title: EphB4 as a therapeutic target in mesothelioma.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. parkashg@usc.edu
authors.forename: Ren
authors.initials: R
authors.lastname: Liu
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Ferguson
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
authors.forename: Kranthi
authors.initials: K
authors.lastname: Naga
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.forename: Parkash S
authors.initials: PS
authors.lastname: Gill
authors.forename: Valery
authors.initials: V
authors.lastname: Krasnoperov
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008654:Mesothelioma / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010997:Pleural Neoplasms / Q000378:metabolism*; D036224:Receptor, EphB4 / Q000008:administration & dosage / Q000378:metabolism*; D012709:Serum Albumin / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D012709:Serum Albumin; D000068258:Bevacizumab; D036224:Receptor, EphB4