Research News via Michigan Medicine-University of Michigan

When scientists at the University of Michigan identified a small molecule that blocked a key pathway in highly aggressive glioma tumors, they were optimistic. These brain tumors are often resistant to traditional therapies, and the environment inside the tumor suppresses the immune system, rendering immunotherapies ineffective. The Castro-Lowenstein Lab at the University of Michigan, funded in part by the Pediatric Brain Tumor Foundation, saw an opportunity. A small molecule inhibitor was developed to block the action of a cytokine released by glioma cells that builds a shield around the immune system. Researchers showed in glioma mouse models that the inhibitor helped keep the immune system intact so that it could fight back against the tumor cells.

A problem remained, though: Getting the inhibitor through the blood brain barrier to reach the tumor.

The Castro-Lowenstein Lab collaborated with University of Michigan colleagues focused on chemical engineering, pathology, and neurosurgery to create protein-based nanoparticles to encapsulate the inhibitor, in the hopes of helping it pass through the bloodstream. As a new study in ACS Nano shows, the nanoparticles not only delivered the inhibitor to the tumor in mouse models, successfully turning on the immune system to eliminate the cancer, the process triggered immune memory so that a reintroduced tumor was also eliminated — a sign that this potential new approach could not only treat brain tumors but prevent or delay recurrences.

“No one could get this molecule into the brain. It’s really a huge milestone. Outcomes for patients with glioma have not improved for the last 30 years,” says Dr. Maria G. Castro, R.C. Schneider Collegiate Professor of Neurosurgery at Michigan Medicine and senior author of the study (pictured above with study author Dr. Pedro R. Lowenstein, Richard C. Schneider Collegiate Professor of Neurosurgery at Michigan Medicine).

Although additional safety testing is necessary before moving to a clinical trial, the nanoparticle is similar to others that have been previously shown to be safe in humans. Initial tests in the treated mice also showed normal blood counts and little to no impact on liver, kidney or heart function.

PBTF supported this discovery through a multi-year basic science grant to Drs. Castro, Lowenstein, Karin Muraszko, and Julian T. Hoff at the University of Michigan. As part of our strategy to accelerate the development of new pediatric brain tumor therapies, PBTF invests in forward-thinking concepts that address critical gaps in scientists’ understanding of the unique biology of childhood brain tumors, lessen the burden of diagnosis, and improve survival rates and patient outcomes. Thank you to the Samson Research Fund and supporters of their Think Fit for Kids initiative for partnering with PBTF to fund this pioneering project.

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