Tumors need to devour enough nutrients to power their uncontrolled growth. For decades, researchers have been trying to develop new drugs that can cut off their “food” supply. A study published on November 8 showed that an upgraded version of a failed anticancer drug can not only prevent tumor cells from taking up an essential nutrient, but also stimulate immune cells to attack the growth of tumor cells.
“This discovery is very encouraging.” Ralph DeBerardinis, a cancer biologist at the University of Texas Southwestern Medical Center in Dallas, said, “You can get rid of tumor cells with just one drug and at the same time boosting immune cells.”
Tumor cells need nutrients in order to acquire molecules that are essential for survival and replication, but their overeating also turns the surrounding environment into an acidic, hypoxic “ditch” that prevents immune cells from destroying these tumor cells.
An amino acid called glutamine is a nutrient that is needed in many tumors and provides a basis for the manufacture of molecules such as deoxyribonucleic acid (DNA), proteins and lipids. “Glutamine is very important for cell metabolism,” said Jonathan Powell, an immunologist at Johns Hopkins University School of Medicine in Baltimore, Maryland.
Since the 1950s, researchers have tried to change the dependence of tumors on glutamine and developed drugs that block their metabolism. For example, a bacterial-derived compound called DON kills tumors by inhibiting several enzymes that help tumor cells take up glutamine. However, in clinical trials, the drug caused serious side effects including nausea and vomiting and was never approved.
Today, Powell and his colleagues have developed a new version of DON that may be more easily absorbed by the stomach. This drug carries two chemical groups, keeping it inert until it reaches the vicinity of the tumor. There, enzymes that typically wander around the tumor remove the “handcuffs” of these molecules, releasing the drug into the tumor cells. Powell says that with this approach, the vast majority of active drugs can reach where they are expected to go.
To test the new compounds, Powell and colleagues injected four types of tumor cells into mice to induce tumors. The researchers then injected the next generation of DON into some rodents. Scientists report in the latest issue of Science that the drug works for all four tumors.
For example, in untreated mice, colon cancer tumors have increased more than five-fold after about 3 weeks. However, in rodents treated with DON, the tumor shrinks and almost disappears. The researchers found that the drug not only inhibits the metabolism of glutamine, but also disrupts other aspects of cells, such as their ability to utilize glucose.
One problem with targeting cancer cell metabolism drugs is that they are also harmful for normal cells, including immune cells that fight tumors. But Powell and colleagues found that DON can speed up the process by which T cells destroy tumor cells.
Scientists have found that T cells that have captured glutamine by DON can use an alternative source to convert the raw materials needed to synthesize DNA and other key molecules, while tumor cells cannot. Powell said that with the new version of DON, the ability of tumors to multiply and evade the immune system no longer exists.
Ji Zhang, a cancer biologist at Indiana University School of Medicine in Indianapolis, said the results of the study were surprising but it was a good finding as this paper shows for the first time that T cells and tumor cells respond differently to glutamine inhibition. If this compound can be converted to be suitable for human treatment, it will have a bright future.
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