Targeting Recurrent Medulloblastoma via Wnt Activation
Demonstrating the ability of the Wnt pathway to suppress tumour progression in childhood medulloblastoma, thus establishing activated Wnt signaling as a novel treatment paradigm.
Medulloblastoma (MB) is the most common type of brain tumour in children, and is thought to arise from an abnormal stem cell.
Recent research has categorized MBs into four subgroups, only one of which consistently has a good patient outcome. This good-outcome subgroup is characterized by the presence of Wnt proteins, which are present in stem cells and usually mark more aggressive cancers. In contrast, subgroups that lack Wnt proteins are poor-outcome subgroups characterized by aggressive metastatic spread of cancer, increased rate of relapse, and poor overall patient survival.
We hypothesized that Wnt activation in stem cells from aggressive MB subgroups would reduce tumour growth. Activated Wnt signaling with small molecule drugs and genetic manipulation of aggressive MB stem cells resulted in a reduction in key stem cell properties in more aggressive human MB stem cells.
The clinical relevance of these findings was demonstrated with a survival advantage in pre-clinical models using a stabilized version of a key protein involved in activation of the Wnt pathway. Wnt-activated MBs were much smaller in size, maintained a much lower rate of proliferation, and reduction in key MB stem cell genes (Bmi1, Sox2, Msi1, FoxG1).