Glioma is the most common form of brain cancer and affects cells that support brain function. Gliomas account for a quarter of childhood cancers, arise throughout adulthood, can be deadly.

A cancer biologist at the University of Texas Southwestern Medical Center is studying gliomas through the lens of their altered metabolism, with an eye toward developing novel therapeutics designed to target cancer cells without harming normal ones.

Samuel McBrayer was recruited in 2019 to the Children’s Medical Center Research Institute at UT Southwestern, from the Dana-Farber Cancer Institute and Harvard Medical School, where he was a postdoctoral fellow. He received a First-Time Tenure-Track Award from CPRIT.

Some gliomas are among cancers that arise from mutations in genes that affect cell metabolism, or how cells utilize resources. In particular, gliomas have mutations in the pathways that cells use to oxidize and release stored energy from proteins, fats, and carbohydrates.

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Glioma is the most common form of brain cancer and affects cells that support brain function. Gliomas account for a quarter of childhood cancers, arise throughout adulthood, can be deadly.

A cancer biologist at the University of Texas Southwestern Medical Center is studying gliomas through the lens of their altered metabolism, with an eye toward developing novel therapeutics designed to target cancer cells without harming normal ones.

Samuel McBrayer was recruited in 2019 to the Children’s Medical Center Research Institute at UT Southwestern, from the Dana-Farber Cancer Institute and Harvard Medical School, where he was a postdoctoral fellow. He received a First-Time Tenure-Track Award from CPRIT.

Some gliomas are among cancers that arise from mutations in genes that affect cell metabolism, or how cells utilize resources. In particular, gliomas have mutations in the pathways that cells use to oxidize and release stored energy from proteins, fats, and carbohydrates.

Mutations in a gene called IDH1 change the way glial cells process carbohydrates, allowing a normally rare metabolite to accumulate in large amounts inside tumor cells. Once it has accumulated, this metabolite can have profound effects on a variety of pathways, including regulating how cells respond to lowered levels of oxygen. Hypoxia is typical inside solid tumors, and the way cells respond to this can affect how well they survive, thrive, and metastasize.

This metabolite competes with the normal substrate of a variety of enzymes and impacts their function. "Which of those enzymes actually controls cancer formation? That’s the question," McBrayer says.

Some of these enzymes help break down branched-chain amino acids, he says, and inhibiting their breakdown leads to a deficit in nitrogen metabolism within the cell. These cells compensate by using an alternate pathway that is less active in normal cells. That opens a window to targeting cancer cells specifically. By blocking that compensatory pathway during standard brain tumor therapy, cancer cells with IDH1 mutations may be killed more effectively, while normal cells are unaffected.

McBrayer’s work was the impetus for a clinical trial funded by the National Cancer Institute exploring the effectiveness of a therapeutic that blocks the compensatory pathway in gliomas with an IDH1 mutation.

"I’m waiting with bated breath to see how that pans out," he says. "We have a lot of data from mouse models but there is a big hurdle to clear with translating that to efficacy in the clinic. We are really hopeful that this will provide a treatment for a subset of brain tumor patients that really need a new option."

IDH mutations are also common in acute myeloid leukemias, cholangiocarcinomas—a type of liver cancer—and a type of sarcoma, a cancer of the body’s connective tissues. "We’ve been very focused on glioma," he says. "But obviously there are clear implications for other IDH mutated cancers as well."

In his lab, McBrayer and his team are engineering mouse models of brain tumors. Mouse models are costly and high-risk, he says, "but come with higher rewards if you are able to model a particular type of human disease."

CPRIT funding has allowed him to come a long way toward building better mouse models of brain cancer than he otherwise would have been able to attempt. Another benefit, too, he says, is "is that I am able to mentor and train the people in my laboratory much more closely than I would have if I had to spend my time seeking outside funding."

McBrayer received his undergraduate degree in biochemistry from Baylor University, and his Ph.D. in cancer biology from Northwestern University’s Feinberg School of Medicine. He began his postdoctoral fellowship at Dana-Farber and Harvard in 2012.

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