New therapy for childhood brain cancer halts tumor formation

Childhood malignant brain tumors remain a significant challenge for clinicians and researchers around the world, largely because they are often only discovered after they have already become complex and difficult to treat. 

Among these cancers, medulloblastoma stands out as the most common malignant brain tumor in children, frequently leading to devastating outcomes. 

Now, a team of scientists at The Hospital for Sick Children (SickKids) has made a pivotal finding that could stop a subtype of medulloblastoma – known as sonic hedgehog (SHH) medulloblastoma – from forming at its earliest stages.

Detection of childhood brain cancer

Because brain tumors typically trigger noticeable symptoms only after considerable growth, crucial details about the cancer’s initial formation can remain hidden.

By the time a young patient is diagnosed, the tumorous cells may have already undergone numerous mutations. 

In response to this clinical hurdle, a research group led by Dr. Peter Dirks at SickKids focused on the earliest cellular steps of SHH medulloblastoma. 

Halting tumor formation

The new study, published in the journal Nature Communications, shows that a single protein serves as a critical “on switch,” awakening dormant stem cells that then give rise to a tumor.

“Our findings offer a novel strategy to target cancer stem cells, providing hope for more effective treatments against aggressive brain tumors,” said Dirks, a senior scientist in the Developmental, Stem Cell & Cancer Biology program and Chief of the Division of Neurosurgery.

One of the study’s most significant insights is that by preventing the reactivation of these dormant, cancer-initiating cells, the entire cascade of tumor formation can be intercepted. 

SHH medulloblastoma arises in a particular subset of patients, and this discovery suggests that if the first molecular trigger is blocked, the disease may be prevented from taking root in the brain.

An opportunity for intervention 

In the study, the team looked at how SHH medulloblastoma unfolds at the cellular level. They found that the protein OLIG2 plays a central role in “waking up” quiescent stem cells – cells that are otherwise inactive – and prompting them to divide uncontrollably, eventually forming tumors. 

As the scientists dug deeper, they identified the exact window in which this reactivation occurs and recognized it as a prime opportunity for intervention.

“There is order to how the cancer initiating stem cells undergo fate changes to form tumors. We can target an early transition event and intercept the entire process – essentially stopping the cancer in its earliest form,” said study first author Kinjal Desai, a postdoctoral researcher in the Dirks lab.

Potential to prevent relapse

By pinpointing OLIG2’s critical role, the researchers tested whether blocking its action could halt tumor initiation and, importantly, prevent relapse in cases that had already undergone conventional treatments. 

The experts used a small molecule called CT-179, which disrupts OLIG2 function and stops the dormant stem cells from waking. 

When combined with an existing therapeutic approach, this treatment not only blocked SHH medulloblastoma formation in a preclinical model but also effectively prevented residual cancer stem cells from becoming reactivated later on. 

This two-pronged effect significantly reduced the chance of tumor regrowth and improved survival outcomes.

Targeting brain tumors in the early stages

Simultaneously, researchers at Children’s Healthcare of Atlanta and the QIMR Berghofer Medical Research Institute in Australia carried out related experiments, published concurrently in Nature Communications. 

Their work corroborates the SickKids findings, hinting that this kind of OLIG2-targeting strategy could go beyond SHH medulloblastoma to combat other pediatric brain tumors, including diffuse intrinsic pontine glioma (DIPG) – an aggressive cancer that has proven particularly resistant to conventional therapies.

This latest discovery advances previous research from the Dirks Lab on the early stages of brain tumors. While the new findings will require validation in clinical trials, they highlight the advantages of what Dr. Dirks describes as ‘precision biology.’

“At SickKids, we’re already genetically testing every child with cancer to inform their diagnosis and treatments – our study goes beyond genetic testing to precision biology,” Dirks said. “I am excited for a future where this ‘magic bullet’ for early treatment could be combined with diagnostic tests to potentially prevent the cancer from developing at all.”

By intervening at the very root of tumor formation, the team’s approach could offer a transformative path for children with medulloblastoma and other aggressive brain cancers. 

If these promising strategies move successfully through clinical trials, early intervention might indeed stop pediatric brain tumors before they can even take hold, heralding a new era in cancer treatment.

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