In the JournalsPerspective

Ephrin B2 receptor could be therapeutic target for malignant mesothelioma

The Ephrin B2 receptor was overexpressed in malignant pleural mesothelioma, and its inhibition demonstrated significant in vitro effects on the invasive characteristics of the disease and apoptosis control, according to study results.

Previous studies have suggested a correlation between ephrin receptors and ligand overexpression in the progression of several types of cancers, potentially due to the effects on the angiogenic pathways and apoptosis.

In the current study, Harvey I. Pass, MD, the Stephen E. Banner professor of thoracic oncology at New York University Langone Medical Center, and colleagues investigated Ephrin receptor B2 (EPHB2) expression in malignant mesothelioma compared with benign mesothelial cells.

 

Harvey I. Pass

“Despite advances in the treatment of [malignant mesothelioma], the median survival remains 12 months from the time of diagnosis,” Pass and colleagues wrote. “Increased understanding of the molecular basis for the diverse signaling pathways involved in cancer progression should promote the discovery of novel biomarkers for early diagnosis and potentially lead to more effective therapeutic tools for the disease.”

The researchers used reverse-transcriptase polymerase chain reaction and immunoblotting methods to evaluate EPHB2 and downstream target expression. The biological significance of EPHB2 was assessed using in vitro functional assays with and without targeting by EPHB2-short hairpin RNA (shRNA) or blocking peptide in two mesothelioma cell lines, HP-1 and H2595.

Study results showed EPHB2 was overexpressed in all malignant mesothelioma cell lines but not in benign mesothelial cells. EPHB2 levels also were significantly higher in malignant mesothelioma tumor tissue compared with matched normal peritoneum.

“Targeting EPHB2 in H2595 and HP-1 cells with shRNA resulted in a significant decrease in the tumorigenic properties but has no effect in LP9 benign mesothelial cells,” Pass and colleagues wrote.

Inhibition of EPHB2 resulted in a significant reduction in scratch closure (1.25-fold to 1.8-fold), proliferation (1.5-fold), and invasion (1.7-fold to 1.8-fold) compared with controls. Most importantly, the researchers noted that EPHB2 silencing resulted in a significant elevation in apoptotic proteins and activity.

“Targeting EPHB2 might provide a novel therapy to improve the prognosis in people suffering from malignant mesothelioma,” Pass and colleagues concluded. “Further investigation in vitro using specific inhibitors of EPHB2 is required to determine the importance of EPHB2 and its interactions with other members of the receptor kinases and their ligands to prove its role as a marker of progression and metastasis for malignant mesothelioma.”

Disclosure: The researchers report no relevant financial disclosures.

The Ephrin B2 receptor was overexpressed in malignant pleural mesothelioma, and its inhibition demonstrated significant in vitro effects on the invasive characteristics of the disease and apoptosis control, according to study results.

Previous studies have suggested a correlation between ephrin receptors and ligand overexpression in the progression of several types of cancers, potentially due to the effects on the angiogenic pathways and apoptosis.

In the current study, Harvey I. Pass, MD, the Stephen E. Banner professor of thoracic oncology at New York University Langone Medical Center, and colleagues investigated Ephrin receptor B2 (EPHB2) expression in malignant mesothelioma compared with benign mesothelial cells.

 

Harvey I. Pass

“Despite advances in the treatment of [malignant mesothelioma], the median survival remains 12 months from the time of diagnosis,” Pass and colleagues wrote. “Increased understanding of the molecular basis for the diverse signaling pathways involved in cancer progression should promote the discovery of novel biomarkers for early diagnosis and potentially lead to more effective therapeutic tools for the disease.”

The researchers used reverse-transcriptase polymerase chain reaction and immunoblotting methods to evaluate EPHB2 and downstream target expression. The biological significance of EPHB2 was assessed using in vitro functional assays with and without targeting by EPHB2-short hairpin RNA (shRNA) or blocking peptide in two mesothelioma cell lines, HP-1 and H2595.

Study results showed EPHB2 was overexpressed in all malignant mesothelioma cell lines but not in benign mesothelial cells. EPHB2 levels also were significantly higher in malignant mesothelioma tumor tissue compared with matched normal peritoneum.

“Targeting EPHB2 in H2595 and HP-1 cells with shRNA resulted in a significant decrease in the tumorigenic properties but has no effect in LP9 benign mesothelial cells,” Pass and colleagues wrote.

Inhibition of EPHB2 resulted in a significant reduction in scratch closure (1.25-fold to 1.8-fold), proliferation (1.5-fold), and invasion (1.7-fold to 1.8-fold) compared with controls. Most importantly, the researchers noted that EPHB2 silencing resulted in a significant elevation in apoptotic proteins and activity.

“Targeting EPHB2 might provide a novel therapy to improve the prognosis in people suffering from malignant mesothelioma,” Pass and colleagues concluded. “Further investigation in vitro using specific inhibitors of EPHB2 is required to determine the importance of EPHB2 and its interactions with other members of the receptor kinases and their ligands to prove its role as a marker of progression and metastasis for malignant mesothelioma.”

Disclosure: The researchers report no relevant financial disclosures.

    Perspective
    Matthew Gubens

    Matthew Gubens

    In a disease like mesothelioma, in which there has been no recent progress in the standard of care, efforts directed toward finding new potential therapeutic targets are essential. The authors make a compelling case for further study of the receptor tyrosine kinase EPHB2, finding a strong link to mesothelioma pathogenesis and metastasis, and specifically showing that its silencing leads to increases in apoptotic proteins and activity. Given that tyrosine kinase inhibitors and monoclonal antibodies against other EPH family members are in active development, this evidence may prompt a targeted therapy worth investigating in malignant pleural mesothelioma. Certainly as these and other novel approaches come to be studied in mesothelioma trials — notably including immunotherapy and FAK inhibitors — we should be diligent about enrolling our patients whenever possible.

    • Matthew Gubens, MD, MS
    • Assistant clinical professor, thoracic oncology University of California, San Francisco

    Disclosures: Gubens reports no relevant financial disclosures.