Study Identifies Novel Approach to Overcome the Blood-Brain Barrier in Pediatric Glioma Treatment

A new study in mice by researchers at the Herbert Irving Comprehensive Cancer Center (HICCC) has identified a novel combination therapy and delivery method that could prolong survival for an aggressive type of pediatric brain tumor. Concurrent with radiation therapy, the researchers infused the drug napabucasin, which works by blocking stem cell activity in cancer cells, directly into the tumor via a catheter, a technique called “convection-enhanced delivery.” The study was published in the journal Neuro-Oncology in October.  

Diffuse midline glioma occurs in the middle regions of the brain, mainly affects children, and has a near-zero survival rate. Radiation therapy, the only current standard of care treatment, provides marginal benefit – the median survival time remains less than a year.  

“The fatality rate is nearly 100%, and one of the reasons why it's so difficult to treat is that these tumors are characterized by a very intact blood-brain barrier that prevents chemotherapies from getting into the brain to exert their effects,” says study author Matthew Gallitto, MD, PhD, assistant professor of radiation oncology at Columbia’s Vagelos College of Physicians and Surgeons and member of the HICCC. “Our lab is working to find novel technologies to bypass that blood-brain barrier to treat a variety of childhood brain tumors, including diffuse midline glioma.”

One of those techniques is convection-enhanced delivery. A small hole in the skull is used to insert a thin catheter into the brain, then a liquid form of the drug is pumped through the catheter directly into the tumor tissue. The method maximizes delivery of the drug to the tumor while avoiding toxicity to healthy brain tissue and the rest of the body.

Recently, HICCC members Peter Canoll, MD, PhD and Jeffrey N. Bruce, MD reported the results of Columbia’s phase I clinical trial demonstrating the safety and efficacy of convection-enhanced delivery in adult patients with relapsed glioblastoma. They successfully completed infusion of the drug topotecan safely in five human patients, and the treatment was well tolerated without substantial complications.  

The current study — performed on a mouse model — is the first to show that convection-enhanced delivery of napabucasin can be safely combined with radiation therapy to prolong survival in pediatric diffuse midline glioma mouse models. Mice that received combination therapy experienced a nearly 30% improvement in survival compared to those that had radiation therapy alone.  

“The only standard of care right now for these patients is radiation therapy, which does provide symptomatic benefit, but very little survival advantage. Finding agents and techniques that work in conjunction with radiation is a big step forward,” says Gallitto. “Our hope is that we can translate this work to clinical trials to help patients and their families.”  

Next, the researchers aim to optimize the timing of radiation therapy and drug delivery, as well as test other drug candidates besides napabucasin. Based on which agent has the most promising effect in mouse models, they plan to open a phase 1 feasibility study for convection-enhanced delivery of that drug in combination with radiation therapy for patients with diffuse midline glioma at Columbia.  

“Napabucasin therapy with radiation represents an exciting step forward, in the sense that tumors relapse much slower when using this regimen — but, unfortunately, it doesn't cure them. The tumors do come back,” Gallitto says. “So, that’s really our group’s big-picture goal, to optimize targeted therapy with an agent that gives us even more of a survival benefit or cures the mice of the tumor completely."