Work from Dr. Taylor’s lab has significantly impacted health care and advanced the treatment of brain tumours for children in Canada and around the world. Highlights of recent contributions include:
1) Discovery that Medulloblastoma is a Heterogeneous Entity Comprised of Distinct Diseases
Taylor et al. Acta Neuropathologica 2012, PMID 22134537, Shih et al. Journal of Clinical Oncology 2014, PMID:24493713, Ramaswamy et al. Neuro-Oncology 2015, PMID: 25605817, Cavalli and Remke et al. Cancer Cell 2017, PMID:28609654.
Medulloblastoma had been considered to comprise one heterogeneous entity diagnosed using the light microscope. The Taylor Lab demonstrated, and it is now accepted by a global consensus that medulloblastoma is in fact comprised of at least four distinct diseases, each with their own epidemiology, demographics, genetics, transcriptomics, and response to therapy. Clinical trials across the globe both account for, and stratify patients based on this classification. Subgroup affiliation determined in the SickKids CLIA lab is now part of the standard of care for medulloblastoma patients at SickKids.
2) Discovery of Novel Medulloblastoma Oncogenes and Tumour Suppressor Genes.
Northcott et al. Nature 2012. PMID: 22832581. Huang et al. Nature Neuroscience 2015 PMID: 26258683.
The Taylor Lab 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.
3) 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.
Northcott et al. Nature 2012. PMID: 22832581. Northcott et al. Nature Genetics 2009. PMID: 1927076. Taylor et al. Nature Genetics 2002. PMID: 12068298. Huang et al. Nature Neuroscience 2015 PMID: 26258683.
Ependymoma can arise at all levels of the nervous system, and was thought to arise from post-mitotic cells of the ependymal. The Taylor Lab 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.
4) Discovery of clinically significant heterogeneity in metastatic/recurrent medulloblastoma and unearthing haemotageounous dissemination of metastatic disease.
Wu et al. Nature 2012. PMID: 22343890. Ramaswamy et al. Lancet Oncology 2013. PMID: 24140199. Wang et al. Acta Neuropathologica 2015. PMID: 25689980. Garzia et al. Nature 2016, PMID: 26760213. Morrissy et al., Nature Genetics 2017, PMID: 28394352. Garzia et al., Cell 2018, PMID:29474906
Current modus operandi are to discover and validate novel targets for therapy on untreated primary tumors, 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 the Taylor Lab have shown that children die from metastases rather than the primary tumor, that metastases are vastly different from the primary tumor, and that recurrent disease has undergone extensive clonal divergence from the untreated primary tumor. These findings necessitate re-biopsy at recurrence for targeted therapy, and considering temporal and spatial heterogeneity when studying medulloblastoma to develop novel therapies. Despite the previous notion that medulloblastoma CNS metastases occur via local seeding of the spinal cord, the Taylor Lab recently published evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrated in vivo, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form metastases.
5) Discovery and delineation of the importance of epigenetic mechanisms in childhood brain tumors.
Mack et al. Nature 2014. PMID: 24553142. Hovestadt et al. Nature 2014. PMID: 24847876. Leprivier et al. Cell 2013. PMID: 23706743. Dubuc et al. Acta Neuropathologica 2013. PMID: 23184418. Mack et al. Nature 2017. PMID: 29258295.
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. The Taylor Lab 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.