[Truncated abstract] Background: Medulloblastoma (MB), the most common type of malignant paediatric brain tumour, is a heterogeneous disease with poorly understood differential clinical progression. Despite major progress in the understanding of the molecular pathogenesis of MB, treatment regimens continue to be determined by clinical parameters and are associated with severe side effects for survivors. Although there are only two clinical categories for risk assessment, there are at least four molecular subgroups of MB. This discrepancy suggests that it may be possible to design therapies specifically tailored to particular MB variants. Indeed, sonic hedgehog (SHH)-dependent MB are currently the best understood and new tailored drugs for this subgroup are being assessed in phase II clinical trials. Generally, the development of treatment regimens specific for MB subgroups is hampered by an incomplete understanding of MB pathogenesis, difficulties associated with the unequivocal identification of the cell of origin, and a paucity of adequate subgroup-specific models. The recent advances in MB subgroup classification will be beneficial for identifying the MB cells of origin and consequently elucidating the underlying molecular mechanisms causing neoplastic transformation of healthy neural cells into MB initiating cells. Small populations of CD133+ brain tumour stem cells (BTSCs) that phenotypically and functionally resemble normal CD133+ neural stem cells (NSCs) have been shown to drive progression in some MB, suggesting that CD133+ BTSCs could arise from transformed CD133+ NSCs residing in the developing cerebellum.
|Qualification||Doctor of Philosophy|
|Publication status||Unpublished - 2011|