Advancing novel treatment strategies for MYC-amplified medulloblastoma, one of the most fatal brain tumours of childhood

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Medulloblastoma (MB) is the commonest malignant childhood brain tumour. Advances in standard upfront-treatments (surgical removal of tumour, radiotherapy and chemotherapy) have led to survival rates of approximately 70%. Our research has identified four consensus molecular subgroups (MBWNT, Wnt/wingless-activated; MBSHH, Sonic-hedgehog-activated; MBGroup3, Group3; and MBGroup4, Group4), with divergent second-generation subtypes, genomic characteristics, and clinical relevance. Importantly, MYC oncogene amplification in MBGroup3 (MBGroup3-MYC) conveys a dismal prognosis; patients typically progress, or relapse shortly after standard upfront-treatment and subsequently die of disease (<10% survival). MBGroup3-MYC thus accounts for a high proportion of childhood cancer deaths, and is one of the most significant unmet clinical challenges in childhood cancer. This project aims to develop new therapies for MBGroup3-MYC using comprehensive disease modelling approaches. To date, we have developed three independent isogenic MBGroup3 cell-line models (iMBGroup3-MYC) with regulable MYC expression to investigate the role of MYC in drug resistance. High-throughput drug screening in these cell-line models has already identified promising new MYC-targeting drugs for further investigation. This project will advance these early findings and will develop novel MBGroup3-MYC mouse models, then use these to test new MYC-targeting drugs and understand their mechanism(s) of action. The major objectives are: Objective I: To use integrated chemo-informatics approaches to prioritise MYC-targeting drugs identified from high-throughput screens in our iMBGroup3-MYC cell-line models. Objective II: To develop and characterise novel iMBGroup3-MYC mouse models with regulable MYC expression. Objective III: To establish new MBGroup3-MYC mouse models using patient-derived xenografts, to provide disease-relevant models which re-capitulate intra-tumoural heterogeneity, for further assessment of MYC-targeting drugs identified. Objective IV: To test and validate MYC-targeting drugs in our novel MBGroup3-MYC mouse models, including, efficacy, pharmacokinetic and pharmacodynamic studies, to identify best agents to advance into future clinical trials. In summary, this studentship will provide; new therapeutic opportunities in tumours refractory to standard upfront-treatment and the rationale for alternative upfront-strategies in MYC-driven treatment-refractory MBGroup3. Importantly, translation of these findings will be expedited through established networks and international roles of the supervisory team within groups such as the Children's Cancer and Leukaemia Group, the International Society of Paediatric Oncology Europe (SIOPE), and Innovative Therapies for Children with Cancer (ITCC).