Metabolic processes may yield a new therapeutic window for hard-to-treat brain tumors

Stephen Mack, PhD, St. Jude Developmental Neurobiology, was sitting in a lecture hall in Toronto when he first heard about the work of neurosurgeon Michael Taylor, MD, at The Hospital for Sick Children (Sick Kids). Taylor, a former St. Jude neurosurgery fellow, was studying the genetic underpinnings of cancer. That was the spark that led Mack to a career researching the hidden drivers of brain tumors such as ependymomas and high-grade gliomas.

After completing a PhD in Taylor’s lab, Mack worked at Baylor College of Medicine before arriving at St. Jude in the summer of 2021. Bringing his lab to St. Jude didn’t feel foreign because Mack knew so many St. Jude researchers from their work.

“In addition to getting to work with researchers I’ve known and respected for years, I was excited by the translational potential of bringing our work to St. Jude,” Mack said. “The clinical trials apparatus at St. Jude makes it possible to bring new ideas more quickly into the clinic. We’re also excited to collaborate outside the brain tumor research community with scientists pursuing interests that may synergize with our work.”

Searching for vulnerabilities in childhood brain tumors

Pediatric brain tumors are the leading cause of cancer-associated death in children. Diffuse midline gliomas, are a classification of pediatric brain tumors. This classification was introduced by World Health Organization in 2021, and includes around 80% of diffuse intrinsic pontine gliomas (DIPGs). These tumors are classified by radiographic imaging as well as genetic underpinnings.

DIPGs start in the brain stem, the part of the brain above the back of the neck and connected to the spine. The brain stem controls vital processes such as breathing, heart rate, and the nerves and muscles that control the senses. These tumors grow from glial cells, a type of supportive cell in the brain. There is no cure for DIPG.

As one of the most intractable challenges in cancer research, finding viable treatments for DIPG is a priority. Tried-and-true approaches, such as genome sequencing, have already been done and haven’t yielded successful therapies. Scientists are trying creative new approaches to understanding this cancer. Mack’s lab is looking at the interplay in these tumors between metabolic processes and epigenetic regulation.

Metabolic processes refer to the life-sustaining chemical reactions of metabolism that convert energy into the building blocks for proteins, lipids, nucleic acids and carbohydrates. Epigenetic regulation is the reading and writing of marks on the genome that control how genes are expressed. Mutations can affect the epigenetic regulation of genes, and thus how much or how little of the related proteins gets produced. Mutations of histone 3 lysine 27 (H3K27M) occur often in DIPGs and are involved in epigenetic regulation. In collaboration with Sameer Agnihotri, PhD, University of Pittsburgh, Mack’s team created a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors.

Metabolic target shows promise

Metabolism influences epigenetic programs and therefore might present ways to target cancers with abnormal epigenetic regulation. Modulating metabolism isn’t totally straightforward because it can create toxic effects, so Mack and his team needed to understand the interplay between processes.

Using their H3K27M model, the researchers looked at which amino acids the tumor cells relied on for survival. In a study published recently in Nature Cancer, Mack and his team shared the results, showing tumor cells relied on the amino acid methionine. The researchers found that the methionine cycle depends on an enzyme called methionine adenosyltransferase 2A (MAT2A). Mack and his team worked out how MAT2A functions. They found that DIPG cells have lower MAT2A protein levels, due to a negative feedback mechanism initiated by a metabolite called decarboxylated 13 SAM (dcSAM).

Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M-mutant glioma. Too much or too little MAT2A will impede cell growth, because the cancer cells strive for balance.

“These tumors have vastly different epigenetic programs than normal cells,” Mack said. “So, potentially, there's a therapeutic window where you can modulate the metabolic process. It’s a first start for us to think about how using this target to modulate the epigenetic program might be therapeutically useful combined with other treatment approaches.”

Dietary restrictions can affect methionine and might provide some benefit to cancer patients with H3K27M mutations, but such restrictions have not been tested clinically in pediatric patients. The researchers don’t expect modulating the methionine dependency to be a stand-alone treatment but are interested in pursuing it as a combination approach with radiation or other therapies.

Finding hope for treating pediatric brain tumors

Treatment for brain tumors such as DIPG hasn’t significantly changed in over 20 years. In his St. Jude lab, Mack will continue to study ependymomas and high-grade gliomas such as DIPG. His work is designed to be translational, which means making basic discoveries and then finding ways to create real-world solutions.

“My primary goal as a researcher is to learn more about the biology to figure out what is driving cancer, and specifically these types of brain cancer,” Mack said. “I believe you have to study the mechanisms, figure out how to develop new models, and think about how we can leverage our findings to identify therapies.”

“There’s really two components to our lab: the basic biology component and the translational component,” Mack said. “There's such a clear need for new trials for these patients, which means we need to come up with new therapies to test. Learning more about the biology of these tumors will help us identify therapeutic approaches that haven’t been tried before.”