Related Experiment Video
Updated: Jun 3, 2026
In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
Anti-tumor activity of motesanib in a medullary thyroid cancer model
1Department of Oncology Research, Amgen Inc., Thousand Oaks, CA 91320, USA. acoxon@amgen.com
Background:
Medullary thyroid cancer (MTC) is frequently associated with mutations in the tyrosine kinase Ret and with increased expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Motesanib is an investigational, orally administered small molecule antagonist of VEGFR1, 2, and 3; platelet-derived growth factor receptor (PDGFR); Kit; and possibly Ret.
Aim:
The aim of this study was to investigate the effects of motesanib on wildtype and mutant Ret activity in vitro and on tumor xenograft growth in a mouse model of MTC.
Methods/Results:
In cellular phosphorylation assays, motesanib inhibited the activity of wild-type Ret (IC(50)=66 nM), while it had limited activity against mutant Ret C634W (IC(50)=1100 nM) or Ret M918T (IC(50)>2500 nM). In vivo, motesanib significantly inhibited the growth of TT tumor cell xenografts (expressing Ret C634W) and significantly reduced tumor blood vessel area and tumor cell proliferation, compared with control. Treatment with motesanib resulted in substantial inhibition of Ret tyrosine phosphorylation in TT xenografts and, at comparable doses, in equivalent inhibition of VEGFR2 phosphorylation in both TT xenografts and in mouse lung tissue.
Conclusions:
The results of this study demonstrate that motesanib inhibited thyroid tumor xenograft growth predominantly through inhibition of angiogenesis and possibly via a direct inhibition of VEGFR2 and Ret expressed on tumor cells. These data suggest that targeting angiogenesis pathways and specifically the VEGF pathway may represent a novel therapeutic approach in the treatment of MTC.
Insights
Motesanib effectively inhibited medullary thyroid cancer xenograft growth by targeting angiogenesis and VEGFR2, though it showed limited activity against mutant Ret. This suggests the VEGF pathway is a promising therapeutic target for MTC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Medullary thyroid cancer (MTC) is linked to Ret mutations and increased vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2).
- Motesanib is an investigational drug targeting VEGFRs, PDGFR, Kit, and potentially Ret.
Purpose of the Study:
- To assess motesanib's effects on wild-type and mutant Ret activity in vitro.
- To evaluate motesanib's impact on MTC tumor xenograft growth in a mouse model.
Main Methods:
- In vitro cellular phosphorylation assays to determine IC50 values for Ret inhibition.
- In vivo studies using MTC (TT cell line) xenografts in mice to assess tumor growth, angiogenesis, and cell proliferation.
- Analysis of Ret and VEGFR2 phosphorylation in tumor tissues.
Main Results:
- Motesanib inhibited wild-type Ret (IC50=66 nM) but had limited efficacy against mutant Ret C634W (IC50=1100 nM) and Ret M918T (IC50>2500 nM).
- In vivo, motesanib significantly reduced TT tumor xenograft growth, tumor vascularization, and cell proliferation.
- Motesanib treatment led to substantial inhibition of Ret and VEGFR2 phosphorylation in xenografts and VEGFR2 in lung tissue.
Conclusions:
- Motesanib inhibited MTC xenograft growth primarily by inhibiting angiogenesis, likely via VEGFR2 and potentially Ret.
- Targeting angiogenesis pathways, particularly the VEGF pathway, offers a novel therapeutic strategy for MTC.
