Researchers Join Forces to Accelerate Progress in Pediatric High-Grade Gliomas

Roger J. Packer, MD

Roger J. Packer, MD

Significant advancements have been made over the past few decades in treating childhood brain tumors. In medulloblastoma (MB), one of the most malignant variants, survival rates have nearly doubled, said Roger J. Packer, MD.

In pediatric low-grade gliomas, there are now drugs to molecularly target the tumors, rather than using often destructive radiation therapy.

In pediatric high-grade gliomas, however, survival rates have not improved, said Packer, the senior vice president of the Center for Neuroscience and Behavioral Medicine and director of the Brain Tumor Institute at Children’s National Health System, especially in the most malignant variant of pediatric high-grade gliomas, diffuse intrinsic pontine gliomas (DIPG).

“Unfortunately, the same type of survival rates that we quoted 30 years ago are what we are quoting now to families,” Packer said during a press conference earlier this month launching "Project Impact: A Campaign to Defeat Pediatric Brain Tumors." “As we take a look at these children, we know despite what we do, 90% will be dead within 18 months if they have a DIPG. That is the same as it was in the 1990s and 2000s.”

Packer said there are a variety of reasons why significant gains had not been made in the field. Researchers initially thought the disease was a variant of an adult disease, and whatever treatment was used on adults could also be used on children. Over the past 5 to 7 years, though, researchers have acquired the molecular tools that have shown them for the first time that even though the tumors might look identical in children and adults, they are molecularly different and require different treatments, Packer said.

Now that researchers have the appropriate tools, they have been able to start looking at the molecular makeup of the tumor, which can help them determine a target.

Additionally, over the past 3 to 5 years, researchers have identified some of the major drivers of pediatric high-grade gliomas to genetic changes, called anti-histones.

“This is a very promising and exciting era for pediatric high-grade glioma research,” said Suzanne J. Baker, PhD, director of the Brain Tumor Research Division, co-Leader of the Neurobiology & Brain Tumor Program, and endowed chair in brain tumor research at St. Jude Children’s Research Hospital. “The opportunity to look across the entire genome and identify mutations in pediatric high-grade gliomas led us to some unexpected, surprising findings.”

Researchers found that 80% of DIPDs had the same mutation that was important in driving cancer, according to Baker.

“This is an extremely high frequency for any particular mutation, as a cancer researcher would get quite excited if we found a mutation in a gene that involves, say, 15 to 20% of the tumors,” Baker said.

The mutation is in a gene called histone H3, which is important in the way that DNA is packaged in the nucleus and in how genes are regulated, Baker said. This was the first mutation in this class of proteins ever identified in human cancer. These are very rare mutations not only seen in DIPD, but also in pediatric high-grade gliomas found outside the brain stem, Baker said.

Part of the challenge in cancer in general is that there is a lot of variation in mutations from tumor to tumor, so it is difficult to design a therapy that would address all of the tumors, she added.

“Finding a single mutation that accounts for 80% of these diseases suddenly presented an all new unifying mechanism that drives this disease and made us think maybe there would be a useful way to target this therapeutically,” she said.

To further this research, the National Brain Tumor Society (NBTS), the largest nonprofit organization dedicated to the brain tumor community in the United States, and the St. Baldrick’s Foundation, the largest private funder of childhood cancer research grants, have partnered with experts in the field of pediatric neuro-oncology around the world in an awareness and fundraising campaign to support a research and drug discovery focused on pediatric high-grade gliomas, including DIPG.

The campaign, “Project Impact: A Campaign to Defeat Pediatric Brain Tumors” was announced during a press conference at the National Press Club in Washington, D.C. earlier this month.

Goals of the campaign include improving clinical outcomes for pediatric brain tumor patients and informing the development of the first-ever standard of care for treating pediatric high-grade gliomas.

“Getting all these people to work together and knowing that they will in addition bring in other laboratories from across Europe and across the United States to work together is really one of the major steps we can do to accelerate brain tumor research,” Packer said.

Packer said the researchers involved in the consortium have agreed to share their data immediately, rather than wait for it to be published so there will be no delays.