Study published in Molecular Therapy also reports that these viruses also changed the activity of three genes linked to angiogenesis.

Researchers at the Ohio State University Comprehensive Cancer Center have figured out why viruses genetically designed to kill glioblastoma cancer cells do not always work completely.

The investigators found through animal studies that as the viruses destroy the tumor cells, they cause the cells to make proteins that stimulate the growth of new blood vessels to the tumor. These vessels transport immune cells that eradicate the viruses and actually stimulate regrowth of the tumor.

“This study points to an important side effect of oncolytic viral therapy that may limit its efficacy,” notes principal investigator, Balveen Kaur, Ph.D., a researcher with Ohio State’s Comprehensive Cancer Center and the Dardinger Laboratory for neuro-oncology and neurosciences. “Knowing this, we can now work on designing a combination therapy that will inhibit this effect and enhance the action of the viral therapy.”

The researchers also discovered that, in infected tumor cells, the viruses changed the activity levels of three genes linked to blood-vessel growth in gliomas. CYR61 was nine times more active in virus-treated tumor cells than in uninfected tumors. The researchers also showed that the higher the dose of virus used, the greater the gene’s activity.

Dr. Kaur’s team implanted human glioma cells into rodents with a working immune system. They then injected the resulting tumors of some with an oncolytic virus called hrR3. The treated animals lived 17 days compared with 14 days for the untreated controls. The virus-treated tumors had roughly five times more blood vessels in them than the untreated tumors.

Treated tumors also showed changes in gene activity for three of 11 genes thought to play a role in blood-vessel development in gliomas. Of these, CYR61 showed an 8.9-fold increase in activity 12 hours after treatment.
Finally, the investigators verified the virus-caused increase in CYR61 gene activity using different glioma cell lines, glioma cells from patients, and strains of active, replicating oncolytic viruses.

“In all cases, we observed a rise in CYR61 gene activity, which indicates that this change in gene activity may represent a host response to the viral infection,” explains Dr. Kaur. “Nonreplicating viruses had no effect on the gene’s activity.”

Dr. Kaur and her colleagues are now studying why cells turn on this gene when infected with oncolytic viruses and whether the protein that results from this gene activation might serve as a biomarker reflecting patients’ response to oncolytic virus therapy.

The research was published in the June 10 issue of Molecular Therapy.