When Danny Powers showed gross motor delays and poor balance as a toddler, early intervention specialists told his mother, Christi, that the problem was likely weak muscle tone. But when Danny developed severe headaches at age 4 during a family vacation, Christi took him to a local emergency room, where a CT scan revealed a mass in his head. His eventual diagnosis back home in Massachusetts was low-grade glioma, the most common pediatric brain tumor.
Fortunately, low-grade gliomas are non-malignant, slow-growing and highly curable, and most children can look forward to decades of survival. Unfortunately, the standard treatment — chemotherapy and, in some cases, radiation, in addition to surgery — is toxic and can damage the developing brain and body. Moreover, the tumors often regrow, requiring retreatment. By the time Danny was 13, he had been treated twice with surgery and once with a year of chemotherapy, which Mark Kieran, MD, PhD, clinical director of the Brain Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, likens to carpet bombing.
Instead of undergoing another course of chemotherapy when his tumor regrew yet again, Danny entered a clinical trial of a new, targeted drug that acts more like a guided missile — aimed directly at his cancer-causing mutation. The mutation found in Danny’s tumor — the BRAF V600E mutation — occurs in about 10 percent of low-grade gliomas as well as a number of other tumors. It was first discovered in a subset of adult melanoma skin cancers, which are treated with the federally approved targeted drug dabrafenib.
Compared to the two craniotomies and the year of chemotherapy, this was much less invasive and had fewer side effects. The pediatric trial, led by Kieran, is testing dabrafenib in a variety of tumors that have the same BRAF mutation, with a separate arm for each disease. (The first child enrolled was a New Hampshire girl with metastatic high-grade gliomas that had stopped responding to chemotherapy. Her tumors have disappeared.) Danny’s case was among the promising early results for low-grade gliomas that Kieran recently presented at the European Society for Medical Oncology meeting in Copenhagen.
Of 32 relapsed patients treated with dabrafenib, 23 (72 percent) saw their tumors either shrink or, like Danny’s, stop growing. Two of the responders had their tumor disappear and 11 saw it shrink by more than half. Thirteen, including Danny, had stable disease for at least six months. None suffered serious side effects, although one was allergic to the drug.
“Compared to the two craniotomies and the year of chemotherapy, this was doing the same job except it was much less invasive and had fewer side effects,” says Christi. “It allowed him to do his typical teenage boy things. He played lacrosse and football and went fishing and didn’t miss much school.”
Upending cancer treatment
The low-grade glioma trial, opened in 2012, 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 geography. The BRAF V600E mutation is a dramatic example. Melanomas caused by the mutation responded so well to dabrafenib that the Food and Drug Administration approved it for those skin cancers in 2013. Meanwhile, investigators were finding the mutation in a wide range of other malignancies, from some adult lung and colon cancers to a variety of pediatric cancers and tumors, including low-grade gliomas.
The common thread among these tumors is a cellular pathway called RAS/RAF.
“The RAS/RAF pathway is one of the major gas pedals of the cell,” says Kieran. “Molecules along the pathway send a signal to the cell telling it to divide. When molecules on this route are altered — such as BRAF being altered by the V600E mutation — the gas pedal gets stuck and the signal telling the cell to divide is constantly ‘on.’ So the cell keeps dividing. The result is cancer.”
Curbing tumors, with fewer side effects
Low-grade gliomas often stop growing for a while, as Danny’s did, then grow again, then stop again after retreatment with chemotherapy and/or radiation or, if appropriate, surgery. Radiation, Kieran notes, can be particularly damaging; possible late effects include subsequent radiation-induced cancers, stroke and cognitive impairment. The regrowth-retreatment cycle can repeat itself several times before the tumor either dies or permanently stops growing, usually in early adulthood.
“Although most kids are long-term survivors,” Kieran says, “they’ve had multiple therapies, and those therapies can do a ton of damage.”
“The clinical trial was more appealing than another course of chemo, but deciding to go on it was also scary because we don’t know the long-term effects of this medication,” Christi says. “They know the long-term effects of chemo. So you weigh the evil you know versus the evil you don’t know. When we weighed it, it seemed like the dabrafenib was a good option.”
On dabrafenib, Danny’s glioma has stabilized. After 13 months he stopped taking the drug, though he still requires regular monitoring.
Kieran and his colleagues are now expanding the trial to test the addition of a second therapy aimed at another mutated molecule along the RAS/RAF pathway. “We want to see if we can do even better,” Kieran says. If so, he adds, the approach could eventually 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. “It’s also easier to tell when a drug causes a physical side effect, like damaging a kidney, than seeing if it affects learning. We want to be absolutely sure that these therapies are safe before we start using them with large numbers of children who could be cured with the old ways. Still, I think that, over time, we will find that these therapies are more effective and less toxic.”