Open Access Research article

EphB4 as a therapeutic target in mesothelioma

Ren Liu1, Benjamin D Ferguson2, Yue Zhou1, Kranthi Naga3, Ravi Salgia2, Parkash S Gill1* and Valery Krasnoperov3*

Author Affiliations

1 School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA

2 Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA

3 VasGene Therapeutics Inc, 1929 Zonal Avenue, Los Angeles, CA 90033, USA

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BMC Cancer 2013, 13:269  doi:10.1186/1471-2407-13-269

Published: 30 May 2013

Abstract

Background

Malignant pleural mesothelioma (MPM) often develops decades following exposure to asbestos. Current best therapy produces a response in only half of patients, and the median survival with this therapy remains under a year. A search for novel targets and therapeutics is underway, and recently identified targets include VEGF, Notch, and EphB4-Ephrin-B2. Each of these targets has dual activity, promoting tumor cell growth as well as tumor angiogenesis.

Methods

We investigated EphB4 expression in 39 human mesothelioma tissues by immunohistochemistry. Xenograft tumors established with human mesothelioma cells were treated with an EphB4 inhibitor (monomeric soluble EphB4 fused to human serum albumin, or sEphB4-HSA). The combinatorial effect of sEphB4-HSA and biologic agent was also studied.

Results

EphB4 was overexpressed in 72% of mesothelioma tissues evaluated, with 85% of epithelioid and 38% of sarcomatoid subtypes demonstrating overexpression. The EphB4 inhibitor sEphB4-HSA was highly active as a single agent to inhibit tumor growth, accompanied by tumor cell apoptosis and inhibition of PI3K and Src signaling. Combination of sEphB4-HSA and the anti-VEGF antibody (Bevacizumab) was superior to each agent alone and led to complete tumor regression.

Conclusion

EphB4 is a potential therapeutic target in mesothelioma. Clinical investigation of sEphB4-HSA as a single agent and in combination with VEGF inhibitors is warranted.

Keywords:
EphB4; Mesothelioma; sEphB4; Cancer therapy