Oral Presentation Lowy Cancer Symposium 2015

Paediatric glioblastoma: unique targets in unique diseases (#5)

Chris Jones 1
  1. Institute of Cancer Research, London, United Kingdom

Glioblastomas in children are rare central nervous system tumours with a universally dismal clinical outcome, and are distinct from similar-looking, and more common, tumours arising in adults. They may occur in different anatomical locations of the brain, and are comprised of multiple subgroups marked by specific epigenetic and genetic drivers. Recent integrated molecular profiling studies have revolutionised our understanding of this heterogeneous group of diseases and have pointed the way forward for novel targeted therapy specific to each subgroup. We have accumulated such genome-wide data, both published and unpublished, on more than 1000 such tumours with a view to prioritise preclinical development for children with these tumours. Some targets, such the elements upstream (PDGFRA, FGFR1) and downstream (PIK3CA, PIK3R1) in the PI3-kinase pathway are well recognised in other cancer types, whilst others appear unique to paediatric glioblastoma. In particular, highly specific and recurrent mutations in the oncohistones H3.3 and H3.1 mark subsets of cerebral hemispheric glioblastomas in older children (G34R/V), and midline / brainstem tumours in younger children (K27M). Diffuse intrinsic pontine gliomas, found only in the paediatric age group, additionally harbour somatic ACVR1 mutations, otherwise found only in the germline of patients with the congenital malformation syndrome fibrodysplasia ossificans progressiva, pointing to distinct developmental origins of these tumours. Glioblastomas arising in infants may be biologically different again, driven instead by specific gene fusions. In order to translate these findings into novel therapies, a range of new model systems are required in order to gain mechanistic insight into processes hitherto not linked to cancer, as well as to test innovative treatment strategies aimed at subverting them. Although these are still lacking for certain subgroups, a range of genetic and epigenetic targeted therapies  are now beginning to be considered, offering hope for these otherwise incurable diseases.