New Therapeutic Approach Targets Protein Synthesis in MYC-Driven Medulloblastoma

Research study background

Medulloblastoma (MB) is the most common malignant brain tumor occurring in children. The Group 3 (G3) MYC-driven subtype is particularly aggressive, with a long-term survival rate of less than 5%. This subgroup is characterized by a high incidence of relapse, metastasis and local recurrence.  

Dysregulated expression of the MYC proto-oncogene contributes to the development of many human tumors by playing a key role in protein synthesis regulation. MYC influences cell proliferation, growth and ribosome biogenesis by affecting chromatin structure, RNA polymerases and auxiliary factors involved in ribosome assembly.

A cross-institutional team of physicians and scientists from the Morgan Adams Family Pediatric Brain Tumor Program at Children’s Hospital Colorado and the University of Colorado School of Medicine have spent years pursuing a deeper understanding of these dysregulated processes. Their goal is to develop targeted therapies that will attack the weaknesses in MYC-driven oncogenesis so these young patients have a better chance.

In an earlier investigation, the team targeted 1,140 druggable genes in three MYC-amplified human G3-MB cell lines using CRISPR-Cas9 screening, a gene-editing technology. Their work demonstrated that a novel, orally available polo-like kinase 1 inhibitor makes MYC-MB more sensitive to radiotherapy.

In this more recent study, the team further analyzed the CRISPR results and identified that mediator-associated cyclin-dependent kinase 8 (CDK8), a protein-coding gene, was essential for MB tumor growth. Investigators studied how reducing CDK8 affects ribosome biogenesis — the process by which ribosomes are assembled in the cell — and overall protein production using various methods, including special assays and genome sequencing.

They evaluated eight CDK8 selective inhibitors in MB cells, identifying RVU120 as a new therapeutic target. They found that treatment with RVU120 decreased CDK8 expression while simultaneously lowering the level of phosphor-STAT1, a direct target of CDK8. Additionally, the team explored the combined effect of CDK8 and mammalian target of rapamycin (a protein kinase) inhibitors, using models to assess potential synergy. When they measured the effectiveness of these treatments in promoting cell death in vivo and in vitro, they found that CDK8 inhibition suppresses tumor growth by modulating the protein synthesis pathway.

Clinical implications

Taken together, these findings connect transcription and translation regulation, suggesting a promising therapeutic approach to target multiple aspects of the protein synthesis pathway in MYC-driven MB. The team is currently working to identify other molecular inhibitors that synergize with CDK8 inhibition and is collaborating with a biopharmaceutical company based in Poland to develop a clinical trial of RVU120.