Title: Curing the underserved - developing transformative therapies for rare childhood brain tumours
Funder: The Brain Tumour Charity

Abstract: Aims and background: What is known about the problem?: Choroid plexus carcinoma (CPC) and supratentorial C11orf95-RELA ependymoma (ST-EP-RELA) are aggressive paediatric brain tumours that kill most affected children within 10 years of diagnosis. No new treatments have been developed in the last 30 years, and even ‘standard’ therapy remains controversial. Identifying curative therapies has been hampered by inadequate drug development efforts that recommend ineffective treatments for clinical trial; thereby inadvertently condemning generations of children with these tumours to ineffective therapies. What will you find out?: We will develop three new mouse models of CPC and ST-EP-RELA; validate two ‘clinic-ready’ novel treatments of CPC and ST-EP-RELA for immediate clinical trial; identify up to five completely novel chemicals and natural products as potential treatments for future clinical development; and establish two innovative approaches to deliver new treatments directly into brain tumours in children. What is innovative?: Our ambitious proposal will generate a sea change in the way the world develops new treatments for children with brain tumours. Based within the first CRUK Children’s Brain Tumour Centre of Excellence (CRUK-CBTCE), and the US National Centre for Natural Products Research, our drug discovery effort involves: the largest ever high-throughput drug screen (>1.2 million compounds) conducted in any childhood cancer; the first and only models of CPC and ST-EP-RELA; international expertise in childhood brain tumours, drug development and chemical biology; and the world’s only small animal ‘brain tumour hospital’ capable of delivering preclinical trials of sequential neurosurgery, radiotherapy and chemotherapy in mice. Why this research is needed? How will the research benefit patients? Our research will provide the first ever, rational and validated molecular targeted treatments for current and future clinical trials in CPC and ST-EP-RELA. The approaches developed through our studies have great potential to advance the treatment of more common brain tumours and other rare cancers. How is it value for money? Decades of research at the cost of billions of pounds have yielded only six drugs for treating brain tumours: none are specific for these cancers or curative. We will leverage the resources provided by the CRUK-CBTCE to change completely the way the world approaches brain tumour development, delivering the first, rationally selected and biologically validate drugs for paediatric clinical trials in CPC and ST-EP-RELA. Methodology What methods will be used?: We will deploy innovative technologies across the drug development pipeline including: highly-accurate, genetically engineered mouse and patient-derived orthotopic xenograft models; advanced genomic approaches to validate critical drug targets in tumours; the latest in chemical and structural biology to design new treatments; and accurate mouse modelling of sequential, neurosurgery, radiotherapy and chemotherapy. Patient and Public Involvement Involvement of those affected by a brain tumour: The International Children’s Brain Tumour Board in the CRUK-CBTCE includes parents of children battling a brain tumour who give invaluable input to our work. We are in the process of extending this input to the RIN via the Patient Advocacy Strategic Programme (Chaired by Sarah Lindsell) of the Tessa Jowell Brain Cancer Mission (Chaired by Gilbertson).

Lay abstract: Aims and background: What is known about the problem?: Choroid plexus carcinoma (CPC) and supratentorial C11orf95-RELA ependymoma (ST-EP-RELA) are aggressive paediatric brain tumours that kill most affected children within 10 years of diagnosis. No new treatments have been developed in the last 30 years, and even ‘standard’ therapy remains controversial. Identifying curative therapies has been hampered by inadequate drug development efforts that recommend ineffective treatments for clinical trial; thereby inadvertently condemning generations of children with these tumours to ineffective therapies. What will you find out?: We will develop three new mouse models of CPC and ST-EP-RELA; validate two ‘clinic-ready’ novel treatments of CPC and ST-EP-RELA for immediate clinical trial; identify up to five completely novel chemicals and natural products as potential treatments for future clinical development; and establish two innovative approaches to deliver new treatments directly into brain tumours in children. What is innovative?: Our ambitious proposal will generate a sea change in the way the world develops new treatments for children with brain tumours. Based within the first CRUK Children’s Brain Tumour Centre of Excellence (CRUK-CBTCE), and the US National Centre for Natural Products Research, our drug discovery effort involves: the largest ever high-throughput drug screen (>1.2 million compounds) conducted in any childhood cancer; the first and only models of CPC and ST-EP-RELA; international expertise in childhood brain tumours, drug development and chemical biology; and the world’s only small animal ‘brain tumour hospital’ capable of delivering preclinical trials of sequential neurosurgery, radiotherapy and chemotherapy in mice. Why this research is needed? How will the research benefit patients? Our research will provide the first ever, rational and validated molecular targeted treatments for current and future clinical trials in CPC and ST-EP-RELA. The approaches developed through our studies have great potential to advance the treatment of more common brain tumours and other rare cancers. How is it value for money? Decades of research at the cost of billions of pounds have yielded only six drugs for treating brain tumours: none are specific for these cancers or curative. We will leverage the resources provided by the CRUK-CBTCE to change completely the way the world approaches brain tumour development, delivering the first, rationally selected and biologically validate drugs for paediatric clinical trials in CPC and ST-EP-RELA. Methodology What methods will be used?: We will deploy innovative technologies across the drug development pipeline including: highly-accurate, genetically engineered mouse and patient-derived orthotopic xenograft models; advanced genomic approaches to validate critical drug targets in tumours; the latest in chemical and structural biology to design new treatments; and accurate mouse modelling of sequential, neurosurgery, radiotherapy and chemotherapy. Patient and Public Involvement Involvement of those affected by a brain tumour: The International Children’s Brain Tumour Board in the CRUK-CBTCE includes parents of children battling a brain tumour who give invaluable input to our work. We are in the process of extending this input to the RIN via the Patient Advocacy Strategic Programme (Chaired by Sarah Lindsell) of the Tessa Jowell Brain Cancer Mission (Chaired by Gilbertson).

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