Brain Cancer: Zika Virus Selectively Kills Glioblastoma Stem Cells

Zika virus can cause damage to the brains of developing fetuses, but it one day we may be able to harness the virus as a weapon against a deadly form of brain cancer.

The virus kills brain cancer stem cells, the kind of cells most resistant to standard treatments, according to new research from Washington University School of Medicine in St. Louis and the University of California San Diego School of 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 the study’s co-senior author, Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine at Washington University School of Medicine. Each year in the United States, about 12,000 people are diagnosed with glioblastoma, the most common form of brain cancer. It is is most often fatal within a year of diagnosis.

Glioblastoma Stem Cells

Standard treatment for glioblastoma is aggressive.

Surgery is followed by chemotherapy and radiation, but most tumors recur within six months. A small population of cells, known as glioblastoma stem cells, often survives the onslaught and continues to divide, producing new tumor cells to replace the ones killed by the cancer drugs.

Their neurological origins and near-limitless ability to create new 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.

Researchers injected either the Zika virus or a placebo directly into brain tumors of 18 and 15 mice, respectively. Tumors were significantly smaller in the Zika-treated mice two weeks after injection, and those mice survived significantly longer than the ones given saltwater.

Were Zika to be used in people, it would need to be injected into the brain, most likely during surgery to remove the primary tumor. If introduced through another part of the body, the person’s immune system would attack it before it could reach the brain.

Safety In Adults

Although the thought of injecting a virus known for causing brain damage into people’s brains might seems not all that smart, 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, is packed with such cells, part of the reason why Zika infection before birth produces widespread and severe brain damage, while natural infection in adulthood causes mild symptoms.

The researchers then made additional experiments using brain tissue from epilepsy patients and demonstrated that the virus does not infect noncancerous brain cells.

In a further safety measure, the researchers engineered 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 strong antiviral response.

More mutations are planned which will additionally sensitize the virus to the innate immune response and prevent the infection from spreading, Dr. Diamond said. If all is successful, the researchers could begin human trials in 18 as short as months.

Support for the research came from the National Institutes of Health, the Elsa U. Pardee Foundation, the Concern Foundation, the Cancer Research Foundation, and the McDonnell Center for Cellular and Molecular Neurobiology of Washington University.

Zhe Zhu, Matthew J. Gorman, Lisa D. McKenzie, Jiani N. Chai, Christopher G. Hubert, Briana C. Prager, Estefania Fernandez, Justin M. Richner, Rong Zhang, Chao Shan, Xiuxing Wang, Pei-Yong Shi, Michael S. Diamond, Jeremy N. Rich, Milan G. Chheda
Zika virus has oncolytic activity against glioblastoma stem cells
Journal of Experimental Medicine Sep 2017, jem.20171093; DOI: 10.1084/jem.20171093

Image: Cynthia Goldsmith CDC