Some brain cancers are easier to treat than others, and while many solid tumors can be removed surgically, others, such as diffuse midline gliomas (DMGs), are much trickier. The results of studies in lab-grown cells and in mouse models, carried out by researchers at the University of Pittsburgh School of Medicine (Pitt), could now point to the development of a potentially better, noninvasive way to help improve DMG tumor therapy.
The physician-scientists from Pitt and UPMC Children’s Hospital of Pittsburgh discovered that DMG tumors are uniquely dependent on methionine—an essential amino acid that humans obtain from their diet. The findings suggest that developing drugs that specifically target methionine-processing machinery in cancerous cells in the brain, but not in the rest of the body, might pave the way for the development of new noninvasive treatments. It’s also feasible that reducing methionine in the diet may prove beneficial for patients with DMG tumors.
“The Achilles’ heel of these tumors is that they are rapidly growing and use a lot of nutrients,” said Sameer Agnihotri, PhD, assistant professor of neurological surgery at Pitt. “Combining metabolic approaches—changes in diet—with next-generation scientific tools might become a way of harnessing our understanding of how nutrient needs of cancer cells differ from normal cells and lead to more effective personalized cancer therapies in the future.”
Agnihotri and colleagues described their research and findings in Nature Cancer, in a paper titled, “Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome.”
Brain cancer is the second most common type of cancer in children, surpassed only by leukemia. But unlike leukemia, which has relatively high survival rates thanks to the medical advancements of the last century, brain cancers represent the number one cause of cancer deaths among children. And, of all brain cancers, DMGs are especially deadly. “The 2021 World Health Organization (WHO) classification of central nervous system cancers established a new subclass of very aggressive high-grade gliomas (grade IV), called DMGs, which is inclusive of most diffuse intrinsic pontine gliomas (DIPGs),” the authors wrote.
“DMGs bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes … The discovery of H3K27M mutations in a subset of gliomas usually diagnosed in children and young adults has already yielded possible therapeutic sensitivities, but these tumors remain universally lethal,” the authors added. In fact, the investigators further noted, “ … patients with DIPG and H3K27M mutations have a five-year survival rate of less than 10% and a median survival time of 9–12 months.” Children who have been diagnosed with a DMG tumor are projected to live for less than a year.
The midbrain, where DMG tumors often arise, is a critical connection point linking the brain cortex—an area responsible for complex information processing, logical reasoning, and thinking—to the spinal cord. Because DMG tumors are buried deep inside the brain, surgery may be impossible, and they often don’t respond to radiation therapy.
“None of the standard chemotherapy approaches that have been successfully tested in adults were a home run in children with this type of cancer,” said Agnihotri. “Pediatric cancers are so distinct and different from adults. In young children, brain tumors grow just as the brain is trying to develop normally, so anticancer therapies can have many side effects.”
However, DMG cells might have a special vulnerability that could be exploited for therapeutic benefit. Careful analysis of those cells’ genetic code revealed that they have a unique feature—a mutation in proteins that provide structural support to the DNA—that makes them particularly vulnerable to methionine depletion.
Methionine is one of nine amino acids (AAs)—these are the building blocks that our bodies use to make proteins—that are known as “essential.” The human body lacks the machinery to make methionine from scratch, so we can only acquire this amino acid from our diets. Poultry and legumes are examples of foods that are rich in methionine.
To find out whether manipulating cancer cells’ diet could slow the growth of DMG tumors, the researchers first put the cells in a Petri dish and recorded their behavior while depleting one nutrient at a time. When the cells were depleted of methionine, the cancer cells’ growth was dramatically repressed. “H3K27M mutant cells were highly dependent on methionine,” the investigators noted. They then wanted to look at this dependency in greater detail. Methionine doesn’t serve just one function, the scientists pointed out, and they hypothesized that identifying genes important to its metabolism would help to suggest which aspects of the process are essential for tumor growth. “Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors,” they reported. The enzyme catalyzes the production of SAM [S-adenosyl methionine] from methionine and serves as a cofactor in methyltransferase (MTase) reactions.
The investigators also showed that removing this key enzyme that is involved in converting methionine into other components indispensable for many cellular functions stymied cancer cells’ growth and increased the survival of mice with aggressive DMG cancers. Experiments in mouse models of DMG confirmed that putting the animals on a methionine-restricted (MR) diet increased life expectancy by nearly 50%. The results, the team said, “… indicate that an MR diet or MAT2A knockdown represents a therapeutic target in DIPG cells.”
Interestingly, the authors noted in their published paper, “Methionine is an essential AA and its dietary restriction has been shown to extend the lifespans of several organisms … At present, radiation is the only treatment approved for DMG and DIPGs. MR diets have extended the survival of several in vivo cancer models, with encouraging patient data.”
The team is now busy developing a proposal for a clinical trial to test drugs targeting methionine metabolism in people. They are optimistic that the trial’s launch won’t be too far in the future. Summarizing their reported findings in the Nature Cancer paper, the team noted, “ … we provide a rationale and therapeutic strategy, whereby targeting a metabolic vulnerability would be an approach for brain tumors, opening up an avenue for treatment that is under-explored. This study offers the possibility that dietary modulation can provide a promising treatment approach for an otherwise incurable brain tumor of childhood.”
