Intrapleural Gene Therapy Slows Tumor Growth in Mice with Malignant Mesothelioma

Intrapleural Gene Therapy Slows Tumor Growth in Mice with Malignant Mesothelioma

The endothelial cell protein C receptor (EPCR) suppresses tumor growth in malignant pleural mesothelioma (MPM) by rendering cells more susceptible to cell death-activating mechanisms, according to a study published in Scientific Reports.

The study, “Intrapleural Adenoviral-mediated Endothelial Cell Protein C Receptor Gene Transfer Suppresses the Progression of Malignant Pleural Mesothelioma in a Mouse Model,” revealed that EPCR gene therapy slowed the progression of tumor growth in a MPM mouse model, suggesting that this might be a promising treatment approach for MPM patients.

Current therapeutic management routes of MPM, a highly aggressive form of thoracic cancer often linked to asbestos exposure, are limited and prolong patients’ survival only modestly. Since no effective treatment currently exists, researchers have hypothesized that gene therapy might be a good alternative for mesothelioma patients.

However, although a few Phase 1 trials have demonstrated that gene therapy is feasible and safe in MPM patients, these studies have shown only limited effectiveness.

The development of effective therapeutic approaches requires an in-depth understanding of the mechanism underlying the disease. Recent studies have shown that EPCR functions as a negative regulator of MPM, inducing tumor cell death and suppressing tumor growth when inserted in highly aggressive MPM cells.

Therefore, researchers aimed not only to clarify the underlying mechanism leading to suppression of MPM tumor growth by EPCR, but also to investigate whether intrapleural EPCR gene transfer could have a therapeutic effect in a malignant mesothelioma mouse model.

They found that EPCR induced tumor cell death and reduced tumor growth through different mechanisms. First, they found that the levels of certain inflammatory cytokines (which secrete substances that activate the immune system) were altered, with mice implanted with MPM cells expressing EPCR showing higher levels of interferon gamma (IFNγ) and tumor-necrosis factor alpha (TNFα) when compared to mice injected with MPM cells lacking EPCR.

Additional in vitro studies revealed that EPCR expression in MPM cells rendered them more susceptible to the cell death pathways activated by IFNγ and TNFα.

The researchers then proceeded to test whether EPCR gene therapy delivered to the intrapleural space could be used as a therapeutic approach for MPM. Mice were injected with a virus carrying the EPCR gene at three-day intervals over 30 days.

After that period, researchers looked at the thoracic cavities of the mice and found that those injected with the EPCR gene therapy had fewer tumors and reduced tumor volume and tumor burden compared to control mice. In addition, tumors from mice treated with EPCR gene therapy showed increased cell death.

The researchers also found that the therapy increased the levels of pro-inflammatory proteins like IFNγ and TNFα, and increased the recruitment of certain immune cells into the tumor microenvironment, which helped attack the tumor.

“Overall, our present data suggest that intrapleural EPCR gene therapy has the potential to slow the progression of MPM but requires further refinement in the delivery and expression to make this option more viable,” the researchers wrote.

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Malika Ammam received her MS degree from the University of Pierre et Marie CURIE in July 2002 and her PhD from the University of Paris Sud XI, France in September 2005. From 2006 to 2007, she worked as a research fellow at the University of Kansas in collaboration with Pinnacle Technology Inc. (USA). From 2007 to 2010, she was a research associate at KU Leuven, Belgium. From 2010 to 2012, she worked at the University of Ontario Institute of Technology in collaboration with Alcohol Countermeasure Systems Corporation, Canada. She has also held the prestigious Rosalind Franklin fellowship.

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