Targeted Therapy of VEGFR2 and EGFR Significantly Inhibits Growth of Anaplastic Thyroid Cancer in an Orthotopic Murine Model

Abstract

Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most lethal human cancers with a median survival of 6 months. The inhibition of epidermal growth factor receptor (EGFR) alone, or with VEGF receptor 2 (VEGFR2), represents an attractive approach for treatment of ATC. Several reports have examined agents that target these receptors. However, with the misidentification of as many as 60% of all commonly used ATC cell lines, the significance of these past findings is unclear.Experimental Design: Cell lines authenticated by short tandem repeat profiling were selected to establish xenograft tumors in an orthotopic murine model of ATC. These mice were then treated with vandetanib to evaluate its effects on ATC tumor growth. Dynamic contrast-enhanced (DCE) MRI was utilized to measure the impact of vandetanib on tumor vasculature.Results: Vandetanib inhibited tumor growth of the ATC cell lines Hth83 and 8505C in vivo by 69.3% (P < 0.001) and 66.6% (P < 0.05), respectively, when compared with control. Significant decreases in vascular permeability (P < 0.01) and vascular volume fraction (P < 0.05) were detected by DCE-MRI in the orthotopic xenograft tumors after 1 week of treatment with vandetanib as compared with control.Conclusion: The inhibition of EGFR and VEGFR2 by vandetanib and its tremendous in vivo antitumor activity against ATC make it an attractive candidate for further preclinical and clinical development for the treatment of this particularly virulent cancer, which remains effectively untreatable. Vandetanib disrupts angiogenesis and DCE-MRI is an effective method to quantify changes in vascular function in vivo. Clin Cancer Res; 17(8); 2281-91. Ó2011 AACR.

Vandetanib, an Inhibitor of VEGF Receptor-2 and EGF Receptor, Suppresses Tumor Development and Improves Prognosis of Liver Cancer in Mice

“…Gule and colleagues (16) reported that the antitumor effects of vandetanib were mediated through inhibition of VEGF signaling and antiangiogenesis rather than through direct antiproliferative effects on tumor cells. In our in vivo study, vandetanib dose dependently suppressed the phosphorylation of VEGFR-2 and microvascular development.…”

“…Vandetanib (Zactima; ZD6474) is an orally bioavailable, small-molecule VEGFR-tyrosine kinase inhibitor with additional activity against EGFR-tyrosine kinase and RET receptor tyrosine kinase (16). Therefore, vandetanib, in addition to inhibiting endothelial cell proliferation through the blockade of VEGF-induced signaling, can suppress tumor cell growth more directly through the blockade of EGFR autocrine signaling (17).…”

Clinical Application of MRI in an Animal Bone Graft Model

“…Table 2 Analysis of variance of the maximum linear slope value SS max of three rabbit groups 2, 4, and 6 weeks after surgery (Mean±SD) (%/s). a indicates significant differences between groups A and C, P < 0.05; b indicates significant differences between groups A and B, P < 0.05; and c indicates significant differences between groups B and C, P < 0.05. ture of a tissue or tumor [6][7][8][9][10][11][12][13], such as microvasculature perfusion and capillary permeability, and mean transit time [Several compartmental models could also be used to fit these data (e.g., the bi-exponential Brix model), of them one could calculate the area under the curve (IAUC) as another measurement]. Nowadays, DCE-MRI is commonly used to assess bone graft viability [14,15].…”

Unravelling the best combination of therapies to treat anaplastic thyroid cancer

“…This is thought to be due to an 'off target' effect of pazopanib on inhibition of Aurora A kinase, a critical step in mitotic cell spindle formation, stabilization and separation during cell cycle [12]. RET and RET/PTC targeted agents (sorafenib, sunitinib, vandetanib) have also shown some success [13][14][15][16][17].…”