Project 458267

Medulloblastoma is the most common malignant paediatric brain tumour and is currently treated with surgery, external beam radiation and chemotherapy. Current treatments are debilitating to the developing and this is particularly problematic in younger children where radiation results in long-term cognitive dysfunction. A subset of these tumours harbour a TP53 mutation resulting in fatal prognosis where local re-occurrence and radio-resistance is prominent. There is an urgent need to develop faithful models which recapitulate the disease to understand the mechanism of resistance and develop novel targets and therapeutics to sensitize tumours to radiation. The proposed study aims to identify therapeutic and genetic vulnerabilities in response to radiation therapy. I established multiple models which have shown to retain the phenotypic and genotypic characteristics of SHH medulloblastoma. These models recapitulate the human disease demonstrating genomic instability and radiation resistance. Using these unique models, initial results of a high-throughput drug screen revealed a novel class of radio-sensitizers termed bromodomain inhibitors which re-sensitize these high-risk tumours to radiation. Additionally, using a large-scale genomic screen, I have identified essential genes in addition to context-essential genes which confer radiation sensitivity and radiation resistance in our models. Using a combination of high-throughput drug screening and a functional genomic approach I expect to identify the achilles heel of genetic and therapeutic vulnerabilities in response radiation to develop new insights into the biology of treatment resistance within this high-risk group of medulloblastoma. Using this robust approach, I can identify new combinational therapies to enhance current treatments by sensitizing tumours to radiation.