Brain tumors can be very difficult to treat, but at least we know what to do about them. For years, a mix of surgery, radiation and chemotherapy has been used to treat brain tumors like medulloblastoma.
These treatments are fairly successful, but for a rare, almost always fatal tumor called diffuse intrinsic pontine glioma (DIPG), we haven’t had any success—in fact, we haven’t known where to start.
The problem has to do with where DIPGs are located: nestled among the nerves in a portion of the brain stem, the pons, that controls critical functions like our breathing, blood pressure and heart rate.
“For 40 years, we lacked the neurosurgical techniques to biopsy DIPGs safely,” say Mark Kieran, MD, PhD, director of the Brain Tumor Program at Dana-Farber/Children’s Hospital Cancer Center (DF/CHCC). “In fact, one of the first lessons every oncologist is taught still is, ‘Don’t biopsy brain stem gliomas.’ The dogma was that the risk of severe or fatal damage was too great.” And because we couldn’t biopsy them, we couldn’t study them to learn what makes them tick.”
A lot can change in four decades. Techniques for operating on the brain have advanced considerably, as have the tools for probing tumors at the molecular level. So, looking to turn the dogma about DIPGs on its head, Kieran has launched a clinical trial that aims to use advanced surgical and diagnostic tools to target and individualize DIPG treatment.
Kieran points out that there have been 250 DIPG clinical trials conducted over the years, both here and elsewhere. But none have improved the tumor’s median survival time—nine months—or mortality—99 percent.
“We’ve historically treated and studied DIPG based on imaging results, clinical symptoms and what we know about adult or other pediatric brain tumors,” Kieran explains. “We need to take a targeted approach, but because we haven’t been able to collect samples of newly diagnosed tumors, we haven’t been able to conduct the kinds of molecular studies that have been used to pinpoint vulnerabilities in other tumors.”
The new trial takes just that approach. Kieran is working with Boston Children’s Hospital neurosurgeons Liliana Goumnerova, MD, and R. Michael Scott, MD, to carry out surgical biopsies on children newly diagnosed with DIPG. Based on the results of the biopsy, patients will receive the current standard of radiation therapy, along with bevacizumab, a drug that stops the growth of blood vessels to and within tumors. Patients will receive other drugs based on the analysis of their tumor, including erlotinib—which zeroes in on a certain genetic mutation found in some tumors—and/or temozolomide—which attacks tumor cells directly.
The decision will be driven entirely by what the team learns from looking at the tumor itself.
In putting the trial together, Kieran says, the toughest job was challenging the surgical dogma about DIPG. “A colleague, neuro-oncologist Michael Prados, MD, from the University of California, San Francisco (UCSF) and I advocated for a decade, saying that the time was ripe to take a fresh look at surgical sampling and analysis of DIPGs. We were booed off the stage of every conference we spoke at,” he says.
Kieran’s team knew the opportunity was there, because surgeons in France had started operating on DIPGs two years ago, taking biopsies from more than 20 children with no ill effects. “The French blazed the trail, but they didn’t have access to the kinds of molecular tools we have here for finding out which treatments might work best for each individual tumor,” he says.
Their break came three years ago when a colleague, neurosurgeon Nalin Gupta, MD, PhD, from UCSF, spoke at a neurosurgical conference on Prados and Kieran’s behalf. Suddenly, everyone’s heads started nodding. “The difference was that we had a neurosurgeon speaking to neurosurgeons, instead of an oncologist.”
Kieran hopes to recruit between 25 and 100 children for the trial; one has already signed up, and underwent the biopsy surgery with flying colors. While the trial is currently only open at DF/CHCC, in the coming months another 19 centers will start participating.
The trial opens up hope that, in the future, more children will be able to survive this largely mysterious tumor.
“For the first time, we should be able to give children with DIPG personalized treatment options based not on a population average, but on the makeup of their individual tumor,” Kieran says. “We have the opportunity to look within DIPG and understand why it differs so greatly from other tumors, which will help us map out better strategies for the future.”