Abstract
BackgroundMalignant 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.MethodsWe 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.ResultsEphB4 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.ConclusionEphB4 is a potential therapeutic target in mesothelioma. Clinical investigation of sEphB4-HSA as a single agent and in combination with VEGF inhibitors is warranted.
Highlights
Malignant pleural mesothelioma (MPM) often develops decades following exposure to asbestos
EphB4 overexpression in MPM tumors 39 human MPM tumor samples consisting of 27 epithelioid, 8 sarcomatoid, 2 papillary epithelioid, 1 mixed, and 1 desmoplastic subtypes were studied for EphB4 expression by immunohistochemistry. 85% of epithelioid, 38% of sarcomatoid, and 100% of mixed cell type were positive for EphB4 overexpression
Combination of sEphB4-HSA and vascular endothelial growth factor (VEGF) antibody We have shown previously that VEGF and VEGFRs are expressed in MPM, which is one of the few tumors that utilizes VEGF as an autocrine growth factor [33]. sEphB4-HSA has been shown to markedly inhibit tumor angiogenesis leading to elevated tumor VEGF levels [14], suggesting that the combination of sEphB4-HSA with VEGF inhibition may lead to enhanced anti-angiogenesis and antitumor activity
Summary
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. Malignant pleural mesothelioma (MPM) is a uniformly fatal disease. It originates from normal mesothelial cells lining the pleural or peritoneal cavity long after exposure to asbestos [1,2]. The most effective treatment regimen (cisplatin and pemetrexed) induces partial response in half of patients and improves survival from 9 to 12 months [4].
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