Annual Report 2014

Dr. Barry Stoddard

Dr. Barry Stoddard and his team used a new approach to engineer a molecule in yeast that is now being tested to treat brain cancer. Fred Hutch file

From yeast to brain, engineering a new cancer treatment

Enzyme redesigned at Fred Hutch makes headway in clinical trial

By Susan Keown

Some engineers build skyscrapers, but Dr. Barry Stoddard works on a much smaller scale. Using computer modeling software and genetic manipulation techniques, Stoddard tinkers with molecules.

Today, one molecule reengineered in the Stoddard Lab is getting its chance to prove itself as part of a groundbreaking new therapy for glioblastoma, a fast-growing and difficult-to-treat brain cancer.

Last year, a San Diego-based biotech company began early-phase clinical trials of a yeast enzyme reengineered in 2005 by Stoddard and his collaborators. (An enzyme is a molecule that helps the chemical reactions of life happen.) Thanks to three tweaks that the Stoddard Lab made to its structure, the engineered enzyme is more stable and more precisely honed to its target, which has made it better for use in human therapeutics.

Cancer-fighting enzyme
Model of the cancer-fighting enzyme engineered in the Stoddard Lab that is now being tested against glioblastoma. Image courtesy of the Stoddard Lab

 

"At that time, that type of protein engineering hadn’t been done before," Stoddard said. "Structure-based, computer-aided redesign to alter the properties of an enzyme, to make it better."

In the ongoing trials, researchers infect patients' cancer cells (and not their healthy cells) with a specialized virus that instructs the cells to make the engineered enzyme. Then, the patients take pills containing a compound that is harmless to normal human cells, but fatal to the cancer cells once their new enzyme converts the compound into a deadly poison. Unlike conventional chemotherapy, this type of targeted gene therapy leaves healthy cells untouched.

Stoddard's original research goal was to figure out this enzyme's structure and how it works. Once he'd done that and his team had successfully engineered a new version, Stoddard and collaborators shared their redesigned enzyme with the scientific community for others to build on their results — which is how it made its way into a starring role in the glioblastoma trial.

This trial is "a really good example of a basic scientific study unexpectedly getting turned into a clinical application," said Stoddard.

The Fred Hutch environment was particularly conducive to this advance, he said. "Working in very close proximity to both cancer biologists and to cancer clinicians was extremely motivating and helpful to us in moving the project forward towards a final result with therapeutic potential," Stoddard said.

It's still too early to know whether the treatment will shrink the tumors as intended or if it might need further refining, but some patients have already shown encouraging signs of improvement.

"That there are people walking around with glioblastomas that are getting therapeutic benefit, partly from something we worked on, just blows my mind," said Stoddard, whose mother died of glioblastoma shortly after he came to the Hutch. "To have been able to contribute in a small way to efforts to fight such a terrible disease has been a tremendous blessing."

Through their generous support at the 2013 Hutch Holiday Gala, and as members of Fred Hutch's President's Circle, Bruce and Peggy Wanta help fuel basic science research at Fred Hutch — like Dr. Stoddard's — that paves the way to lifesaving medical advances.

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