Dual Inhibition of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor is an Effective Chemopreventive Strategy in the Mouse 4-NQO Model of Oral Carcinogenesis

Abstract

Despite recent therapeutic advances, several factors, including field cancerization, have limited improvements in long-term survival for oral squamous cell carcinoma (OSCC). Therefore, comprehensive treatment plans must include improved chemopreventive strategies. Using the 4-Nitroquinoline 1-Oxide (4-NQO) mouse model, we tested the hypothesis that ZD6474 (Vandetanib, ZACTIMA) is an effective chemopreventive agent. CBA mice were fed 4-NQO (100 ug/ml) in their drinking water for 8 weeks and then randomized to no treatment or oral ZD6474 (25 mg/Kg/day) for 24 weeks. The percentage of animals with OSCC was significantly different between the two groups (71% in control and 12% in ZD6474 group; p≤0.001). The percentage of mice with dysplasia or OSCC was significantly different (96% in the control and 28% in the ZD6474 group; p≤0.001). Proliferation and MVD scores were significantly decreased in the ZD6474 group (p<=0.001 for both). While proliferation and MVD increased with histologic progression in control and treatment cohorts, EGFR and VEGFR-2 phosphorylation was decreased in the treatment group for each histologic diagnosis, including mice harboring tumors. OSCC from ZD6474-treated mice exhibited features of epithelial to mesenchymal transition (EMT), as demonstrated by loss E-cadherin and gain of vimentin protein expression. These data suggest that ZD6474 holds promise as an OSCC chemopreventive agent. They further suggest that acquired resistance to ZD6474 may be mediated by the expression of an EMT phenotype. Finally, the data suggests that this model is a useful pre-clinical platform to investigate the mechanisms of acquired resistance in the chemopreventive setting.

Critical Role for the Receptor Tyrosine Kinase EPHB4 in Esophageal Cancers

“…The mouse 4-NQO model development of oral and esophageal carcinogenesis has previously been described in detail by Tang and colleagues and us (19,25,26). Here, we report esophageal SCCs as a result of carcinogenic induction by 4-NQO ingestion and the expression of ephb4.…”

“…The samples in this study contained squamous cell carcinoma (94), adenocarcinoma (82), dysplasia (25), Barrett esophagus (13), and adjacent or unrelated normal esophageal tissues (25), all of which were evaluated for EPHB4 protein expression by immunohistochemistry using a specific antibody against EPHB4 (Fig. 1A).…”

Geographic Tongue Induced by Angiogenesis Inhibitors

“…The pathophysiology of benign migratory glossitis is unknown [2]. However, given the established role of VEGF or VEGF receptors in the buccal mucosa homeostasis as well as in some oral diseases, such as squamous cell carcinomas [3,4], we suggest, as the authors, that therapeutic inhibition of those specific targets by angiogenesis inhibitors could induce geographic tongue. Compared with mTOR inhibitors, the clinical presentation of oral adverse events induced by angiogenesis inhibitors is much less characterized [5,6].…”

“…These patients were three white subjects treated with sunitinib (Sutent, Pfizer) (two patients) or sorafenib (Nexavar, Bayer) as monotherapy for metastatic renal cell carcinoma (Figs. 3,4).…”

Targeting the epidermal growth factor receptor for head and neck cancer chemoprevention

“…50 Another clinical trial with vandetanib, a dual EGFR and vascular endothelial growth factor receptor inhibitor is currently under way in patients with oral pre-malignant lesions [NCT01414426], based on results from animal studies (4-NQO mouse model) demonstrating a reduction in the incidence of oral cancer from 71% in the placebo group to 12% in the vandetanib-treated mice. 51 …”