Stopping Sonic Hedgehog-Driven Medulloblastoma Childhood Brain Cancer Before It Starts

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Stopping Sonic Hedgehog-Driven Medulloblastoma Childhood Brain Cancer Before It Starts


Stopping Sonic Hedgehog-Driven Medulloblastoma Childhood Brain Cancer Before It Starts
Credit: Alfred Pasieka/Science Photo LIB / Getty Images/Science Photo Libra

New research from a team at The Hospital for Sick Children (SickKids) has identified a novel approach to combat a subtype of medulloblastoma, the most common malignant brain cancer in children. Published in Nature Communications, this research reveals a strategy that could transform the treatment of sonic hedgehog (SHH) medulloblastoma by intercepting tumor growth at its earliest stages.

Unraveling the complexity of brain tumors

Brain cancers like medulloblastoma present significant challenges for treatment due to their intricate nature. By the time symptoms manifest, tumors often have developed extensive heterogeneity, making it difficult to pinpoint the fundamental mechanisms that drive their growth. The study, led by Peter Dirks, in the Developmental, Stem Cell & Cancer Biology program and chief of the Division of Neurosurgery at SickKids, aims to tackle this complexity head-on.

Targeting tumor-initiating stem cells

The study focuses on SHH medulloblastoma, a subtype characterized by the aberrant activation of the SHH signaling pathway. This subgroup is associated with poor prognosis, treatment resistance, and relapse, especially in cases with TP53 mutations.

Through an integration of gene expression and chromatin accessibility analysis, the researchers identified that the transcription factor Olig2 is critical in activating dormant SOX2+ stem-like cells, which are pivotal in tumor formation and relapse. Once awakened, these stem cells transition into rapidly dividing progenitor cells that form the tumor bulk.

“We have defined a rare but critical transcription factor-orchestrated event of stem cell fate transition from quiescence to activation—one that leads to the generation of rapidly proliferating tumor output in medulloblastoma,” the authors wrote.

Interception with CT-179

The researchers explored a novel approach to block the activation of these stem cells. They utilized a small molecule inhibitor, CT-179, designed to disrupt the function of Olig2. The results were promising: CT-179 significantly hindered early tumor formation and prevented tumor regrowth following conventional therapies. In preclinical models, this approach dramatically increased median survival rates.

The study also demonstrated that targeting the transition from quiescence to proliferation in tumor-initiating cells could be a key treatment strategy. By blocking Olig2, the researchers effectively halted the production of neoplastic progenitors, the rapidly dividing cells responsible for tumor growth.

“Blocking this event constrains the stem cell pool in a non-proliferative state and is sufficient to prevent the onset of tumor initiation and post-treatment relapse,” the authors added.

Implications for  medulloblastoma treatment

Current treatments for SHH medulloblastoma, which focus on targeting the SHH pathway, have not been sufficient in preventing local relapse and often come with concerns regarding their impact on the central nervous system. The discovery of Olig2’s role opens new avenues for more targeted therapies that address the root of tumor recurrence without affecting normal CNS development.

Moreover, this approach shifts the focus from treating the tumor bulk to targeting the rare but critical population of SOX2+ stem-like cells. By intercepting the tumor-initiating process, the potential for relapse is minimized, one that the researchers believe offers a promising strategy for long-term remission.

Further, the authors propose that a targeted approach to block cancer stem cell activation and subsequent generation of proliferative progeny may find a role in combination therapy for medulloblastoma.



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