You can’t advance the care of a disease that you can’t study. And for 40 years, that was the case with a rare, uniformly fatal pediatric brain tumor called diffuse intrinsic pontine glioma, or DIPG.
DIPG isn’t like most brain tumors. Rather than forming a solid mass, it weaves itself among the nerve fibers of the pons—a structure in the brain stem that controls vital functions like breathing, blood pressure and heart rate—making it impossible to biopsy. At least, that’s been the dogma.
“DIPG is the only tumor that historically has not been biopsied, because it’s found in such a critical place in the brain,” says Mark Kieran, MD, PhD, director of the Brain Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “In the 1970s and ‘80s, children with DIPG who underwent biopsy had multiple neurologic complications, so the dogma became ‘no biopsies.'”
As a result, research was stalled by a lack of available tumor tissue to study. To address this, Kieran and his colleagues Nalin Gupta, MD, and Michael Prados, MD, PhD, of the University of California, San Francisco, launched a new clinical trial of DIPG in 2012. The trial is leveraging advances in microsurgery and genomics to give researchers their first peek into the molecular nature of DIPGs.
The black box, opened
The trial—currently open at 25 centers across North America—has already revealed a great deal about DIPGs and how they work. Results on the first dozen tumors biopsied were published in Nature Genetics last April.
“We now think the black box is open,” Kieran says. “We’ve found a number of mutations, some previously unknown in cancer. And we found evidence suggesting that you need certain combinations of mutations to drive the tumor, which will be critical in terms of understanding how to stop it.”
One interesting observation: Like many other pediatric tumors, DIPGs are quite simple from a genomic point of view, lacking the wholesale DNA damage seen in adult tumors.
“I’m convinced, for the first time in my life, that we are going to change the outcome of this disease.”
“If you look at the molecular organization of these tumors, they’re pristine,” Kieran says. “The major defect that we find in 100 percent of the cases is in a chromatin regulating gene”—one that affects the cell’s overall genomic operation. The sparse additional mutations they found may delineate different DIPG subtypes, suggesting that treating DIPG in the future will require a personalized approach.
The trial has also allowed Kieran and his colleagues to start to understand DIPG’s response to therapy.
“We are thankful to the families in the trial who consented to autopsy after their children unfortunately died,” he says. “This means we now have samples of the same tumor from diagnosis and after treatment, and can see how the tumor evolved against the therapy.” This knowledge could allow researchers to understand the pathways tumors use to escape therapy and how to block those pathways.
Still a long road ahead, but there’s hope
Kieran and his collaborators know they have a lot more to learn. Representatives from the 25 centers gathered in November to establish an integrated program for studying different aspects of the tumors’ biology.
“One lab is looking at the immune components of the tumors, one is trying to establish cells lines, another is trying to grow the tumors in mice and others are looking at different drugs and mutations,” Kieran explains. “The goal is to cover the gamut. Over the next decade, this could have enormous payoff in improving therapy choices.”
The trial team is also discussing a new set of DIPG clinical trials based on the genomic data. But Kieran cautions that it will be years before any new treatment regimens will be available to patients. For some of the mutations he and his colleagues found, there are no available drugs. For others, there are drugs, but they either do not penetrate the brain well or have never been used in children.
Despite those obstacles, Kieran takes a glass-half-full view of the research progress to date. For a start, the trial has proved that surgeons can safely biopsy DIPGs and extract meaningful molecular knowledge.
“Having gone from no understanding of these lesions to having characterized all the major mutations is a huge leap forward,” says Kieran. “For the last 30 years we’ve been blindfolded, making no progress against this disease. Now we’ve taken the blindfold off and started asking very serious questions about what makes these tumors tick.”
Which gives him hope for future DIPG patients, who at the moment have none.
“I’m convinced, for the first time in my life, that we are going to change the outcome of this disease,” Kieran says.
UPDATED 11/24/15: The DIPG trial has reached its recruitment goal and is now closed.