Targeting a rare secondary cancer in children — ScienceDaily
It's one of the most heartbreaking things Adam Green, MD, sees as a pediatric oncologist: kids who beat their cancer, only to see an incurable brain tumor develop five years later.
"It's especially tragic because at this point they are generally teenagers, or young adults who are trying to move on with their lives after dealing with cancer and may still be dealing with some of the after-effects of the treatments," he says. Green, a CU Cancer Center member who practices at Children's Hospital Colorado. "Then they suddenly get this secondary tumor that's incurable, and most of them die within a year. It's really terrible."
A rare killer
Known as pediatric radiation-induced high-grade gliomas (RIGs), this particular type of brain tumor is caused by cranial radiation therapy for other cancers, most commonly brain cancers. They are responsible for nearly 4% of all childhood brain tumor deaths, but there haven't been many studies on RIGs and how to treat them.
Green and graduate student John DeSisto have spent the past four years working with patient samples collected over the past decade by the Morgan Adams Foundation Pediatric Brain Tumor Research Program at the University of Colorado School of Medicine. they are different from "de novo" gliomas – or gliomas that do not develop in response to cranial radiation. Green and his collaborators — including several members of the CU Cancer Center, as well as scientists from St. Jude Children's Research Hospital in Memphis and the Children's Cancer Center in Hamburg, Germany — were looking for ways to prevent the formation of RIGs, as well as methods of treating them as soon as they occur. Their research was published Sept. 20 in the journal Nature Communications.
"We found that the mutations that occur in these tumors are quite different from the mutations that are characteristic of de novo pediatric high-grade gliomas. It seems to be a different biological process that causes them to develop," says Green.
The role of DNA repair
Using RNA sequencing, Green and his team examined more than 30 tumor samples and eventually split them into two subgroups based on which genes in the samples were turned off and on. One of the subgroups showed a decreased ability to repair DNA, leading the researchers to hypothesize that patients with conditions that cause impaired DNA repair are at a higher risk of developing RIGs once exposed to radiation. If those specific weaknesses can be detected early, he says, doctors could offer alternative treatments or better monitor patients after radiation to see if RIGs develop.
"What we think is that some patients have problems with their DNA that aren't enough to cause cancer on their own, but if they're exposed to radiation, they're at a much higher risk," he says. The reason the tumors take years to grow is because "radiation can damage DNA, but it takes a long time for that transformation from a normal cell damaged by radiation to a cancer cell to happen," he adds. "If DNA is damaged and that cell isn't very good at repairing its own DNA, then more errors continue to occur in the DNA over time, until the cell can eventually transform into a tumor cell."
Creating a consortium and looking at treatment for a longer life
The researchers also tested a number of FDA-approved chemotherapy drugs on both RIG subgroups, and found that there are certain drugs that appear to be effective against RIGs. In the future, they plan to develop animal models to further test the drugs, and eventually develop a clinical trial in humans to find the best way to treat the tumors.
"We think the treatments that work for the two different types of these high-grade gliomas could be very different between RIGs and de novo tumors," Green says. "If we start a clinical trial, it would be important to do it specifically for RIG. But RIGs are rare, so we're trying to get other researchers around the world interested in studying these tumors and starting a research consortium." that could help with this lab work, help get more patient samples and eventually all contribute to a clinical trial."
Ultimately, Green hopes the research will lead to better treatments for patients at higher risk for RIGs or who have developed RIGs, so that the number of patients dying young from these secondary tumors begins to decline.
"There are other types of secondary cancers in children that arise from their previous cancer treatments, such as leukemias that occur as a result of chemotherapy or sarcomas that occur as a result of radiation," he says. "Those are often curable, but RIGs are not. Our goal is to be able to treat them effectively so that patients have more time with a good quality of life. That even if they get a secondary cancer like this, we can cure it so that they can live a long productive life."
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