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Biomedical engineering research points to a new strategy for glioblastoma treatment

August 4, 2017

Graduate student Jill Ivey

A woman works in the lab
Jill Ivey, a doctoral candidate in biomedical engineering and mechanics, places electrodes in a cell culture dish. Electrical pulses can destroy malignant glioblastoma cells, and Ivey and her coworkers have identified a molecule that makes that process even more effective.

Pre-treating glioblastoma cells with a particular protein molecule  increases the selectivity of a promising treatment for this aggressive form of brain cancer, researchers at Virginia Tech have discovered.

Glioblastoma is the most common and deadly type of brain cancer in adults, with around 12,000 cases diagnosed in the U.S. per year. These aggressive tumors quickly invade surrounding healthy tissue, and there are few effective treatment options; for some age groups, the five-year survival rate is less than 5 percent, according to the American Cancer Society.

Successfully treating invasive cancers like glioblastoma requires eradicating as many cancer cells as possible without damaging the healthy tissue around them. One way to do that is by identifying and targeting the features that distinguish malignant cells from their normal counterparts.

In a paper published in the Biophysical Journal, Virginia Tech doctoral student Jill Ivey and her coworkers show that a potential glioblastoma treatment called high-frequency irreversible electroporation is more effective when combined with a protein of the ephrin family.

The protein, ephrin A1, exaggerates a physical characteristic common in malignant cells, and that structural change may be responsible for making electroporation a more targeted weapon, the researchers say.

Ivey’s advisor is Scott Verbridge, an assistant professor of biomedical engineering and mechanics in the College of Engineering.

“We have this idea that we can target tumor cells specifically based on their altered physical properties, which gives us a little bit of a window where tumor cells are being killed but healthy cells aren’t,” Verbridge said. “What we need are ways to make that window even larger, so that we can push the difference in response between the two cell types apart from each other. That way it will be easier to destroy the malignant cells while preserving the healthy ones”

One of the most common features that differentiates a cancerous cell from a healthy one is that in the malignant cell, the nucleus — the packet containing all the cell’s genetic material — is often enlarged relative to the gelatinous cytoplasm surrounding it.

High-frequency irreversible electroporation, or H-FIRE, uses short, intense electric pulses to perforate a cell’s protective membrane. H-FIRE is a modified version of irreversible electroporation, a technique first applied to cancer treatment by Rafael Davalos, a Virginia Tech professor of biomedical engineering and mechanics and an author of the new paper.

The research team had previously discovered that H-FIRE killed glioblastoma cells at higher rates than normal brain cells. They suspected that the malignant cells’ enlarged nuclei were contributing to the enhanced lethality.

To test their theory, the researchers treated malignant glioblastoma cells with ephrin.

Ephrin is typically found at relatively low levels in glioblastoma tissue compared with healthy brain tissue. At the same time, cancer cells have additional receptors for ephrin, so the molecule interacts readily with those cells.

When a glioblastoma cell is exposed to additional ephrin, its cytoplasm shrinks, making its nucleus bigger in comparison. In other words, it looks even more like a stereotypical cancer cell.

When the ephrin-treated glioblastoma cells were exposed to H-FIRE, they could be killed at lower voltages than were normally required for untreated cells.

And when the researchers applied H-FIRE pulses to a mixture of ephrin-treated malignant and normal cells, to approximate the conditions in real patient tissue, they found that while the ephrin treatment had lowered that lethal threshold for malignant cells, the lethal threshold for normal cells hadn't budged. The range of voltages at which cancer cells could be killed without damaging healthy ones had broadened.

The high-frequency pulses characteristic of H-FIRE can penetrate the cell’s interior, making its internal architecture a more relevant factor in its response. The researchers hypothesize that using ephrin to shrink the cell’s cytoplasm may increase the damage the electric pulses inflict on the cell’s interior.

“We’re enhancing the inherent selectivity we saw with H-FIRE by using ephrin to change the cell morphology,” explained Ivey, who recently defended her dissertation.  

In addition, ephrin may be effective against glioblastoma on its own. Verbridge’s group collaborates with a team led by Waldemar Debinski at the Brain Tumor Center of Excellence at Wake Forest Baptist Medical Center. Debinski’s group developed an ephrin-based therapy that uses the protein to deliver a bacterial toxin to brain tumor cells.

“Ultimately we could combine this drug, which has had impressive initial efficacy by itself, with H-FIRE,” Verbridge said. “Together they synergize.”

Irreversible electroporation (at lower frequencies) has been used in clinical settings to treat cancers of the liver and pancreas. The enhanced selectivity of the combined ephrin-H-FIRE treatment raises the possibility of using lower voltages for electroporation, reducing the risk to healthy cells without compromising the effectiveness of the treatment.

For glioblastoma, which rapidly invades healthy brain tissue, this would be especially useful around the diffuse edges of the tumor, where malignant cells are scattered among normal ones.

The researchers are continuing to investigate the mechanism underlying the synergy between ephrin and H-FIRE; they’re also moving towards clinical applications of the technique for treating glioblastoma.

Verbridge and Davalos have won a grant from the National Institutes of Health to pursue those applications, collaborating with John Roberston, a research professor of biomedical engineering and mechanics, and John Rossmeisl, a professor of neurology and neurosurgery at the Virginia-Maryland College of Veterinary Medicine.

Glioblastoma treatment is an active area of research across the university, pulling together faculty from the College of Engineering, the College of Science, the Virginia Tech Carilion Research Institute, and the Virginia-Maryland School of Veterinary Medicine.

Verbridge, Davalos, Ivey, and Robertson are all affiliated with the Virginia Tech - Wake Forest University School of Biomedical Engineering and Sciences, which is supported in part by the Institute for Critical Technology and Applied Science.

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