Revamped cancer drug starves tumors in mice

Tumors are hogs, gobbling nutrients to fuel their runaway growth, and for decades researchers have tried to develop drugs that cut off their food supply. A study out today shows that an updated version of a failed cancer drug can not only prevent tumor cells from using an essential nutrient, but also spur immune cells to attack the growths.

“It’s a pretty striking paper,” says cancer biologist Ralph DeBerardinis of the University of Texas Southwestern Medical Center in Dallas, who wasn’t connected to the study. “With a single drug, you can in effect starve the tumor and beef up the immune cells.”

Cancer cells eat to obtain molecules vital for survival and replication, but their gluttony also turns their surroundings into an acidic, oxygen-deprived moat that stymies immune cells trying to eliminate them. One of the nutrients many tumors need in abundance is the amino acid glutamine, which provides the building blocks for fabricating molecules such as DNA, proteins, and lipids. “Glutamine is incredibly important for cellular metabolism,” says immunologist Jonathan Powell of the Johns Hopkins School of Medicine in Baltimore, Maryland.

Starting in the 1950s, researchers tried to turn tumors’ glutamine dependence against them, developing drugs to block its metabolism. A bacteria-derived compound called DON, for instance, kills tumors by inhibiting several enzymes that allow cancer cells to use glutamine. In clinical trials, however, the drug provoked severe nausea and vomiting, and it was never approved.

Now, Powell and colleagues have crafted a new version of DON that may be easier to stomach. It carries two chemical groups that keep it inert until it reaches the tumor’s neighborhood. There, enzymes that normally loiter around tumors remove these molecular handcuffs, unleashing the drug on the cancerous cells. With this approach, “the vast majority of the active drug is where we want,” Powell says.

To test their new compound, he and colleagues injected four types of cancer cells into mice, inducing tumors. They then dosed some of the animals with their next-generation DON. The drug worked against all four kinds of tumors, the scientists report today in Science . In untreated mice, for example, colon cancer tumors had grown more than five times larger after about 3 weeks. But in rodents that received DON, the tumors shrank and almost disappeared. The researchers found that the drug wasn’t just throttling glutamine metabolism. It was also disrupting other aspects of the cells’ biochemistry, such as their ability to use the sugar glucose.

One concern about drugs that target cancer cell metabolism is that they will also poison normal cells, including the immune cells that battle tumors. But Powell and colleagues found that their version of DON revved up T cells to destroy cancer cells. The scientists discovered that T cells deprived of glutamine by DON could switch to an alternative source of the raw materials needed to synthesize DNA and other key molecules, whereas tumor cells couldn’t. With the new DON version, “we disable the ability of the tumor to proliferate and to evade the immune system,” Powell says.

The study’s findings are a surprise—but a good one, says tumor biologist Ji Zhang of the Indiana University School of Medicine in Indianapolis. “This paper is the first to show that the response to glutamine inhibition in T cells and cancer cells is different.”

“That T cells are not inhibited by this compound, that is the miracle” that may allow the drug to become a cancer treatment, says biochemist Stefan Kempa of the Max Delbrück Center for Molecular Medicine in Berlin. He cautions that drugs that shine in mouse studies often don’t work in people, but “if this compound can be translated to humans, it has a bright future.”

That bright future could begin next year, when Powell says safety testing of the drug will begin in people.