Scientists target root of relapse in aggressive childhood brain tumors

Stopping cancer from coming back is the goal of new research from MUSC Hollings Cancer Center, where scientists are targeting cells that fuel the return of an aggressive pediatric brain tumor.

For most children diagnosed with medulloblastoma, the most common malignant pediatric brain tumor, survival rates are encouraging. But for a subset, remission is not the end of the story. Roughly 30% of patients will see their cancer return, and once it does, outcomes are often devastating.

"Once the tumor comes back, long-term survival is close to zero," said Jezabel Rodriguez Blanco, Ph.D., who holds dual appointments at Hollings and the Darby Children's Research Institute at MUSC."That's the group we're trying to help with this research."

In a study published in Cell Death & Disease, researchers led by Blanco identified a potential way to reduce relapse in medulloblastoma by targeting the tumor cells most likely to survive treatment and drive regrowth.

Going after the root of relapse

The research centers on a small but powerful group of tumor cells that can self-renew. Unlike the rest of the tumor, these cells divide more slowly and rely on different biological pathways, allowing them to evade standard treatments and promote new tumor growth.

These cells are resistant to therapy. They don't divide as much, so many treatments miss them. But they're the ones that enable the tumor to come back."

Jezabel Rodriguez Blanco, Ph.D., MUSC

That dynamic helps to explain a persistent challenge in medulloblastoma care. Treatments can initially shrink tumors, only for the cancer to return – often more aggressively.

To tackle this problem, the team tested an expanded strategy. Instead of targeting only tumor growth, they also set out to disrupt the signals that sustain these relapse-driving cells.

They focused on a protein called CK1α that regulates two key cancer-signaling pathways:

• Glioma-associated oncogene homolog (GLI), linked to tumor growth.
• Wingless-related integration site (WNT), which supports tumor self-renewal.

This work builds on earlier research by Blanco, showing that GLI inhibition can slow tumor growth and reduce the risk of relapse. In this new study, the researchers tested pyrvinium, a Food and Drug Administration-approved drug with emerging potential in cancer research because of its ability to block GLI.

By activating CK1α, pyrvinium suppressed GLI-signaling pathways and, therefore, attenuated tumor growth. Pyrvinium also targeted WNT-driven self-renewal, conferring an advantage over other GLI-targeting approaches. In preclinical models, pyrvinium blocked medulloblastoma self-renewal, extending the time to relapse and reducing the overall risk of relapse.

That dual targeting may be what makes the approach more effective.

"Cancer cells are very good at escaping when you hit just one pathway," Blanco explained. "If you hit both, you have a better chance of preventing that escape."

In comparison, treatments targeting only one pathway often shrink tumors at first – but miss the cells that drive regrowth – helping to explain why they have not delivered lasting results for some patients. The new approach may offer a workaround by hitting the same biology through a different mechanism.

Promising – but early – progress

Despite encouraging results, Blanco stressed that the work is still in early stages.

"This is working very well in our models," she said. "But there's a long path before it becomes a treatment for patients."

One major hurdle is delivery. Pyrvinium does not readily cross the blood-brain barrier, limiting its direct use for brain tumors. To address that, the team tested a modified version of the drug that can reach the brain, with promising results in preclinical models. The next step will be to develop and refine the compound to ensure it is effective and safe for use in children.

For young patients with medulloblastoma, the impact extends beyond survival to life after treatment. Current therapies can leave lasting effects, from developmental challenges to increased risk of future cancers.

"We're often adapting adult cancer treatments for children. But pediatric tumors are different, and the long-term side effects can be severe," Blanco said. "Especially for families whose children relapse, the stakes couldn't be higher."

By shifting focus to the cells that drive recurrence, the research points to a new direction –one aimed not just at shrinking tumors but at stopping them from returning.

"This is about going after the root of relapse," she said. "If we can do that, we have a real chance to change outcomes for these kids."