A customized virus in a mouse study killed stem cells that cause an extremely aggressive, tenacious brain cancer, researchers report.
Scientists at the University of Texas M. D. Anderson Cancer Center in Houston, Texas announced the findings in the Sept. 18 issue of the Journal of the National Cancer Institute.
The virus “can target and eliminate the cells that drive brain tumors,” by essentially forcing them to eat themselves, said study co-author Juan Fueyo. The researchers said they expect to submit a request to launch a clinical trial of the virus, called Delta-24-RGD, this month.
They tested the virus against the most aggressive brain tumor, glioblastoma multiforme, which originates in specialized cells known as glia, Fueyo said. Glia surround and support neurons, the brain cells that conduct electrical signals.
Glioblastoma multiforme resists radiation and chemotherapy treatments and is so invasive that surgery almost never eliminates it, Fueyo and colleagues said. Patients suffering from this malignancy live on average for about 14 months with treatment.
The researchers developed the virus to exploit a weakness in tumors but leave normal tissue unharmed. They found in a 2003 study that the virus eliminated brain tumors in 60 percent of mice who received injections directly into their tumors. The virus spreads in a wave through the tumors until there are no cancer cells left, then it dies.
Since 2004 scientists have found that brain tumors are driven by out-of-control stem cells, a type of “master cell” capable of developing into a variety of other cell types, the researchers said. Even when surgery destroys a tumor, the rogue stem cells can produce a new one.
Fueyo’s team grafted four different lineages of the stem cells into mouse brains and treated the resultant tumors with injections of the virus. Untreated mice survived 38.5 days on average, and treated mice 66 days, they reported. But two of the treated ones lived for 92 days, until the end of the experiment, with no neurological symptoms.
“An animal model doesn’t fully represent humans,” Fueyo cautioned. “But the tumors grown by these stem cells closely resemble the tumors we see in our patients, which is an exciting finding in itself.” Usually, tumors artificially induced in lab animals don’t mimic real tumors very well, he remarked—but these did, sprawling out and deeply invading other brain areas before the virus beat them back.
The virus exploits the fact that a molecule called retinoblastoma is missing or defective in brain tumors. The molecule normally guards against both the proliferation of cancerous cells and against viral infection. So the virus, a member of a family of viruses called adenoviruses, has an easier time invading tumors and replicating in its cells.
Adenoviruses attacking normal cells normally employ a molecule called E1A to counteract the retinoblastoma defense. So to keep the virus out of normal cells, Fueyo and colleagues explained, they simply needed to delete a small part of the viral gene that produces E1A. The virus forces tumor cells to devour themselves until they die, a form of self-cannibalization called autophagy, they wrote.
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