University of Vermont

Vermont Quarterly

Colleague’s memory motivates researchers

Dr. Andrew Tsen and  Professor Diane Jaworski
Dr. Andrew Tsen and Professor Diane Jaworski are part of a UVM team discovering potential new brain cancer treatments. Photograph by Raj Chawla

THE GREEN/
MEDICINE

Colleague’s memory motivates researchers

For billions of people, cancer is personal, but a relative handful of them are in a place to have an impact on the disease. Diane Jaworski, professor of neurological sciences, and her former PhD student Patrick Long G’13 are among them.

Jaworski and her colleagues in UVM neurological sciences had a close, heartbreaking experience with the brain cancer glioblastoma when their colleague Bruce Fonda, a longtime anatomy lecturer beloved by generations of medical students, succumbed to the disease in 2005.
 
It’s a form of cancer that Jaworski already knew well. Her research focuses on developing therapies to treat gliomas, highly malignant brain tumors that originate in the glial cells of the brain. Patients with glioblastoma, which is the most aggressive type of these tumors, have a median survival of only fourteen months. Even with treatments like surgery—not always an option—and radiation and chemotherapy, glioma stem cells are able to rapidly reform tumors.

Reduced acetate levels are a hallmark of all cancers, Jaworski says. “Most notably, the lack of acetate silences tumor suppressor genes, the ‘brakes’ that limit cell division.” As the UVM scientists explored ways to boost acetate levels, they lived the truth of medical research—always a long road, where the knowledge of what doesn’t work can sometimes be the trigger to what treatments can be effective. It was on the flight back from an April 2011 cancer conference that Jaworski and Long talked and came to one of those fabled “aha moments,” insight that pushed them to try another possibility in their efforts to boost acetate levels.

The key solution turned out to be an FDA-approved food additive—glyceryl triacetate (GTA)—used to treat Canavan disease, an inherited disorder that causes progressive damage to nerve cells in the brain. A previous clinical trial using GTA, conducted by collaborators at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, was fundamental to Jaworski’s pursuit of this avenue. “Their work found that both rodents and infants can tolerate GTA very well,” she says.

Within a few weeks back in the lab, the UVM research team had the first promising results that GTA decreased the growth of glioma stem cells, but not normal brain cells, in culture. The next critical test, performed with the help of Jeffrey Spees, director of UVM’s Stem Cell Core Facility, and Dr. Andrew Tsen, Fletcher Allen neurosurgery resident, would be to determine if GTA reduced the growth of tumors formed in mouse brains. The group’s second “aha moment” came when the test data were decoded, and it was revealed that GTA increased the effectiveness of chemotherapy treatment and increased survival.

Because almost all types of cancer cells have reduced acetate, Jaworski believes that GTA will not only be effective on glioma cells, but potentially other cancers.  Preliminary cell culture results support her hypothesis. Further recommending its use: GTA can be orally administered, is easily absorbed by the stomach and gastrointestinal tract, has a low risk of side effects, and minimal toxicity to non-cancerous cells. The next step is a Phase 1 clinical trial.

“The driving force for this project is the fond memories of my friend and colleague Bruce Fonda,” says Jaworski. “I often wonder, what if GTA was available for him? However, I must now focus on the fact that there are other patients receiving the dire diagnosis of glioblastoma every day and GTA may help them. It is through this work that Bruce’s legacy lives on.”



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