Canadian researchers discover key driver in rare childhood brain cancer that offers hope for accurate diagnosis and treatment

A decade ago a study led by researchers at The Hospital for Sick Children (SickKids) made critical advancements in describing a deadly childhood brain tumour (embryonal tumours with multilayered rosettes (ETMRs)).

Now, in the largest report on this rare tumour to date, the researchers, along with an international team of scientists, have released new information about ETMRs that for the first time gives a clue to the cause of the disease’s rapid progression and offers critical therapeutic insights.

In 2009 we led the discovery of C19MC gene cluster as a genetic marker of ETMRs. Since then, there has been limited progress in our biological and therapeutic understanding of the disease,” says Dr. Annie Huang, Staff Oncologist, Paediatric Brain Tumour Program and Senior Scientist, Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre at SickKids; and Professor of Paediatrics, Medical Biophysics, Lab Medicine and Pathobiology at the University of Toronto. “Now, we have not only reaffirmed C19MC as a disease marker, but have also discovered unconventional characteristics of this gene that offer hope for accurate diagnosis and more treatment options.”

The study, published on July 8 in Cancer Cell has underscored C19MC as the major gene driving the development of this rare childhood brain cancer. Upon further investigation into its genetic properties, the researchers also discovered a circuit that could explain ETMRs’ aggressive nature.

“Our findings were surprising. We discovered that C19MC is not a conventional gene – it’s essentially a powerhouse that is fueled by multiple complex loops and super enhancers,” says Huang, who is also a Professor in the Department of Paediatrics at the University of Toronto. “This has huge implications for beginning to develop real-world models for this rare disease.”

The discovery of a whirlpool-like composition of the C19MC gene offers a critical clue in what drives prolific cell growth and maintains the cancerous state that characterizes ETMRs. It also presents a therapeutic breakthrough – the presence of a genetic circuit may mean that ETMRs are susceptible to certain forms of intervention.

“The discovery of a potent oncogenic circuit fueling the sustainability of ETMRs presents a therapeutic vulnerability in this form of cancer. With this information, we can, for the first time, begin to explore therapeutic measures to control the aggressive nature of this disease,” says Huang.

The researchers did just that. Collective findings uncovered the power of a class of drugs called bromodomain inhibitors to promote ETMR cell death. In the future, drugs targeting bromodomains may represent promising therapeutics for ETMRs; the hope is that this may lead to increased chances of survival in infants with this highly lethal brain cancer.

“This is the first time that we identified a circuit that targets to this disease. With this groundbreaking finding, we can begin to better diagnose ETMRs in young children, explore treatment options other than radiation, and unlock the powers of precision medicine,” says Huang.

Embryonal brain tumours, the largest category of malignant brain tumours diagnosed in children aged 0 to 14, comprise a spectrum of diseases that include the discovery of ETMRs. ETMRs are now increasingly recognized as a distinctly aggressive brain tumour arising in infants and young children less than four years of age with long-term survival of only 10 to 20 per cent.

For her work in the field, Huang was recently named a Canada Research Chair in Rare Childhood Brain Tumours (Tier 1). Findings from the current study will be added to the global Rare Brain Tumour consortium and ETMR tumour bank established by Huang, which has over 3,000 types of rare tumours from 111 centres from over 40 countries worldwide. These findings highlight how studying rare paediatric brain tumours can provide invaluable insight into unsuspected molecular mechanisms of brain development.

This projected was supported by the Canadian Institutes of Health Research (CIHR), Grace’s Fund, Miracle Marnie Foundation, The Phoebe Rose Rocks Foundation, b.r.a.i.n.child, and SickKids Foundation.