Exploiting biological heterogeneity to improve outcomes in childhood medulloblastoma


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Steven Clifford1
1Northern Institute for Cancer Research, Newcastle University, Newcastle, UK

Abstract

Overall survival rates for medulloblastoma, the most common malignant paediatric brain tumour, now stand at around 70%. However, clinical improvements have plateaued and the majority of survivors suffer life-long side-effects associated with current therapies. Recent advances in genomic and epigenomic profiling are revolutionising our understanding of the biological heterogeneity which underlies medulloblastoma, and these discoveries offer major opportunities to individualise therapy and improve outcomes. I will review recent progress, with focus on four major areas:

First, how medulloblastoma now represents a paradigm for the molecular sub-classification of cancer and its translational exploitation. Critically, we now understand the clinical entity 'medulloblastoma' as an umbrella term encompassing at least four distinct molecular subgroups (termed WNT, SHH, Group 3 and Group 4), which are characterised by unique genomic, epigenomic and mutational signatures, clinical demographics and outcomes.

Second, how these advances, coupled with the identification and validation of a series of molecular and histopathological biomarkers of favourable- (e.g. WNT subgroup) and poor-risk (e.g. MYC amplification) tumours, allow more accurate outcome prediction. These findings have led to ground-breaking pan-European clinical trials opening in late-2014, which will stratify therapy based on molecular risk biomarkers, with the aim of improving survival rates and reducing side-effects.

Third, how the new molecular pathology is informing the next wave of biological discovery, aimed at the identification of novel disease biomarkers and therapeutic targets. I will particularly focus on emerging data which are providing a first picture of the molecular evolution of medulloblastoma over its disease course, the unique biological characteristics which emerge at relapse, and how these could be targeted therapeutically.

Finally, how complex molecular profiles are being developed into low-cost molecular diagnostics assays for routine clinical application, to support the targeted delivery of individualised therapies in paediatric neuro-oncology across Europe.