Researchers Shrink Brain Tumors in Mice

Imagine being diagnosed with a glioblastoma, the most common—and deadly—type of brain tumor. Now imagine that with a single injection, your brain cells could be engineered to secrete a protein that would eliminate the tumor.

A team of researchers at Harvard-affiliated Mass. General Hospital recently developed a therapy to suppress brain tumor growth by using a cancer-killing gene delivered via a virus vector to cells surrounding the tumor. Testing their treatment on mice, they said, yielded “spectacular” results.

“Our goal was to show that if you genetically engineer normal cells within the brain you can actually control the growth of brain tumors,” said Miguel Sena-Esteves, a neuroscience researcher at MGH and one of the authors of the study.

To do that, Casey A. Maguire, the lead author of the study, used “adeno-associated virus vectors”—the best vectors for global delivery—to introduce a gene that, when expressed, causes production of the protein interferon-beta.

The protein is currently being tested in combating several cancers.

Maguire then injected human tumor cells into the brains of the mice.

After four days, the size of the tumor in mice with the beta-interferon gene had been substantially reduced compared to the mice that had not received the gene.

Within two weeks, the tumors had been completely eliminated in mice with the interferon-beta gene.

One of the advantages of creating this “zone of resistance” around the tumor is that doing so provides a continuous source of normal cells that produce a therapeutic product that prevents tumor cells from forming, Esteves said.

Many other therapies directly attack dividing tumor cells, but when the cells then die the therapeutic source is lost.

This is a problem for tumors like glioblastomas, which only have some of their cells dividing at any given time, according to Xandra O. Breakefield, a professor of neurology at Harvard Medical School and one of the authors of the study.

Another benefit of creating a “zone of resistance” is that when the gene is injected in one side of the brain, it can eliminate a tumor on the other, or contralateral, side, according to Anat O. Stemmer-Rachamimov, a pathologist at MGH and another of the study’s authors.

Esteves said that despite radiation therapy, the most aggressive tumors, like glioblastomas, are still untreatable and patients have a survival rate of only about one year.

The new breakthrough, he said, could eventually improve the treatment of the most advanced types of brain tumors.

“Yes, we have accomplished this in a tiny little mouse,” Esteves said.

“How can we apply that to a brain tumor in a person? That’s the next step.”

The researchers are now looking to test the therapy in brain tumors of dogs, which would prove beneficial for veterinarians, who currently can do little more than diagnose the tumor.

Dogs provide a good model system, not only because they have bigger brains than mice, but also because they would allow researchers to test the toxicity of the cancer-killing protein and the efficacy of the therapy, Breakefield said.

—Staff writer Alissa M. D’Gama can be reached at adgama@fas.harvard.edu.

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