In 1955, an American doctor named Harry Eagle made a surprising discovery about cancer cells growing in a dish: They required ridiculous amounts of glutamine. Without this chemical, the cells would stop growing and eventually die, despite having all the other known requirements for life.
Glutamine is an amino acid, one of 20 such molecules that cells string together into proteins. It’s rich in the element nitrogen and can be broken down to provide that element for the assembly of other molecules, like DNA.
You hear far less about glutamine than you do about sugar, the other nutrient that cancer cells tend to consume in abundance. But it’s just as important.
“Cells are dependent on glutamine in so many ways,” says Natasha Pavlova, a biochemist who studies cancer metabolism in the lab of MSK President and CEO Craig Thompson in the Sloan Kettering Institute. “It’s not only involved in the production of DNA nucleotides and other molecules but it also acts as a currency to pay for the import of other amino acids into the cell.”
Cancer cells’ addiction to glutamine has long tempted cancer biologists as a potential Achilles’ heel for treating the disease. Perhaps by cutting off the supply of this amino acid, one could starve cancer cells to death. Inconveniently, normal cells need glutamine too. Therefore, drugs that affect glutamine levels in the entire body are too toxic to use as cancer therapy.
But as scientists learn more about how cancer cells use glutamine, they hope to find other ways to selectively target cancer’s particular dependence while sparing normal cells.
Glutamine: An Essential Nonessential Amino Acid
Cancer’s dependence on glutamine is actually somewhat surprising. Glutamine is technically a nonessential amino acid. Unlike essential amino acids, which cells can’t make on their own and must obtain from the foods we eat, cells can easily synthesize glutamine from other starting materials. But glutamine’s other virtues make it unique.
“What’s special about glutamine is that all the other nonessential amino acids can be made from it, but other nonessential amino acids cannot substitute for glutamine,” Dr. Pavlova explains. It’s also central to several biochemical pathways that cancer cells use to build new cell parts.
Cancer’s need for glutamine is so great that some cancer-causing oncogenes alter how much of it the cells take up and digest. One of the best known, the gene MYC, promotes cancer in part by increasing cancer cells’ access to a steady supply of glutamine. Cells with an amplified MYC gene make more of the enzyme that converts glutamine into its downstream products. Such cells essentially become addicted to MYC amplification.
Mutations in the genes IDH1 and IDH2, which also change how glutamine products are used in a cell, are common in certain types of brain cancer and leukemia.
This high demand for glutamine means that supplies of it inside of a tumor are often quite low. Yet cancer cells still manage to grow there. How?
This suggests that cells have alternate ways to supplement their glutamine supply, Dr. Pavlova says.
One such adaptation she and her colleagues have been studying is an increase in the amount of the enzyme glutamine synthetase, which makes glutamine from other starting materials, namely glucose.
Her colleagues from the Thompson lab and collaborators at Princeton University and New York University (NYU) have also found that cancer cells can engulf surrounding cells and scavenge their nutrients for glutamine.
Cancer cells’ adaptability in acquiring nutrients even when they are scarce makes any simple approach to cutting off cancer’s glutamine supply likely to fail.
Nevertheless, there are possible approaches. One is to block the import of glutamine by tumor cells specifically. Some research suggests that the protein transporter that tumor cells use to import glutamine is different from the one that normal cells use, and that this transporter is more abundant on tumor cells. These cancer-specific transporters might make a good target for drugs that would prevent the cells from satisfying their fix.
Cancer cells’ dependence on glutamine could also serve as a basis for tailoring therapies to specific people. One amino acid product dependent on glutamine is glutathione. This important cellular antioxidant defuses dangerous chemicals called reactive oxygen species and even certain drugs.
“Glutathione attaches itself to the drug and kind of flags it for removal out of the cell,” Dr. Pavlova explains.
Studies from investigators at NYU have shown that lung cancer tumors with certain genetic mutations are very dependent on glutathione. Interfering with their use of it (through drugs called glutaminase inhibitors) could be a potential treatment approach.
Several ongoing clinical trials are combining these glutamine-altering drugs with immune checkpoint inhibitors or with inhibitors of receptor tyrosine kinase signaling, the major signal that tells cells to acquire nutrients and grow.
Besides the therapeutic possibilities, there are also diagnostic opportunities. In the same way that cancer’s love of glucose serves as the basis for FDG-PET scans, its reliance on glutamine could serve as another valuable diagnostic tool. It would be particularly useful for brain tumors. PET scans are less useful for monitoring primary brain tumors or tumors that have spread to the brain from elsewhere in the body because the brain itself takes up a lot of glucose. A glutamine-based scan would allow doctors to tell cancer cells apart from normal brain cells.
Research teams at MSK are actively pursuing this approach.
No Dietary Fix
One approach to starving cancer of glutamine that is almost sure to fail is changes in diet. “We cannot easily alter glutamine levels with the diet because the body seems to be doing such a good job at maintaining the level at a very steady concentration,” Dr. Pavlova says. “The only time glutamine levels fall is during intense trauma or sepsis, which is not something you’d want to replicate.
“At least with glucose we can say, ‘Try to avoid spikes of glucose by eating low glycemic foods’ and so on,” she adds. “But with glutamine, it’s a lot trickier to make any useful recommendations.”