Central nervous system tumors are the second most common pediatric malignancy and remain the leading cause of cancer-related mortality in childhood. Originating in the cerebellar region of the brain, medulloblastoma (MB) represents the most common malignant childhood brain tumor. Although advances in multimodal therapies have yielded a 5-year survivorship in 75% of patients, survivors still face severe neurocognitive deficits. The poor patient survival has been shown to correlate with the increased presence of brain tumor-initiating cells (BTICs). We originally identified a subpopulation of cells with the unique stem cell properties of self- renewal and multi-lineage differentiation in vitro and in vivo. BTICs are known to be resistant to both radiotherapy and chemotherapy, which may explain why some MB patients relapse, despite current best therapies.
Given the limitations of current clinico-pathological parameters to accurately predict treatment response, multiple integrated genomic platforms have been used to characterize the aberrant expression of signaling pathways in MB. This has re-conceptualized the heterogeneity that exists within pathological subtypes and has given context to the role of key stem cell signaling pathways in MB pathogenesis. The recent molecular classification of MB consists of several subtypes, each distinct in terms of prognosis and predicted therapeutic response. Unsupervised hierarchical clustering methods of segregating these data have produced four subgroups, two of which (Groups 1 and 2) are characterized by upregulation of genes in the Wnt and Sonic hedgehog (Shh) pathways, respectively. However, in contrast to Wnt and Shh MBs, Group 3 and 4 MBs are associated with metastatic disease and poor patient outcome. These MBs remain refractory to current treatment modalities and appear to lack aberrant activation of known major signaling pathways. As Group 3 MBs are the most aggressive, our lab aims to study the genes that regulate stem cell signaling pathways in MB patients and develop specific, individualized BTIC-targeted therapies.
Dr. Sheila Singh | Pediatric Neurosurgeon, McMaster Children’s Hospital | Principal Investigator, McMaster Stem Cell and Cancer Research Institute
Michael G. DeGroote Centre for Learning and Discovery, Room 5027 | McMaster University | 1280 Main Street West | Hamilton, Ontario L8S4K1
Dr. Sheila Singh | Pediatric Neurosurgeon, McMaster Children’s Hospital | Principal Investigator, McMaster Stem Cell and Cancer Research Institute | Michael G. DeGroote Centre for Learning and Discovery, Room 5027 | McMaster University | 1280 Main Street West | Hamilton, Ontario L8S4K1