Grant: Project Grant

Brain tumors represent the leading cause of childhood cancer mortality, due to their highly aggressive and often incurable nature. Medulloblastoma (MB), the most common malignant pediatric brain tumor, is defined by four molecular subgroups (Wnt, Shh, Group 3, Group 4) based on gene expression profiles. Clinically, Wnt MB patients who have high activity of a developmental signaling pathway called Wnt, have the most favorable prognosis with a >95% 5-year survivorship. By contrast, non-Wnt MB patients are characterized by metastatic disease, increased rates of recurrence, and intermediate-poor overall survivorship. Given that Wnt MBs represent the only subgroup in which metastasis is not indicative of a poor prognosis, it has been suggested that Wnt signaling may contribute to their remarkable response to therapy. Given the excellent clinical outcome in Wnt-driven MB, we aim to convert treatment-resistant Group 3 and 4 MBs into ostensibly benign tumors by activation of Wnt signaling. Our preliminary results show that the non-Wnt MB cells have reduced growth when they are treated with Wnt activators. By using animal models, we found that Wnt-activated cells have decreased tumorigenicity. In the current work we aim to understand the mechanism by which the Wnt pathway can be modulated for therapy of poor prognosis MBs. We also aim to identify novel Wnt activators through genetic screens using CRISPR technology. Ultimately, this work will lead to increasing our molecular understanding of treatment-refractory MB, and identify new therapeutic targets for MB patients who still die from relapse.