Scientist in the Spotlight: Timothy Gershon, MD, PhD
After uncovering a metabolic process that appears to fuel the growth of brain cancer, Timothy Gershon is now using AICR support to investigate how a ketogenic diet may improve treatment for medulloblastoma, the most common malignant brain tumors in children.
Medulloblastoma accounts for approximately a quarter of all pediatric brain tumors. Chemotherapy and radiation make it possible for children with medulloblastoma to become long-term survivors, but these therapies can cause cognitive impairment, reduced growth and hormonal issues. “For many of the kids, although we can save their lives, the treatment doesn’t succeed in giving them their life as it was before they had their brain tumor,” says Gershon, an Assistant Professor in the Department of Neurology at The University of North Carolina School of Medicine.
It was caring for children with brain cancer that led Gershon to investigate the possibility of new, less toxic treatments, including changes to diet. “Having to take responsibility for giving kids treatments that cause a lot of side effects – and staying with the families when the treatments fail… that’s a powerful motivator,” said Gershon. “When my patients are either getting sick from their tumors or their treatments, it gives me extra energy to work harder in the lab."
All cells in the body need glucose to survive, but Gershon’s work suggests that medulloblastoma cells are heavily dependent on glucose for growth. In lab research, Gershon and his colleagues recently found that brain cancer cells thrive using the same metabolic process that normal brain cells use to survive when deprived of oxygen.
Glycolysis is how our cells get energy from glucose without using oxygen. Most cells combine glycolysis with oxidative metabolism to get the most energy possible. Without oxygen, cells can only use glycolysis, generating less energy from glucose and leaving behind a molecule called lactate.
Yet even with oxygen available, Gershon found that medulloblastomas growing in transgenic mice use glycolysis, converting the glucose into lactate. This metabolic process of cancer cells using glycolysis in the presence of oxygen was first observed by Otto Warburg in the 1920s and is popularly known as the Warburg effect.
“I think cancers do have a special metabolism and have more limitations on metabolism than the rest of the body."
Gershon found that brain cancer cells use an enzyme called hexokinase-2 (HK2) to trap glucose, allowing the cells to have an abundant supply of glucose for growth. When Gershon removed the HK2 gene, fewer animals developed medulloblastoma and within the tumors that formed, many cells left to become normal brain cells.
Gershon had hypothesized there would be some anti-tumor effect but the amount was surprising, he says. “We can really reverse tumor formation in our mice by manipulating their metabolism. In this study, we did it with genetic manipulation.”
Cancer and the Ketogenic Diet
With AICR support, Gershon is now taking the next step in his research: investigating how a ketogenic diet may disrupt medulloblastoma cell growth, providing an effective and safe way to treat the cancer.
The ketogenic diet is high in fat and low in carbohydrates. It forces the body to burn fat for energy rather than glucose. The diet is used to treat children with epilepsy and is offered by most children’s hospitals by individual physicians familiar with its use, according to the Epilepsy Foundation.
Humans only have a 24-hour supply of glucose and Gershon hopes that by limiting glucose, medulloblastoma cells may be deprived of the energy they need to grow. Research has shown that healthy cells will adapt to changing energy sources to survive, taking in energy from fat or protein. “We think that the tumor cells may be less able to adapt to other metabolic patterns than normal brain cells,” says Gershon.
His study will test this hypothesis on mice with medulloblastoma by having one group eat a conventional diet and another group eat a ketogenic diet. He will then measure any changes in glucose metabolism, tumor growth and survival.
By understanding cancer metabolism and using metabolism to treat cancer, we can hopefully find ways to fight cancer that are less damaging to the rest of the body, says Gershon, “I think cancers do have a special metabolism and have more limitations on metabolism than the rest of the body. If we can find a way to exploit that limitation, we can change cancer care.”
This story is adapted from ScienceNow.