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Many children with cancer receive chemotherapy, but a new study suggests a drug that blocks DNA repair may work against pediatric tumors.

Ahmed Gomaa Xinhua News Agency/Newscom

Researchers find fatal flaw in childhood tumors

Childhood tumors aren’t duplicates of their adult counterparts. They often carry distinct mutations, respond differently to drugs, and stem from other causes. Those are some of the reasons that only four new drugs for treating cancer in children have received approval from the U.S. Food and Drug Administration in the past 25 years, versus more than 100 drugs for adult cancers. Now, researchers say they’ve found a new way to fight cancer in children, one that targets a tumor cell’s ability to repair its DNA.

The work is “a big step in the right direction,” says pediatric oncologist John Maris of the Perelman School of Medicine at the University of Pennsylvania.

Tumors that strike kids have a potential vulnerability, pediatric oncologist Alex Kentsis of Memorial Sloan Kettering Cancer Center in New York City and colleagues revealed earlier this year. Most produce PGBD5, a protein that can cause mutations in cancer-thwarting genes, as well as in other genes. (The gene encoding the protein is inactive in most healthy cells in children and adults, and its normal function is unclear.) The researchers also found that to survive, a cell that makes lots of PGBD5 needs to be able to repair its DNA, possibly because the protein triggers mutations than can kill the cell. Block this repair, the researchers reasoned, and you should be able to stop the tumor in its tracks.

Kentsis and his team have now tested that idea. They started by choosing five molecules that researchers knew inhibited the messages that prompt cells to mend their broken DNA. When the scientists added these molecules to noncancer cells they had engineered to pump out PGBD5, one drug, known as AZD6738, outperformed the others, killing about 80% of PGBD5-manufacturing cells.

Physicians are already testing AZD6738 in adult cancer patients because of its ability to thwart DNA repair, but its effects on childhood tumors were unknown. So Kentsis and colleagues gauged whether the compound slays cultured cells from four types of childhood cancers: the bone tumor Ewing’s sarcoma; the nervous system tumors neuroblastoma and medulloblastoma; and rhabdoid tumor, which usually forms in the kidneys. Compared with normal cells, cells from all four tumor varieties were more vulnerable to the drug, the researchers found. But if the team turned down the cancer cells’ production of PGBD5, the drug was less effective.

The scientists next measured AZD6738’s impact on human childhood tumors growing in mice. After implanting cells from the four types of these cancers into the animals, the researchers allowed tumors to develop and then dosed some of the mice with AZD6738. The drug curbed tumor growth in mice that received neuroblastoma or medulloblastoma cells, the researchers report today in Science Translational Medicine. In the animals implanted with neuroblastoma cells, for instance, tumors were more than 10 times larger in the control animals than in the animals treated with AZD6738. However, the drug did not work against Ewing’s sarcomas and rhabdoid tumors in the animals. Kentsis says the results support clinical trials of AZD6738 in children as well. “We intend to advance its testing for children and adults with tumors that express PGBD5.”

“What’s exciting about this paper is that it identifies a different mechanism to confer sensitivity to a drug,” says pediatric oncologist Katherine Janeway of the Dana-Farber Cancer Institute in Boston. She says the team’s approach of targeting DNA repair with AZD6738 or related drugs is “worthy of a clinical trial.”

But Maris says that such clinical trials are premature because the drug doesn’t appear to be powerful enough. In the animal experiments, he notes, AZD6738 didn’t destroy the tumors; they just stopped growing. “They are far from curing the mice.”