A Virus as ‘Smart Bomb’

“These cells appear to have a dreadful capability to originate a tumor,” says Juan Fueyo, MD, of the University of Texas M.D. Anderson Cancer Center in Houston. Even as few as 100 stray cells can seed a new glioma.

Fueyo is one of many scientists experimenting with an idea that is getting new attention after producing discouraging results a decade ago: gene therapy. Gene therapy enlists remodeled viruses to slip inside cancer cells and deliver a fatal blow. While the first tests in the 1990s were disappointing, scientists today are armed with better knowledge of tumor biology, including the possible role of stem cells.

The goal is to one day produce a virus that could mop up any remaining cells capable of giving rise to a recurrence of a glioma. Through viruses, nature already provides an elegant vehicle for getting inside cells; the challenge is to develop a virus that will deliver a payload designed by scientists that attacks only dangerous cells.

With this in mind, Fueyo and his colleagues have customized a virus that began as an ordinary adenovirus, which most commonly causes a simple cold. By slicing out several of the virus’s genes, the researchers produced a virus that appears to infect cancer stem cells while bypassing healthy cells in the body. Once inside the cancer stem cell, the virus begins to hijack the cell’s internal machinery to make copies of itself. This is what viruses are born to do, and the cell doesn’t usually survive the encounter.

In a recent study in the Journal of the National Cancer Institute, Fueyo and his colleagues describe tests in mice with the genetically modified virus. The mice had tumors that were induced from the cells of four different patients with glioblastomas, the most aggressive type of glioma. The scientists then infected the mice with the experimental adenovirus and measured the effects on the tumors. As a comparison, the researchers also infected another group of mice with an inactivated form of the virus.

In the journal, lead author Hong Jiang and the rest of the 12-member team reported that the mean survival time was about 38 days for the mice that received the inactivated virus. However, the mice that received the virus designed to attack the cancer stem cells survived for 66 days. The brain tissue of the mice, when inspected under a microscope, indicated that the virus had successfully infiltrated and destroyed the tumors.

The Houston scientists caution that the experiment was undertaken in mice, so the human implications are still unclear, but researchers are now preparing to test the approach in people. The first study, which will look at the safety of the virus, is scheduled to take place at three sites. If federal regulators approve, the study could begin recruitment later this year, but details remain to be finalized.

This isn’t the only virus under study with hopes of leading to gene therapy as a way to treat brain tumors. But the technology still faces a daunting list of obstacles. Among them: how to best infect the tumors in the brain, how to ensure that surrounding brain tissue remains protected, and how to entice the virus to infect enough of the stem cells to mortally wound the tumor.Given the past failures of gene therapy, Fueyo and his colleagues are proceeding with equal parts optimism and realism. Scientists point out, however, that many other techniques that today have become standard medical practice, such as organ transplantation, also stalled dismally in early studies.

“These cells can play many tricks,” he says of the stem cells. But in the future, doctors may have some new tricks of their own.

Gliomas, the most common type of malignancy arising from the brain, often resurrect themselves after treatment — usually showing an aggression far greater than they possessed the first time. Many scientists believe the engines of these recurrent gliomas, as well as an array of other malignancies, are cancer stem cells — cells so resilient they can arise from the tiniest residue of a treated tumor.

Gene therapy enlists remodeled viruses to slip inside cancer cells and deliver a fatal blow. While the first tests in the 1990s were disappointing, scientists today are armed with better knowledge of tumor biology, including the possible role of stem cells.