Brain cancers are a notoriously difficult prognosis, and many have bleak outlooks for a number of patients. Glioblastomas, in particular, are relentless and hard to treat. And while the world has its attention fixated on coronavirus, researchers at Yale University have released new preclinical data showing that one of the world’s deadliest viruses can be used to fight brain tumors. The researchers—showing that elements of the Ebola virus were effective at treating glioblastoma in mice—published their data recently in the Journal of Virology through an article entitled “Mucin-like domain of Ebola virus glycoprotein enhances selective oncolytic actions against brain tumors.”
“The irony is that one of the world’s deadliest viruses may be useful in treating one of the deadliest of brain cancers,” remarked senior study investigator, Anthony van den Pol, PhD, professor of neurosurgery at Yale University.
The new approach takes advantage of a weakness in most tumors and of an Ebola defense against the immune system response to pathogens. Unlike normal cells, a large percentage of cancer cells lack the ability to generate an innate immune response against invaders such as viruses. This has led cancer researchers to explore the use of viruses to combat a variety of cancers.
The authors explained that “given that the Ebola virus (EBOV) infects a wide array of organs and cells yet displays a relative lack of neurotropism, we asked whether a chimeric vesicular stomatitis virus (VSV) expressing the EBOV glycoprotein (GP) might selectively target brain tumors. The mucin-like domain (MLD) of the EBOV GP may enhance virus immune system evasion.”
While using viruses such as Ebola carries an obvious risk—as they can introduce potentially dangerous infections—the research team circumvented this problem by creating chimeric viruses, or a combination of genes from multiple viruses. Chimeras have the ability to target cancer cells without harming patients.
In the current study, the investigators focused on one of the seven genes of the Ebola virus that helps it avoid an immune system response and also contributes to its lethality, creating a chimeric virus containing a glycoprotein with an MLD from Ebola. In wild-type Ebola virus, the MLD plays a role in hiding Ebola from the immune system. They injected this chimeric virus into the brains of mice with glioblastoma—and found that the MLD helped selectively target and kill deadly glioblastoma brain tumors.
“We compared chimeric VSVs in which EBOV GP replaces the VSV glycoprotein, thereby reducing the neurotoxicity associated with wild-type VSV. A chimeric VSV expressing the full-length EBOV GP (VSV-EBOV) containing the MLD was substantially more effective and safer than a parallel construct with an EBOV GP lacking the MLD (VSV-EBOVΔMLD),” the authors wrote. “One-step growth, RT-qPCR, and Western blot assessment showed VSV-EBOVΔMLD produced substantially more progeny faster than VSV-EBOV. Using immunodeficient SCID mice, we focused on targeting human brain tumors with these VSV-EBOVs. Similar to our previous report using an attenuated VSV-EBOV with no MLD that expressed GFP (VSV-EBOVΔMLD-GFP), VSV-EBOVΔMLD without GFP targeted glioma, but yielded only a modest extension of survival. In contrast, VSV-EBOV containing the MLD showed substantially better targeting and elimination of brain tumors after intravenous delivery, and increased the survival of brain tumor-bearing mice.”
The authors noted that MLD’s beneficial effect appears to be that it protects normal cells from infection—but not cancer cells, which lack the ability to mount an immune response to pathogens. A key factor may be that the virus with the glycoprotein MLD replicates less rapidly, potentially making it safer than viruses without the MLD part of the glycoprotein. In theory, such a virus might be used in conjunction with surgery to eliminate glioblastoma tumors and help prevent a recurrence of cancer.
