Discovery that medulloblastoma is a heterogeneous entity comprised of distinct diseases
Northcott et al. Journal of Clinical Oncology 2011, Taylor et al. Acta Neuropathologica 2012, Shih et al. Journal of Clinical Oncology 2014, Ramaswamy et al. Neuro-Oncology 2016, Cavalli et al. Cancer Cell 2017, Vladoiu et al. Nature 2019
We demonstrated, and it is accepted by the World Health Organization, that medulloblastoma (MB) comprises at least four distinct diseases, each with their own epidemiology, and response to therapy. Globally, clinical trials stratify patients based on this classification. Subgroup affiliation is now part of the standard of care for MB patients at SickKids and we have trained clinicians/scientists around the globe to make this highly available. More recently we showed that the MB, are a disorder of early brain development, a finding which provides an explanation for the peak incidence in early childhood.
Discovery and delineation of the importance of epigenetic mechanisms in childhood brain tumours
Leprivier et al. Cell 2013, Dubuc et al. Acta Neuropathologica 2013, Mack et al. Nature 2014, Hovestadt et al. Nature 2014, Mack et al. Nature 2017
Both medulloblastoma and ependymoma have a paucity of recurrent somatic mutations, particularly SNVs. Due to a lack of somatic genetic targets, alternatives must be found. We have shown in a number of publications that non-genetic, particularly epigenetic mechanisms (both DNA CpG methylation and histone post-translational modifications) are important in medulloblastoma and ependymoma biology, and might serve as novel targets for rational therapy.
Discovery of molecular distinct subgroups of ependymoma brain tumors from different parts of the central nervous system that are biologically distinct, likely arise from radial glial cell progenitor cells
Taylor et al. Cancer Cell 2005, Johnson et al. Nature 2010, Witt et al. Cancer Cell 2011, Mack et al. Clinical Cancer Research 2015
Ependymoma can arise at all levels of the nervous system, and was thought to arise from post-mitotic cells of the ependymal. We have shown that in fact, ependymomas arise from radial glial cells (CNS progenitors), and that there are several distinct molecular subgroups of ependymoma with widely variant biology and outcomes. The next round of clinical trials for ependymoma are all accounting for these molecular subgroups.
Discovery of clinically significant heterogeneity in metastatic and recurrent medulloblastoma
Wu et al. Nature 2012, Ramaswamy et al. Lancet Oncology 2013, Wang et al. Acta Neuropathologica 2015, Garzia et al. Nature 2016, Morrissy et al. Nature Genetics 2017
Current modus operandi are to discover and validate novel targets for therapy on untreated primary tumours, and then to take novel agents to clinical trials and test them on patients with highly treated, recurrent, metastatic disease. This approach is doomed to failure, as we have shown that children die from metastases rather than the primary tumour, that metastases are vastly different from the primary tumour, and that recurrent disease has undergone extensive clonal divergence from the untreated primary tumour. These findings necessitate re-biopsy at recurrence for targeted therapy, and considering temporal and spatial heterogeneity when studying medulloblastoma to develop novel therapies.
Discovery of novel medulloblastoma oncogenes and tumour suppressor genes
Taylor et al. Nature Genetics 2002, Northcott et al. Nature Genetics 2009, Northcott et al. Nature 2012, Huang et al. Nature Neuroscience 2015
We have described and characterized a number of somatic and germline mutations that are drivers in subgroups of medulloblastoma. These driver events are useful for modeling the disease, and as targets for rational therapy.