The Effect of Combination Anti–Endothelial Growth Factor Receptor and Anti–Vascular Endothelial Growth Factor Receptor 2 Targeted Therapy on Lymph Node Metastasis

Abstract

Objective To evaluate the therapeutic effect of treatment with a combination of the monoclonal antibodies to the VEGFR (DC101) and the EGFR (cetuximab) in an orthotopic nude mouse model of metastatic squamous cell carcinoma of oral tongue (SCCOT). Design In vivo study. Subjects 8- to 12- week-old male athymic nude mice. Intervention To develop orthotopic nude mouse models of SCCOT, OSC-19 cells or luciferase-expressing human OSC-19-luc and JMAR-luc cells were injected into the tongues of nude mice. Animals were randomly divided into 4 groups: DC101 alone, cetuximab alone, DC101 plus cetuximab, or placebo, all given twice per week for 4 weeks. The in vivo anti-tumor activity was monitored noninvasively by bioluminescence imaging. Tumors were resected at necropsy, and immunohistochemical and immunoflourescent staining were performed. Results At the conclusion of the treatment period, the average tumor volumes in the cetuximab alone and the DC101 plus cextuximab treatment groups had decreased significantly compared with those that received control (68%, P=0.002 and 84%, P=0.0003 respectively). Significant effects of the treatment were also observed in bioluminescence imaging. Mice treated with DC101 plus cetuximab also lived longer and had a lower incidence of neck lymph node metastases compared with the control group (P=0.003). Conclusion Treatment with DC101 plus cetuximab inhibited the growth of SCCOT and decreased the incidence of the neck lymph node metastases in vivo. These results suggest that this combination treatment may be an effective stategy against metastatic SCCOT and warrants further pre-clinical trials.

Vandetanib Restores Head and Neck Squamous Cell Carcinoma Cells' Sensitivity to Cisplatin and Radiation In Vivo and In Vitro

“…While the difference was not significant, OSC-19 mice treated with vandetanib alone and OSC-19 mice treated with vandetanib plus radiation had a much lower incidence of cervical lymph node metastases than control mice. These findings are consistent with our previous reports in which the blockade of both EGFR and VEGFR-2 pathways decreased the incidence of the neck lymph node metastases of HNSCC (22, 30). Moreover, treatment with vandetanib, cisplatin, and radiation produced the most marked decrease in cervical lymph node metastasis incidence.…”

Targeted molecular therapy of head and neck squamous cell carcinoma with the tyrosine kinase inhibitor vandetanib in a mouse model

“…This finding is consistent with our previous report in which combined anti-EGFR and VEGFR-2 antibody targeted therapy using DC101 and cetuximab inhibited the growth of SCC of the oral tongue and also decreased the incidence of the neck lymph node metastases on orthotopic xenografts of metastatic squamous cell carcinoma of the oral tongue (32). As angiogenesis is thought to play an important role in tumor growth and metastasis (33) and the EGFR pathway is one of the major growth and survival signaling pathways in HNSCC, blocking these two pathways could be very helpful in the treatment of cervical nodal disease in HNSCC patients.…”

High-frequency Ultrasound Imaging of Mouse Cervical Lymph Nodes

“…In addition to ultrasound, bioluminescence imaging has also been used to visualize orthotopic oral tumor formation and cervical lymph node metastasis in live mice 26,27 . As an alternative approach, bioluminescence imaging has a distinct advantage over HFUS in being able to directly quantify tumor progression and metastatic burden over time in the same animal.…”