Title: The New Roads Team – INNOVATIVE APPROACHES TO CURING BRAIN TUMOURS
Funder: Cancer Research UK

Abstract: BACKGROUND: Despite decades of research, adult glioblastoma remains incurable and paediatric brain tumours kill and damage more children than any other cancer. The only reasonable conclusion from this experience is that our approach to treating brain tumours is wrong, and completely different ways of treating these diseases will be required if we are to enable all patients to lead healthy lives. AIMS: With a particular focus on paediatric brain tumours, we have assembled a team of world-leaders in neuroscience, developmental biology, immunology, multi-omics and brain tumour research to produce a sea change in brain tumour treatment; unmasking and exploiting differences in the biology of the normal and malignant brain to produce safe and effective therapies. Our research tests the hypothesis that brain tumours comprise corrupt cell hierarchies that exploit neural cell processes to survive. Comparative mapping of normal and malignant brain biology will therefore identify these neural cell processes and their vulnerability to a new generation of effective and safe therapies. METHODS: Specific Objective 1 will generate at single cell resolution, integrated atlases of the transcriptome, proteome, electrophysiological and stem cell properties of cells within the normal human and mouse brain and their tumours. Specific Objective 2 will deploy these maps together with a comprehensive programme of electrophysiological, optogenetic, stem cell biology and genome-wide gene editing approaches, to unmask critical differences between normal and malignant brain cells that allow targeting of tumour cells while preserving normal brain function. Candidate novel therapies already identified for study include: modulation of neurotransmitter and oxidative phosphorylation pathways in glioma; antibody-drug conjugate targeting of medulloblastoma cell surface proteins; and disruption of the polycomb repressive complex in ependymoma. The inadequacy of current preclinical studies has contributed to the high failure rate of brain tumour clinical trials. Therefore, Specific Objective 3 will test our novel therapies in the context of accurate standard-of-care neurosurgery, radiotherapy and chemotherapy in optimal mouse models. Finally, to begin to establish a new generation of UK-based, brain tumour experts and establish the training and peer-support system needed to grow and sustain this community, Specific Objective 4 will establish a Paediatric Neuro-Oncology Fellowship Programme aimed at attracting and retaining the most talented paediatric oncologists to the UK. IMPACT: By adopting a novel, neuroscience-focused approach to brain tumours, we will: change the way the world thinks about and treats these diseases; identify novel therapeutic approaches for patients; and build much needed capacity in the UK.

Lay abstract: BACKGROUND: Despite decades of research, adult glioblastoma remains incurable and paediatric brain tumours kill and damage more children than any other cancer. The only reasonable conclusion from this experience is that our approach to treating brain tumours is wrong, and completely different ways of treating these diseases will be required if we are to enable all patients to lead healthy lives. AIMS: With a particular focus on paediatric brain tumours, we have assembled a team of world-leaders in neuroscience, developmental biology, immunology, multi-omics and brain tumour research to produce a sea change in brain tumour treatment; unmasking and exploiting differences in the biology of the normal and malignant brain to produce safe and effective therapies. Our research tests the hypothesis that brain tumours comprise corrupt cell hierarchies that exploit neural cell processes to survive. Comparative mapping of normal and malignant brain biology will therefore identify these neural cell processes and their vulnerability to a new generation of effective and safe therapies. METHODS: Specific Objective 1 will generate at single cell resolution, integrated atlases of the transcriptome, proteome, electrophysiological and stem cell properties of cells within the normal human and mouse brain and their tumours. Specific Objective 2 will deploy these maps together with a comprehensive programme of electrophysiological, optogenetic, stem cell biology and genome-wide gene editing approaches, to unmask critical differences between normal and malignant brain cells that allow targeting of tumour cells while preserving normal brain function. Candidate novel therapies already identified for study include: modulation of neurotransmitter and oxidative phosphorylation pathways in glioma; antibody-drug conjugate targeting of medulloblastoma cell surface proteins; and disruption of the polycomb repressive complex in ependymoma. The inadequacy of current preclinical studies has contributed to the high failure rate of brain tumour clinical trials. Therefore, Specific Objective 3 will test our novel therapies in the context of accurate standard-of-care neurosurgery, radiotherapy and chemotherapy in optimal mouse models. Finally, to begin to establish a new generation of UK-based, brain tumour experts and establish the training and peer-support system needed to grow and sustain this community, Specific Objective 4 will establish a Paediatric Neuro-Oncology Fellowship Programme aimed at attracting and retaining the most talented paediatric oncologists to the UK. IMPACT: By adopting a novel, neuroscience-focused approach to brain tumours, we will: change the way the world thinks about and treats these diseases; identify novel therapeutic approaches for patients; and build much needed capacity in the UK.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS