EphB4 as a therapeutic target in mesothelioma

Our plain-English summary of EphB4 as a therapeutic target in mesothelioma, by R. Liu, B.D. Ferguson, Y. Zhou, et al (BMC Cancer, 2013).

The study

• Authors: R. Liu, B.D. Ferguson, Y. Zhou, K. Naga, R. Salgia, P.S. Gill, V. Krasnoperov
• Journal: BMC Cancer
• Published: 2013;13:269
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study looked at a protein called EphB4 in malignant pleural mesothelioma and tested an experimental drug, sEphB4-HSA, that blocks it. It did not study asbestos exposure. The authors stained 39 human mesothelioma tumor samples for EphB4. They found overexpression in 72% overall, including 85% of epithelioid and 38% of sarcomatoid tumors. They then grew human mesothelioma cells as tumors in mice. In mice with tumors from the H2373 cell line, 25 days of sEphB4-HSA left tumors 66% smaller than in control mice and 20% smaller than at the start. Treated tumors had fewer blood vessels, less cell growth and more cell death. In mice with tumors from the 211H cell line, at day 21 bevacizumab alone reduced tumor volume by 71% and sEphB4-HSA alone by 77%, compared with controls. The two drugs together led to complete regression of the tumors, after 38 days of treatment according to the text. The authors concluded that EphB4 is a potential treatment target and that the drug, alone and combined with VEGF inhibitors, should be studied in patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: staining of human mesothelioma tumor tissue for EphB4, plus drug-treatment experiments in mice carrying human mesothelioma tumors (xenografts)
• Who was studied: 39 human malignant pleural mesothelioma tumor samples (27 epithelioid, 8 sarcomatoid, 2 papillary epithelioid, 1 mixed, 1 desmoplastic). Male BALB/c nude mice carrying tumors grown from the human mesothelioma cell lines NCI-H2373 and MSTO-211H, with 8 tumors per group. Where and when the tissue samples were collected is not stated.
• Exposure: No asbestos exposure was studied. The mice received one of four treatments by injection: sEphB4-HSA (20 mg/kg, 3 times a week), bevacizumab (an anti-VEGF antibody, 20 mg/kg, 3 times a week), both drugs combined, or PBS as a control.
• Main results:
  • In the human tumor samples, EphB4 was overexpressed in 72% of all tissues evaluated, in 85% of epithelioid tumors and in 38% of sarcomatoid tumors.
  • In mice with H2373 tumors, after 25 days of treatment, sEphB4-HSA-treated mice had a 66% reduction in tumor volume compared with the control group (P < 0.02) and a 20% regression from the starting tumor volume (P < 0.05).
  • In sEphB4-HSA-treated H2373 tumors, vessel density was 18% of control and the cell proliferative index was 36% of control. Apoptosis (cell death) showed a 19-fold increase over control.
  • sEphB4-HSA-treated tumors showed marked decreases in PI3K signaling. The drug also reduced phosphorylation of Src.
  • In mice with 211H tumors, at day 21, bevacizumab alone reduced tumor volume by 71% and sEphB4-HSA alone by 77%, compared with the control group. The combination led to complete regression of the established tumors after 38 days of treatment.
  • In 211H tumors treated for one week, the combination further decreased vessel density compared with bevacizumab alone (P < 0.01).
• The authors' conclusion: The authors concluded that EphB4 is a potential therapeutic target in mesothelioma. They said clinical investigation of sEphB4-HSA, alone and in combination with VEGF inhibitors, is warranted.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Median Survival, Angiogenesis, Immunohistochemistry, Epithelioid, Sarcomatoid, Apoptosis.

Related studies

• EphB4: A promising target for upper aerodigestive malignancies — R. Salgia, P. Kulkarni, et al. (2018)
• Identification of a novel EphB4 phosphodegron regulated by the autocrine IGFII/IRA axis in malignant mesothelioma — P. Scalia, G. Pandini, et al. (2019)
• In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth — N. Hamaguchi, H. Hamada, et al. (2010)
• The therapeutic efficacy of S-1 against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice — T.T. Van, M. Hanibuchi, et al. (2011)
• Extracellular signal-regulated kinase 5: a potential therapeutic target for malignant mesotheliomas — A. Shukla, J.M. Miller, et al. (2013)
• Gli as a novel therapeutic target in malignant pleural mesothelioma — H. Li, N. Lui, et al. (2013)

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