Title: Biomarker-driven individualisation of medulloblastoma therapy
Funder: Cancer Research UK

Abstract: Background: _x000D_ Medulloblastoma is the most common malignant childhood brain tumour, and one of the most significant challenges in paediatric oncology (~650 cases/year in the EU). Up to 40% of patients die, while cure is associated with disabling life-long therapy-associated late-effects. The accurate identification of medulloblastoma disease-risk and molecular features therefore has major potential to improve outcomes, through guiding (i) therapeutic reduction in favourable-risk cases, (ii) treatment intensification or modification in high-risk cases, and (iii) the targeted delivery of novel molecular agents. Our group have identified key prognostic biomarkers which will, for the first time in paediatric neuro-oncology, direct therapeutic stratification in groundbreaking European clinical trials for the clinical 'standard-risk' group (~50% of all cases). However, the biological basis of the majority of medulloblastomas, and its clinical relevance, remains poorly understood. Importantly, equivalent strategies in the poor prognosis clinical high-risk groups (infants 3 years old and/or patients with metastatic disease), and patients who have relapsed following initial therapy, have not been developed. _x000D_ _x000D_ Aims: _x000D_ To discover, develop and validate prognostic and predictive biomarkers with utility to direct individualised therapy for medulloblastoma. These biomarkers will support new treatment strategies including molecular disease-risk stratification and delivery of targeted therapeutics, together leading to enhanced survival rates and reduced therapeutic late-effects and toxicities._x000D_ _x000D_ Methods: _x000D_ Our programme will address all clinical disease-risk groups. Biological investigations will centre on the identification of putative biomarkers in primary tumour and tumour-associated (e.g. cerebrospinal fluid, blood) material, through (i) genomic and epigenetic screening using microarray and next-generation sequencing methods, and (ii) the detailed characterisation of established, reported and novel biomarkers of potential therapeutic significance. The clinico-pathological significance of biomarkers identified, and their prognostic and predictive utility, will be established and validated in extensive retrospective cohorts. Following the development of routine tests and assessment criteria, biomarker utility for treatment individualisation will be tested prospectively in National and European Phase III trials aimed at the maximisation of survival alongside the minimisation of late-effects (prognostic & predictive biomarkers), and for guiding the delivery of novel molecular targeted therapies in early- and late-phase trials (predictive biomarkers). _x000D_ _x000D_ How the results of this research will be used: _x000D_ This comprehensive strategy links biomarker development directly with clinical application. Findings will be incorporated into (i) planning of the next wave of medulloblastoma trials, through our leading roles in National and European trials groups, and (ii) our ongoing research programme, aimed at delivering improved outcomes for children with medulloblastoma._x000D_


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS