Medulloblastoma is the most common malignant brain tumour of childhood, affecting 60-80 Canadian children per year. The treatment for medulloblastoma comprises surgery, followed by radiation to the entire brain and spinal cord, and high doses of non-specific chemotherapy. Despite such aggressive treatment, survival is only around 60%, with survivors left with long-term side effects of radiation to the developing brain. As such, we urgently need new personalized therapies that are less toxic and more effective. Although classically thought of as one tumour entity, applying next generation genomics it is now known that medulloblastoma is actually comprised of multiple different diseases, where the molecular “subgroup” can predict outcome with a high degree of accuracy. The WNT subgroup have an excellent prognosis and are candidates for reductions in therapy intensity, but one of the groups accounting for a high proportion of relapses is a subset of tumours termed TP53-mutant SHH medulloblastoma. This subset of patients have a very poor survival, and need to be prioritized for new therapies. This proposal will attempt to understand why this group of very high risk medulloblastoma relapse in light of our current treatments. We will employ a technique called functional genomics, where we will try to understand which genes in the tumour are responsible for radiation resistance, and using this information we will try to develop new therapies which allow radiation to work more effectively. We will also study normal brain cells that give rise to SHH medulloblastoma to understand any new insights in the context of the developing nervous system. The overarching goal of this proposal is to identify new personalized, more effective and less toxic treatments for this very high-risk group of childhood brain tumours. This will allow survivors to have an improved quality of life, and lessen the devastating effects of radiation therapy.