Medulloblastomas are the most common malignant primary solid paediatric brain tumour, and although their characterisation has evolved rapidly over the last decade, prognosis for aggressive subgroups of medulloblastoma presenting with extensive metastasis remains dismal. Medulloblastoma tumours can be classified into 4 subgroups, namely Wingless-activated (Wnt, good prognosis), Sonic hedgehog-activated (SHH, intermediate prognosis), Group 3 (G3, poor prognosis) and Group 4 (G4, intermediate prognosis), the latter often being termed non-Wnt/non-SHH medulloblastoma. Wnt and SHH medulloblastomas are so-called due to aberrations in developmental signalling pathways giving rise to their pathogenesis, however G3 and G4 tumours at present lack consistent biomarkers and therapeutic targets for more specified and personalised treatments. Often presenting with metastasis, treatment of G3/G4 MB requires administration of full craniospinal irradiation for patients which meet the criteria, a process which can result in severe side effects such as growth problems, impaired cognitive development and even increased risk of secondary metastases. Recently emerging as a hallmark of cancer, the presence of increased lipid metabolism has been researched in many different cancers, and the discovery of upregulated cholesterol metabolism in medulloblastoma tumours presented an idea for a potential therapeutic strategy. Statins have been used for many years in the treatment of high cholesterol through blocking cholesterol biosynthesis pathways, and with a fairly good safety profile it was hypothesised that statins could be used to target upregulated lipid metabolism in medulloblastoma. Simvastatin, a lipophilic statin with the ability to cross the blood-brain barrier was utilised in this study to examine its effects on medulloblastoma viability, survival, migration and invasion in vitro. Methods implored to elucidate the effects of simvastatin in medulloblastoma included wound-healing and transwell assays, ATP-based viability assays and 3D modelling. Results found that even though simvastatin was unable to induce significant cell cycle arrest in the cell lines tested, it was able to reduce MB cell viability in 2D and 3D settings, reduce MB cell migration in transwell and wound-healing assays and reduce MB spheroid invasion into a surrounding ECM matrix, all without eliciting any antagonistic effects when combined with chemotherapeutic drugs. Mechanisms behind statin-induced MB cell death remain elusive, as reduction in viability was not rescued through addition of mevalonate pathway intermediates, however it was determined most importantly that statins were able to induce cell death and a reduction in migratory capacity in medulloblastoma cells regardless of subgroup affiliation or TP53 status. The data showcased in this study strongly supports the use of simvastatin as a potential treatment for medulloblastoma by affecting upregulated lipid metabolism, suggesting major implications in the treatment of aggressive group 3 and group 4 MB tumours harbouring high metastatic tendencies. Although, the mechanisms behind the anti-cancer effects of simvastatin seen here require further investigation.
Repurposing lipid inhibitors for the treatment of aggressive medulloblastoma
Comer, C. (Author). 10 Dec 2026
Student thesis: Doctoral Thesis › PhD