High risk brain tumour network, INSTINCT, was launched in November 2014 following a £4million funding commitment. Set up by Dr Darren Hargrave, Isla's Oncologist, at Great Ormond Street Children's Hospital and his collaborators - Professor Steven Clifford at the University of Newcastle and Professor Chris Jones at the Royal Marsden Hospital (Institute of Cancer Research) and aims to bring a step change into the research and treatment of childhood high-risk brain tumours with poor survival rates in the UK. These include ETANTR, the type of tumour from which Isla suffered, as well as malignant glioma, brainstem glioma, high-risk medulloblastoma and ATRT. There are approximately 100 cases per year of these very aggressive tumours in the UK with a total of 10,000 estimated worldwide. The survival rates are very low, for the most part below 10-15%, a situation which the consortium believe can materially be improved by better research and coordination.

Through the identificaiton of the genes and proteins which drive the rapid growth of high risk brain tumours, the group can assess how dangerous an individual child's disease is. Quick assessment and effective treatment gives children the best chance of defeating the disease with the least severe side effects.

'High-risk' paediatric brain tumours are the leading cause of childhood cancer death. Biological discoveries, and their translation into effective therapies, will be essential to future clinical advances and save more lives. The INSTINCT programme integrates leading high risk paediatric brain tumour research programmes at The Institute of Child Health, Newcastle University and The Institute of Cancer Research to create a collaborative clinical research network, with the primary aim of delivering improved therapies for children with high risk brain tumours. INSTINCT encompasses a series of strategic initiatives that bring together strengths in: tumour collection, neuropathology, basic science, experimental modelling, biomarker and drug development, clinical investigations and Phase I/II/III clinical trials, to deliver the essential common infrastructure necessary to undertake state-of-the-art bioloigcal investigations and translate findings into clinical advances.These combined strengths are, in turn, applied to support translational research programmes in major high risk paediatric brain tumour types including high-risk medulloblastoma and high-grade and diffuse-intrinsic pontine gliomas (HGG/DIPG).

High-risk medulloblastoma
Since the Summer of 2015, the team have undertaken a comprehensive clinical and biological investigation from recurrent medulloblastoma biopsies from patients at diagnosis and relapse. They observed how genetic mutations within genes (known as P53-MYC) affected how aggressively the cancer developed, and when they corrected the faulty genes, they noticed a reduction in tumour growth and prolonged survival. This is a hugely important discovery. These initial findings identify faulty P53-MYC interactions at medulloblastoma relapse as biomarkers of a clinically aggressive disease. The team are now developing human cell lines and mouse models, in which they can modify the expression of P53-MYC cancer causing genes in order to begin targeting the gene therapeutically. Initially this will be done in genetically engineered mice, before eventually testing the treatment in clinical trials in humans.

High-grade and diffuse-intrinsic pontine gliomas (HGG/DIPG)
This area of the INSTINCT programme is focused on understanding how the highly recurrent and specific mutations in histone genes (which are important to regulating and packing DNA, contribute to tumour development, and therefore, how they might be targeted in the clinic to treat children with HGG/ DIPG.

In collaboration with Professor Maria Castro at the University of Michigan, the team are researching how faulty histone genes can affect brain tumour progression in children with HGG/ DIPG. The team have continued to actively collect and characterise models of paediatric HGG and DIPG obtained directly from biopsy, surgery and autopsy. Also, they have begun to develop genetically-engineered models of faulty histones in order to perform high-throughput screening, so that they can find and test new treatments as quickly as possible.

We will continue to provide updates as and when they become available.

June 2016

High Risk Brain Tumour types:

• Embryonal Tumour with Abundant Neuropil and True Rosettes (ETANTR):
Estimated number in UK, 5 per year, with 20-30 cases per year in USA.
Median survival of 12-16 months; 15% 3-year overall survival rate.

• Diffuse Intrinsic Pontine Glioma (DIPG):
30 cases per year in UK, 150-200 cases per year in USA.
Median survival 8-12 months; <10% 3-year overall survival rate.

• High Grade Glioma (HGG):
30 cases a year in UK, 150 cases per year in USA.
Median survival 18 months; 22% 3-year overall survival rate.

• High-risk Medulloblastoma (HR-MB):
25 cases per year in UK, 140 cases per year in USA.
Ranges from 40-60% 3 year overall survival.

• Atypical Teratoid Rhabdoid Tumour (ATRT):
5-8 cases per year, 30-40 cases per year in USA.
Median survival 8-10 months, 17% 2-year survival in children <3 years.

Lead researchers:

• Dr Darren Hargrave (lead GOSH/ICH)

Consultant Paediatric Oncologist with expertise in childhood brain tumours and drug development. Chair of the SIOP European High Grade Glioma Group. Chief investigator on several completed, on-going or planned international clinical trials with novel agents. Interests on advanced neuro-imaging and molecular biology of malignant glioma and DIPG. Collaborations with Thomas Jacques (neuropathologist -primary tissue collection including autopsy and cell culture), John Anderson (development of immunotherapy and antibody therapies) and David Michod (epigenetics of childhood brain tumours).

• Professor Steve Clifford (lead at Newcastle University)

Senior Scientist at the Northern Institute for Cancer Research and lead of the paediatric brain tumour research group. Interests in the molecular basis of paediatric brain tumours (medulloblastoma, CNS-PNET which includes ETANTR, ATRT), development molecular diagnostics for improved treatment individualisation development and pre-clinical assessment of novel therapies for paediatric tumours. Collaborations with Dan Williamson (ATRT biology) and Simon Bailey (medulloblastoma and DIPG trials).

• Dr Chris Jones (lead at ICR/Marsden)

Senior scientist with an interest in the biology and novel therapies for malignant glioma and DIPG. Development of new models (primary cell culture and mouse models) for systematic drug screening. Collaborations with Louis Chesler (expert in transgenic mouse models and pre-clinical drug trials).


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