Medulloblastoma is among the most common malignant brain tumours of childhood cancer and is responsible for around 5% to 10% of childhood cancer deaths.

Now, findings from the two-phase £5 million INSTINCT studies, published in Neuro-Oncology, could form the foundation of more targeted treatments for many children, leading to improved survival, less severe long-term side effects and improved quality of life.

Led by Professor Steve Clifford, Director of Newcastle University Centre for Cancer, the INSTINCT research programme set out to identify key genetic defects and find effective targeted approaches to treating Group 3 medulloblastoma.

Aggressive tumours in youngsters

Group 3 medulloblastomas are tumours that occur primarily in young children and are effectively incurable, contributing significantly to overall childhood cancer death rates. This cancer is driven by the presence of a gene called MYC which triggers rapid disease growth and often results in treatment failure.

By bringing together the largest cohort of MYC amplified tumours ever studied – drawn from more than 1,600 cases – the study showed critical variation in the clinical outcomes within this group.

For the first time, experts were able to identify specific groups of patients who are currently near incurable and urgently require new approaches.

The two studies, which began in 2015, have provided critical evidence to help guide diagnosis and consider appropriate treatment dependent on the genetic make-up of the tumour.

The researchers also identified the potential for a new approach to treating the disease, using drugs that target the effect of the MYC gene on tumour growth.

Professor Clifford said: “Medulloblastomas with MYC gene amplifications are one of the biggest challenges in paediatric oncology.

“In our latest studies, we have identified an important group of these tumours which are essentially incurable using current therapies, and how to recognise them diagnostically.

“New therapies are urgently required to treat these tumours, but there has been a lag in their development.

“In our second new paper, we report our discovery that MYC tumours are dependent on a critical metabolic pathway – the serine/glycine synthesis pathway – for their growth and development, and that we can target this pathway using PHGDH inhibitor drugs in experimental models to slow tumour growth.

“Together, these studies provide the essential diagnostic characteristics that can immediately be used to identify this critical tumour group in the clinic, as well as an important targetable mechanism for the development of new therapies aimed at improving their outcomes.”

Dr Ed Schwalbe, Associate Professor in Bioinformatics and Biostatistics at Northumbria University, led the first part of the INSTINCT study, which identified a group of patients with a particularly poor prognosis, as well as other patient groups whose disease is curable using current treatments.

He said: “Understanding that children with MYC medulloblastomas have different outcomes helps us to select the best treatments and paves the way for new approaches to treat this devastating disease.”

Dr Magretta Adiamah, a developing postdoctoral researcher, led the second part of the study exploring targeted metabolic therapies for MYC medulloblastoma during her PhD studentship at Newcastle University.

She added: "Our study opens the possibility of targeting MYC medulloblastoma through a metabolic vulnerability created by MYC itself. It is promising that we can selectively target MYC medulloblastoma by understanding what it takes to grow so aggressively.”

The studies were funded by Children with Cancer UK, Cancer Research UK, The Brain Tumour Charity, Great Ormond Street Hospital Charity (GOSH Charity), Blue Skye Thinking and Little Hero.                                                                                                                                                                                                                                            

'Excited by the possibilities'

Both Blue Skye Thinking and Little Hero were formed by families in the memory of their lost sons who passed away from medulloblastoma.

John Rainsbury, Trustee of Little Hero and dad to Will who died of Group 3 medulloblastoma at six years old, said: “As a family we are excited by the possibilities that this discovery provides and hope this new understanding can develop into meaningful treatments for other children facing what Will went through.

“Whilst diagnostics have progressed, surprisingly the actual treatment for medulloblastoma has changed little in 30 years, with the prognosis for high risk versions remaining stubbornly poor.

“It is essential that we develop novel approaches to target high-risk disease far more effectively and give kids like Will a chance for the future.”

Children with Cancer UK’s Head of Research, Dr Sultana Choudhry, said: “We have a long-standing commitment to fund research to accelerate scientific discoveries to clinical translation of new treatments and better outcomes for children with cancer.

“This study represents a significant step towards more effective and targeted treatments for one of the most challenging forms of paediatric brain cancer.

“Through funding vital research such as the INSTINCT programmes we continue to improve outcomes for children with cancer and work towards achieving our vision of a world where every child and young person survives a cancer diagnosis.”