ZIKA VIRUS MAY BE ONCOLYTIC FOR CNS TUMORS

Although Zika virus causes devastating damage to the brains of developing fetuses, it someday may prove to be an effective treatment for glioblastoma. New research from Washington University School of Medicine in St. Louis and the University of California San Diego School of Medicineshowed that the virus may kill brain cancer stem cells, the kind of cells most resistant to standard treatments. These findings were published by Zhu et al in The Journal of Experimental Medicine.

“We showed that Zika virus can kill the kind of glioblastoma cells that tend to be resistant to current treatments and lead to death,” said Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine at Washington University School of Medicine and the study's co–senior author.

Each year in the United States, about 12,000 people are diagnosed with glioblastoma, the most common form of brain cancer. The standard treatment is aggressive—surgery, followed by chemotherapy and radiation—yet most tumors recur within 6 months. A small population of glioblastoma stem cells, often survive treatment and continue to divide.

In their neurologic origins and near-limitless ability to create new cells, glioblastoma stem cells reminded postdoctoral researcher Zhe Zhu, PhD, of neuroprogenitor cells, which generate cells for the growing brain. Zika virus specifically targets and kills neuroprogenitor cells.

Study Findings

In collaboration with other researchers, Dr. Zhu tested whether the virus could kill stem cells in glioblastomas removed from patients at diagnosis. The team infected tumors with one of two strains of Zika virus. Both strains spread through the tumors, infecting and killing the cancer stem cells while largely avoiding other tumor cells.

The findings suggest that Zika infection and chemoradiation have complementary effects. The standard treatment kills the bulk of the tumor cells, but often leaves the stem cells intact to regenerate the tumor. Zika virus attacks the stem cells, but bypasses the greater part of the tumor.

To find out whether the virus could help treat cancer in a living animal, the researchers injected either Zika virus or saltwater (a placebo) directly into the brain tumors of 18 and 15 mice, respectively. Tumors were significantly smaller in the Zika-treated mice 2 weeks after injection, and those mice survived significantly longer than the ones given saltwater.

The idea of injecting a virus notorious for causing brain damage into patient’s brains may seem alarming, but Zika may be safer for use in adults because its primary targets—neuroprogenitor cells—are rare in the adult brain. The fetal brain, on the other hand, has many such cells, which is part of the reason why Zika infection before birth produces widespread and severe brain damage—while natural infection in adulthood causes mild symptoms.

Additional Research

The researchers conducted additional studies of the virus using brain tissue from epilepsy patients and showed that the virus does not infect noncancerous brain cells. As an additional safety feature, the researchers introduced two mutations that weakened the virus's ability to combat the cell's defenses against infection, reasoning that the mutated virus still would be able to grow in tumor cells—which have a poor antiviral defense system—but would be eliminated quickly in healthy cells with a robust antiviral response.

When they tested the mutant viral strain and the original parental strain in glioblastoma stem cells, they found that the original strain was more potent but that the mutant strain also succeeded in killing the cancerous cells.

“We're going to introduce additional mutations to sensitize the virus even more to the innate immune response and prevent the infection from spreading,” said Dr. Diamond, who also is a Professor of Molecular Microbiology and of Pathology/Immunology. “Once we add a few more changes, I think it's going to be impossible for the virus to overcome them and cause disease.”