The childhood nerve cancer neuroblastoma shows weakness

By activating the tumor suppressor p53, a new drug may slow the malignancy, a study in mice shows

A compound that unleashes one of the body’s best tumor-suppressing proteins may someday come to the aid of cancer’s littlest victims — children with neuroblastoma. The compound, called nutlin-3, limits the growth of these nervous system tumors in mice, scientists report in the Nov. 18 Journal of the National Cancer Institute.

What’s more, nutlin-3 slowed the growth of neuroblastoma that was already resistant to the effects of a frontline chemotherapy drug and limited the spread of the cancer in the animals.

Nutlin-3 works by freeing up the cancer-fighting protein p53, which gets bogged down in patients with neuroblastoma and other cancers.

These results and previous laboratory findings have paved the way for tests of nutlin family compounds in cancer patients. The first human trials are just getting under way, with Hoffmann-La Roche recruiting adults with leukemia or bone cancer who have relapsed.

Neuroblastoma is the most common non-brain solid cancer in children, accounting for roughly 10 percent of pediatric cancers overall and 10 percent of childhood cancer deaths. Tumors typically develop in nerve tissues, but can also show up in the adrenal glands.

In the new study, physician Tom Van Maerken of Ghent University Hospital in Belgium and his colleagues used nutlin-3 to neutralize MDM2, a protein that binds to the p53 protein, hampering p53’s ability fight cancer. Earlier studies have shown that nutlin-3 can specifically prevent MDM2 from sabotaging p53. So using a synthetic version of nutlin-3 seemed like a good bet to help p53 do what it does best — trigger programmed cell death in malignant cells.

The researchers injected mice with a particularly lethal form of neuroblastoma, using tumor cells obtained from human patients who had relapsed despite treatment. Before implanting these cells into the animals, however, the scientists took the extra step of culturing the tumor cells with the frontline chemotherapy drug doxorubicin. This left scientists with tumor cells that were resistant to the chemo drug.

Two weeks after implantation with the tumor cells, some of the mice were fed nutlin-3 and others received an inert solution. After three weeks of this treatment, tumors in the nutlin-3-treated animals were less than half as large as those in the mice getting no drugs.

Neuroblastoma can metastasize, or spread, to other organs. After testing tissues from the liver, lungs and blood, the researchers found that mice treated with nutlin-3 had substantially fewer signs of nascent cancer in these areas than did the mice not getting nutlin-3.

“This is a very aggressive cancer,” says pediatric oncologist Jason Shohet of the Baylor College of Medicine in Houston. “The fact that you can knock it back by up-regulating p53 is really kind of exciting.”

Van Maerken and colleagues suggest that other compounds in the nutlin family will probably be more effective than nutlin-3 and might yield better results. They also suggest that a nutlin drug might work effectively in tandem with other treatments for cancer.

Meanwhile, the nutlins could have uses beyond neuroblastoma, leukemia or bone cancer, Shohet says. The machinery for manufacturing p53 remains intact in many cancers, he says, which suggests that suppressing MDM2 with a nutlin drug could help such patients.

Scientists at Hoffmann-La Roche laboratories in Nutley, N.J., discovered and named nutlins several years ago while screening compounds. They found that nutlins prevent MDM2 from latching onto and hindering the action of p53. The discovery has since spawned dozens of scientific papers aimed at using nutlins to inhibit MDM2, Shohet says “We’re going to see a lot more of this strategy of reactivating p53.”

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