Pediatric Brain Tumor Patients Find Success with Targeted Drug

Danny Powers out on a fishing trip.

At first, early intervention specialists told Christi Powers that her young son’s gross motor delays and poor balance were likely the result of weak muscle tone, but when Danny developed severe headaches at age 4, she took him to the emergency room. Soon the suburban Boston boy was diagnosed with a low-grade glioma, the most common pediatric brain tumor.

The good news about low-grade gliomas is that they are highly curable, and most children diagnosed with the non-malignant, slow-growing tumor can look forward to decades of survival. The “but” in this good news is that the standard treatment – chemotherapy and sometimes radiation, in addition to surgery – is toxic and can damage the developing brain and body.

So when researchers discovered that 10 percent of pediatric low-grade gliomas share the same so-called BRAF V600E mutation found in a subset of adult melanomas treated with a federally approved targeted therapy, they established a clinical trial to see if the drug also works on these childhood brain tumors.

Good news came at the recent meeting of the European Society for Medical Oncology meeting in Copenhagen, where Mark Kieran, MD, PhD, clinical director of the Brain Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, presented early results of the trial. Of 32 relapsed patients treated with the drug dabrafenib, 23 (72 percent) saw their tumors either shrink or stop growing. Unlike chemotherapy and radiation, which Kieran likens to carpet bombing, targeted therapies are guided precision missiles aimed only at the cancer-causing mutation, leading to hope that they will prove substantially less toxic.

By the time Danny Powers entered the trial in 2014 at the age of 13, the tumor, as these tumors often do, had regrown and been retreated three times, twice with surgery and once with a year of chemotherapy. The new targeted therapy proved to be much less invasive, with fewer side effects. “It allowed him to do his typical teenage boy things. He played lacrosse and football, went fishing, and didn’t miss much school,” says Christi Powers. “We know that with this type of tumor, we have to be on top of it. You have to balance treating the tumor and minimizing toxicities.”

Danny in his football gear.
Danny in his football gear.

The low-grade glioma trial is part of a larger story that illustrates how molecular analysis of malignancies and the resulting targeted therapies have upended our traditional understanding of cancer. Where cancers were once differentiated by their location in the body, they are now defined by molecular characteristics that often cut across this anatomic geography.

The BRAF V600E mutation is a dramatic example. The mutation was initially discovered in some melanomas, which responded so well in clinical trials of dabrafenib that in 2013 the Food and Drug Administration approved the therapy for those skin cancers. Meanwhile, clinicians sequencing other cancers – adult and pediatric – were finding the mutation in a wide range of malignancies, from some adult lung and colon cancers to a variety pediatric cancers and other tumors, including low-grade gliomas.

“It’s not surprising,” Kieran says. “This pathway – the RAS/RAF pathway – is one of the major gas pedals of the cell. Like falling dominos, molecules along the pathway send a signal to the cell telling it to divide. When molecules on this route – such as BRAF – are altered due to the V600E mutation, the gas pedal gets stuck and the signal telling the cell to divide is on constantly. So the cell keeps dividing. The result is cancer.”

The pediatric trial that opened in 2012, with separate arms for each cancer type, is designed to determine which childhood malignancies respond to dabrafenib. The first child enrolled in the trial was a New Hampshire girl with metastatic high-grade gliomas that had stopped responding to chemotherapy. Her tumors have disappeared. Because low-grade gliomas are more common than other pediatric tumors in the trial, it is the first to have accumulated enough patients to produce reportable results.

Children with low-grade gliomas can survive with a tumor that does not grow.  The tumors often stop growing for a while, as Danny’s did, then grow again, then stop again after additional treatment. The cycle can repeat itself several times before the tumor either dies or permanently stops growing, usually in early adulthood.

Of the patients whose tumors responded to dabrafenib, two had their tumor disappear, and 11 saw it shrink by more than half. In another 13, including Danny, the disease was stable for at least six months. None suffered serious side effects, such as cognitive impairment that often occurs following chemotherapy or radiation, although one patient was allergic to the drug.

The dabrafenib stabilized Danny’s glioma and, after 13 months, he stopped taking the drug, although he still requires regular monitoring. As appealing as going on the clinical trial was, Danny’s mother recalls, facing the uncertainty surrounding the possible late effects of the new approach added an element of fear to the decision to enroll.

“They know the long-term effects of chemo. They’ve been using it a long time. So you weigh the evil you know versus the evil you don’t know,” Christi says. “When we weighed it, it seemed like the dabrafenib was a good option.”

Kieran and his colleagues are now expanding the trial to test the addition of a second targeted therapy aimed at an additional mutated molecule along the RAS/RAF pathway. If long-term follow-up shows that the targeted therapy is both effective and less toxic than traditional therapies, he adds, the approach could become a front-line therapy.

“Because these pathways are new, it’s important to know what the effects are on a child’s growth and development,” Kieran says. “Still, I think that, over time, we will find that these therapies are more effective and less toxic.”

Learn more from the Pediatric Brain Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.