Sophie Henry

Yale researchers have found a way to weaponize structures from the Ebola virus in the fight against glioblastomas ruthless brain tumors that are notoriously difficult to subdue.

A group of researchers, led by neurosurgery and psychiatry professor Anthony Van den Pol, published their study about tumor-destroying applications of a hybrid version of the virus, Ebola VSV, in the Journal of Virology. Ebola VSV contains genes from Ebola and a virus that primarily infects cattle (VSV). The research centers on a section of a specific biological structure called the mucin-like domain (MLD) glycoprotein, a specific stretch of protein that is coded for by one of the genes found in the Ebola virus. According to the findings reported in late January, MLD was found to enhance the Ebola VSV’s ability to encroach on tumor cells without harming brain cells in mice.

“Without the MLD, [the Ebola VSV] targeted tumors but it also tended to infect brain cells … [but] in the majority of the mice, it seemed like the virus with MLD eliminated the tumor, which is a good thing,” Van den Pol said. When asked about the rationale behind using Ebola, Van den Pol explained that it was initially one among several viruses his group had looked at.

“We didn’t say ‘let’s try Ebola, that’s going to be great!’ It was really more like ‘let’s try a lot of different things!’” said Van den Pol. “My lab has probably tested 60 different viruses over the last 20 years, looking at safety and [tumor-destroying] potential. Some of them were really good outside the brain but were not good inside the brain … I’m a neurobiologist, so I want something that is safe in the brain.”

In the paper, the authors highlighted that the fact that the hybrid virus with MLD replicated more slowly made it better to target glioblastomas than the version without it.

“We think that one of the reasons why the [VSV] with the MLD is better and safer is because it’s slower, and the advantage of being slow is that your brain cells [have time to] think ‘there’s something weird that we don’t like,’” Van den Pol explained. “On one hand, [MLD] is protecting the Ebola virus from the immune system out in the wild, while in this particular focus it actually is making the virus replicate more slowly, which makes it a little bit safer for us to use [to treat glioblastomas].”

Viruses including polio, herpes and measles have been tested in the past for their potential to kill tumor cells, but the fact that many individuals around the world have either been vaccinated against or exposed to these viruses means that most people’s immune system is better able to fight them, making them harder to use. According to Van den Pol, a benefit of using Ebola and VSV is that most of the world is unlikely to have been exposed to either of them. Another benefit of looking at Ebola is that, in a fight against a brutal kind of tumor, there is much to be learned from a brutal kind of virus.

“We are looking at [viruses like Ebola] because we know that if they are lethal they have to have evolved very efficient means of entering a cell and killing it, so that’s really what we’re after very effective and extremely efficient means of gaining access to the interior of cancer cells and infecting them so that they can be killed,” said John Davis, a research assistant in Van den Pol’s lab.

However, the hybrid virus does not only destroy cancer cells. It also alerts the immune system of the tumor’s presence as it infiltrates it and recruits immune cells to help kill cancerous ones. Referring to cancer cells’ difficulty in fighting off viruses as “a hole in their armor,” Davis noted that this weakness allows researchers to use viruses against them.

When asked about safety concerns, both Van den Pol and Davis seemed confident that the Ebola VSV with MLD isn’t likely to do harm. Van den Pol noted that Ebola VSV is unlikely to become like the “wild-type virus” that most people recognize, since only one of the seven Ebola genes is being used.

“We think it is safe because what we tested here is almost identical to the Ebola vaccine that they are using in Africa right now,” he pointed out. “It has been put into over 290,000 people, and … there’s been nothing that would raise a red flag.”

Dr. Andrea Marzi, a co-author in the paper and an immunobiology and molecular virology researcher at the National Institute of Allergy and Infectious Diseases, works on vaccines and provided the Ebola VSV from the Ebola vaccine she helped develop.

“It was a great collaboration because I learned something about other properties that my vaccine has,” Marzi said. “Dr. Van den Pol’s study was a great start to explore this new application of the vaccine, but we know too little yet. I hope, since this is so promising, that somebody … might follow up on it and see if it is maybe not just useful for glioblastomas, but for other cancers too.”

According to the American Association of Neurological Surgeons, currently, most people with glioblastomas live only up to 15 months after diagnosis.

 

Maria Fernanda Pacheco | maria.pacheco@yale.edu

 

Correction, Feb. 27: This article has been updated to accurately reflect Van den Pol’s research.