Abstract 4356: EphB4 as a novel therapeutic target for head-neck SCC.

2013 
Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Receptor tyrosine kinase EphB4 and its cognate trans-membrane ligand EphrinB2 regulate venous-artery determination and are critically required for fusion of vein and arterial compartments, as well as vessel maturation in development and in pathological angiogenesis. Aberrant induction of EphB4 in certain tumors and pro-tumor cell survival function independent of its role in tumor angiogenesis have been reported. We have studied the expression and function of EphB4 in head neck squamous cell cancer. Methods: EphB4 expression in 78 freshly frozen head/neck squamous cell carcinoma tumor samples were studied by immunostaining, western blot analysis, gene copy number, and correlated with stage. Head/neck tumor cell lines also were studied for expression and significance of EphB4 expression on survival by knock down studies using EphB4 lentiviral shRNA. Inhibition of EphB4 activation using decoy soluble EphB4 receptor fused in frame at the C-terminus with human albumin (sEphB4-HSA) was evaluated for in vivo studies of human tumor xenografts. Results: EphB4 was expressed in all human tumor tissues, and the levels correlated directly with stage. High EphB4 also predicted shortened survival. EphB4 protein levels varied in tumor cell lines, and loss of cell viability with EphB4 shRNA knock down was highest in cell lines with highest EphB4 levels (range 25-78%). Tumor xenografts in sEphB4-HSA treated mice were reduced over 80% compared to the control PBS treatment. Tissue analysis revealed reduction in tumor vessel density, reduced recruitment of pericytes, and decreased perfusion of the tumor vessels. sEphB4-HSA treatment also decreased tumor tissue PI3K activity manifested by reduced phosphorylated AKT and S6 level. Tumor cell death by apoptosis was widespread consistent with combined anti-angiogenic activity and direct tumor cell toxicity. Conclusion: EphB4 receptor tyrosine kinase is highly expressed in head/neck squamous cell cancer. EphB4 provides survival signal to the tumor cells directly. Decoy EphB4 inhibitor sEphB4-HSA is highly potent in in vivo tumor xenograft models. sEphB4-HSA is thus a candidate for investigation in human trials and the clinical trials are underway. Citation Format: Ren Liu, Hai-yun Yen, Rizwan Masood, Uttam Sinha, Anthony El-Khoueiry, Stephen Liu, Barbara Gitlitz, Parkash S. Gill. EphB4 as a novel therapeutic target for head-neck SCC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4356. doi:10.1158/1538-7445.AM2013-4356
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