Targeting Protein Synthesis in MYC-Driven Medulloblastoma

Research study background

Medulloblastoma is a fast-growing, aggressive brain tumor in the cerebellum and is the most common malignant brain tumor in children. Group 3 medulloblastoma, driven by MYC overexpression, is linked to a more aggressive form of the disease, characterized by a higher likelihood of metastasis and poorer long-term outcomes even with treatment.

MYC overexpression occurs when the MYC gene becomes overactive, causing cells to grow and divide rapidly and increasing protein production. This hinders treatment because directly targeting MYC has proven difficult. Instead, researchers are increasingly focused on identifying pathways MYC‑driven tumors rely on, opening the door to indirect targeted therapies.

In this study, originally funded by a pilot award from the Morgan Adams Foundation, investigators at Children’s Hospital Colorado and The University of Colorado School of Medicine used CRISPR‑Cas9 screening to identify genes essential for the survival of MYC‑driven medulloblastoma cells. They identified cyclin-dependent kinase 8 (CDK8) as a key tumor-specific dependency, with particularly high relevance in MYC‑amplified tumors.

Using a combination of genetic knockdown, selective CDK8 inhibitors, transcriptomic and chromatin analyses and preclinical models, the research team investigated the role of CDK8 in tumor growth. They found that CDK8 supports transcription of ribosomal genes, promotes ribosome biogenesis and sustains global protein synthesis — all processes that MYC-driven tumors rely on.

Consistent with these findings, inhibiting CDK8 reduced protein production, slowed tumor growth, increased cancer cell death and prolonged survival in murine models. Combining CDK8 inhibition with mTOR inhibition (blocking a central cellular pathway that regulates protein synthesis, growth and survival) further amplified these effects.

Clinical implications

This study provides preclinical evidence that MYC‑driven medulloblastomas may be particularly vulnerable to therapies that disrupt protein synthesis at the transcriptional level. While CDK8 inhibition is not yet a standard treatment for pediatric brain tumors, these findings support a targeted approach that could complement existing therapies.

CDK8 inhibitors have already entered early‑phase clinical trials in adult cancers, and mTOR inhibitors are used in pediatric populations, supporting the translational potential of this approach. The investigators tested a novel CDK8 inhibitor called RVU120 made by a Polish company RVYU therapeutics.  The inhibitor worked very well in tumor models and two physicians researchers, Rajeev Vibhakar, MD, and Holly Lindsay, MD, are now developing a first-in-pediatrics clinical trial with this drug for relapsed medulloblastoma patients. However, these findings require clinical validation before informing patient care. Future research will need to identify which patients are most likely to benefit and how these therapies can be safely integrated into existing treatment strategies.