How St. Jude Is Advancing Breakthroughs in Pediatric Brain Tumor Research

Growing up in a small town in Ontario, Canada, Paul Northcott’s early life involved playing ice hockey and shoveling snow. He thought he might always be there. But over the years, his studies at the University of Toronto led him to explore the world of cancer genetics. And as his training continued — taking him to Heidelberg, Germany, and then bringing him to St. Jude Children’s Research Hospital® in Memphis in 2015 — he began to focus on pediatric brain tumors. 

At least 5,000 children in the U.S. are diagnosed with brain tumors every year. Though these tumors are relatively rare, more children die from brain malignancies — at least 500 each year — than any other type of pediatric cancer. That reality underscores the urgent need for better, more effective treatments. Brain tumors present numerous challenges—complicated surgery, spread to surrounding tissues, a lack of druggable targets and a high risk of relapse. The treatments administered to children with brain cancer — chemotherapy and radiotherapy — can cause long-term side effects and diminish quality of life.

To meet the challenges of advancing knowledge, enhancing treatment and improving the outcomes of children affected by malignant brain tumors, St. Jude established the Center of Excellence in Neuro-Oncology Sciences (CENOS).

The center, led by director Northcott, PhD, is a powerhouse team of scientists and bioinformaticians, united behind the singular goal of giving every child with a brain tumor a better chance at life. Together, they focus on some of the most aggressive childhood brain tumors, and their discoveries are changing how doctors in clinics are diagnosing, risk stratifying, treating and monitoring these diseases. CENOS includes the labs of Northcott, Suzanne Baker, PhD, and Stephen Mack, PhD, with a total of around 50 staff and trainees. Northcott said the center hopes to double its size in the next few years to expand bench-to-bedside research dedicated to serving children with brain cancers. While the work is based in the lab, patients are at the center of the work done by CENOS.

Within the St. Jude Comprehensive Cancer Center, Northcott also co-directs, with Giles Robinson, MD, the Neurobiology and Brain Tumor Program (NBTP) at St. Jude. Bridging laboratory research with clinical care and research, NBPT has the goal of improving survival and morbidity of children with brain tumors by developing the most effective, least toxic therapies through a better understanding of disease pathogenesis and normal brain development. 

What St. Jude offers that inspired Northcott when he started his lab at St. Jude over a decade ago. With an emphasis on translating research discoveries into clinical trials, Northcott and his scientist peers form genuine partnerships with their clinical collaborators. The infrastructure exists at St. Jude for laboratory discoveries to impact diagnosis and care for patients.

“Innovation is necessary to drive discovery,” he said. “At the end of the day, we need to make discoveries that will enable more sensitive and accurate approaches to diagnosis and inform more effective treatments for these children.”

Medulloblastoma 

One recent discovery involved a defective gene in children who develop medulloblastoma, a cancer affecting the cerebellum, the part of the brain responsible for coordination and balance. Over the last couple of decades, work led by St. Jude doctors and scientists has helped reveal that medulloblastoma is more complex than previously thought. Four molecular subtypes of the disease further break down to over a dozen subgroups, some more aggressive than others, with survival rates varying greatly from 40% to 90%. Treatment often includes surgery to remove the tumor, chemotherapy and proton beam radiotherapy. 

By analyzing samples from more than 1,000 children with medulloblastoma, Northcott and his team discovered that an inherited deficient ELP1 gene increased the risk for some children to develop a molecular subtype of medulloblastoma called Sonic Hedgehog (SHH) activated medulloblastoma. The ELP1 deficiency causes cells to turn off p53, a protein that suppresses tumors, increasing the risk of developing SHH-medulloblastoma. From this fundamental research, the team was able to use models in the lab to restore p53 activity as a targeted therapy for SHH-medulloblastoma. 

“And now this therapy is being considered as a novel approach for children that have this particular gene mutation,” Northcott said. Research like this is all part of the process of developing innovative new treatments that will prove effective and safe and not have the same undesirable long-term side effects of previous generations of treatment.

When it comes to survivors of medulloblastoma and other pediatric brain and spinal tumors, “What many of us often overlook or take for granted is that survival is not the only end game here,” explains Northcott. “What we want to achieve is a good quality of life after cancer.” 

“Many of [these survivors] will never leave home,” Northcott said. “They won't go on to lead independent lives. They won't have jobs. They're basically homebound for the rest of their lives. That's not sufficient. We need to change that narrative.”

Changing that narrative is rooted in fundamental research like that being conducted in laboratories at St. Jude.

Northcott and his team are also pursuing ways to help children whose medulloblastoma returns —  a form of the disease that is harder to treat. About 30% of children treated for medulloblastoma experience a relapse of their disease, and when the cancer comes back, only 10% of them survive beyond a couple of years. This unacceptable outcome demonstrates a critical need for improved methodology to monitor response during therapy, to surveil disease during follow-up and to identify targets at relapse.

Therefore, Northcott and his team have developed a test to detect if medulloblastoma cells have returned. It’s a biopsy of a few milliliters of spinal fluid. The pathology lab can look for DNA from cancer cells in the biopsy. The new approach is more sensitive than an MRI which is typically used, allowing doctors to spot recurrence sooner when the cancer is more likely to respond to treatments. These new liquid biopsy methods being developed in Northcott’s lab are transitioning into standardized clinical tests that St. Jude patients will soon undergo alongside MRIs to help clinicians better monitor treatment response. 

Currently, there are no effective therapies for children who do not respond to the current standard of care of surgery, chemotherapy and radiotherapy. That reality fuels Northcott, who is driven to find approaches for these cases and to cure what is considered to be incurable.

At St. Jude, the investment into basic science powers discoveries that shape understanding. Through translational research, the work of Northcott and his peers in CENOS can use that understanding to develop new diagnostic methods or test new targets, which, in turn, get shared with clinical researchers who develop new clinical trials to improve survival rates and quality of life for survivors. 

Even though the various brain tumors and subtypes present significant challenges for researchers and clinicians, it is the mission and support to do this research that provide reason for hope. “I believe the future is very bright, and we will continue to make impactful discoveries on this campus,” Northcott said.