angiogenesis, such as hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2). We aimed to investigate the role and mechanism of CBZ in a mouse laser-induced CNV model. In zebrafish embryos, CBZ perturbed intersegmental vessel (ISV) formation without obvious neurodevelopment impairment. In the mouse laser-induced CNV model, phosphorylated hepatocyte growth factor receptor (p-MET) and phosphorylated vascular endothelial growth factor receptor 2 (p-VEGFR2) were increased in the CNV region. CBZ intravitreal injection or oral gavage alleviated CNV leakage and the CNV lesion area without obvious intraocular toxicity, as well as disturbed the phosphorylation of MET and VEGFR2. Additionally, CBZ downregulated the expression of the hepatocyte growth factor (HGF) with no effect on the expression of the vascular endothelial growth factor (VEGF). CBZ downregulated HGF, p-MET, and p-VEGFR2 expressions in vitro, as well as inhibited the proliferation, migration, and tube formation of b-End3 cells. In summary, CBZ alleviates mouse CNV formation possibly via inhibiting the activation of MET and VEGFR2. The findings provide a novel potential therapy method for CNV patients.

Cabozantinib can block growth of neuroendocrine prostate cancer patient-derived xenografts by disrupting tumor vasculature

“…Despite increased MET and RET expression in SCNPC, our results cumulatively suggest that cabozantinib acted through mouse endothelial VEGFR2 and inhibited angiogenesis leading to hypoxia and tumor cell death regardless of MET/RET status in both LuCaP SCNPC PDX models. In support of this hypothesis, cabozantinib inhibits VEGFR2 and endothelial cell tube formation in vitro in both mouse and human endothelial cell models [ 39 , 40 ]. While our study is the first to examine the efficacy of cabozantinib in SCNPC, other preclinical prostate cancer studies in AR-active CRPC agree that VEGFR2 inhibition and disruption of the tumor vasculature could be principal components of cabozantinib-mediated tumor growth inhibition [ 36 , 41 , 42 ].…”

A Pillar-Based High-Throughput Myogenic Differentiation Assay to Assess Drug Safety

“…Doxorubicin has been shown to prevent the formation of DNA double helices during cell proliferation, thus inducing apoptosis [ 23 ], also had a very low MP-DI. In previous studies, regorafenib [ 24 ] and Lenvatinib [ 25 ], Cabozantinib [ 26 ], and 5-FU [ 27 ] reported differentiation inhibition, which is correlated with MP-DI. Thus, the proposed pillar-strip approach to stain nuclei and myotubes was capable of quantifying the inhibition of cell differentiation using the MP-DI as well as CA-DI.…”

A Review of Recurrent Meningiomas with Prolonged Response to Cabozantinib, an Oral Multitarget Tyrosine Kinase Inhibitor

“…Cabozantinib inhibits MET signaling, a receptor tyrosine kinase that is involved in the survival, invasion, and metastasis of tumor cells. Cabozantinib's overall anti-tumor activity relies heavily on its ability to inhibit MET [74]. Cabozantinib inhibits MET signaling through a number of different mechanisms: First, cabozantinib competes with MET to bind, preventing MET's natural ligand, hepatocyte growth factor (HGF), from binding [75].…”