Scientists have discovered four molecular sub-groups of meningioma, one of the most common brain tumours, for the first time identifying viable medical treatment options based on the biological drivers of the disease.
In landmark findings published in Nature, researchers have identified four distinct groups of meningioma, which can be used to predict how tumours will behave and when the disease may return, more accurately than existing World Health Organisation (WHO) criteria.
The study, part-funded by The Brain Tumour Charity, is expected to transform practice globally, defining a new classification able to be tested for in cancer centres around the world. The system will help doctors give a more accurate prognosis and identify patients that may benefit from having more aggressive treatment earlier, rather than being recommended a ‘watch and wait’ approach.
Crucially, the scientists — led by Dr Farshad Nassiri and Professor Gelareh Zadeh at the University of Toronto — also analysed whether the biological characteristics of the four subgroups could be targeted by any existing, FDA-approved drugs.
They found that lymphoma drug vorinostat could target the most aggressive sub-group (known as MG4) and slowed tumour growth in cell-lines and in mice, with experts now calling for clinical trials to confirm whether it may represent the first-ever effective drug treatment for meningiomas.
Over 12,000 people are diagnosed with a primary brain tumour each year in the UK. Meningiomas are one of the most common forms of brain tumour, accounting for over a fifth of all cases. They are tumours that grow in the set of three membranes just inside the skull (called the meninges) that cover and protect the brain and spinal cord.
By the current WHO criteria, meningiomas can be classed as grades 1, 2 or 3 (there are no grade 4 meningiomas). The majority are classified as grade 1 and are slow-growing, but some are classified as grades 2 or 3, which grow faster and are more likely to return after treatment.
Surgery is the main treatment for meningiomas, with radiotherapy offered to certain patients depending on the size and location of the tumour, its grade and the patient’s symptoms.
People who are diagnosed with a grade 1 meningioma are often put on active monitoring, with surgery and radiotherapy offered at a later date if needed. But to date, there are no effective medical therapies for this tumour type.
In a world-first study, scientists at the University Health Network in Toronto comprehensively analysed the biology of meningiomas (looking at DNA, RNA and proteins) from 121 patients, integrating matched molecular data across the epigenome, genome and transcriptome as well as high-quality clinical data.
By combining several datasets and conducting the first analysis of meningioma tumours by single-cell RNA sequencing, the team were able to create an ‘atlas’ of genomic alterations across all grades of meningioma, including rarer, higher-grade meningiomas.
In doing so, the researchers identified four distinct molecular groups:
- MG1 (known as immunogenic)
- MG2 (benign NF2 wild-type)
- MG3 (hypermetabolic)
- MG4 (proliferative)
They found that classification by these molecular groups more accurately predicted time to recurrence and clinical behaviour of the tumours than the current WHO grades or methylation-based classification systems.
The study found that patients with MG3 and MG4 tumours saw their disease return sooner than patients with MG1 and MG2 tumours, with the worst outcomes seen in those with MG4 tumours. Each molecular group also showed distinctive biology and characteristics that could be used to help identify novel, more tailored treatment options for patients.
The team then looked to see whether any FDA-approved drugs targeted the specific biological drivers identified in the different molecular groups, to try to find drugs that could potentially be repurposed for the treatment of meningiomas.
They identified that a drug called vorinostat (Zolinza, Merck) — a histone deacetylase inhibitor currently used to treat a rare type of non-Hodgkin lymphoma — targeted several critical pathways involved in the growth of the most aggressive group of meningiomas (MG4).
Preliminary studies found that vorinostat could slow growth of MG4 meningioma tumours and improve survival in mice — a finding that now warrants further investigation in clinical studies.
The study was funded by The Canadian Institute for Health Research, the Canadian Cancer Society and The Brain Tumour Charity’s Quest for Cures programme.
Lead author, Dr Farshad Nassiri, Neurosurgery Resident at the University of Toronto, said:
“This is a transformation in our understanding of meningiomas. The classification that we’ve discovered gives new insight into the biology of the full spectrum of meningiomas, specifically why some of these tumours behave more aggressively than others.
“Our findings now give us the first real look at more tailored treatments options to add to surgery and radiotherapy. We found that each group of meningioma expressed very specific proteins, and that these proteins could be assayed using conventional techniques that are already available in neuropathology laboratories. This means that this classification can be immediately used in almost all cancer centres around the world.
“We also discovered that the most aggressive group of meningiomas could be targeted using a drug that is already FDA-approved for other cancers. For many years, patients have often needed to have multiple rounds of surgery and radiation, fortunately with very limited lasting effects. But the better understanding of the biology of the disease has now allowed us to discover the option of a medical treatment that could change the landscape for our patients.”
Dr David Jenkinson, Interim CEO at The Brain Tumour Charity, which helped fund the study, said:
“These are extremely exciting findings that we hope will now lead to a step change in the diagnosis and treatment of meningiomas both in the UK and globally.
“This new classification of four molecular groups of meningiomas could now enable patients to be given a more accurate prediction of how their tumour may behave and help identify those in need of more aggressive treatment sooner, rather than taking a ‘watch and wait’ approach.
“It’s really promising that an existing lymphoma drug has been found to target the biological drivers of the most aggressive meningiomas and could represent the first-ever drug treatment for the disease. We hope this can be swiftly advanced to clinical trials to fully assess its potential to be repurposed as a meningioma treatment and to understand whether it could help extend or improve patients’ lives.
“As the world’s leading brain tumour charity, we remain committed to supporting the most pioneering researchers in the UK and internationally who are working tirelessly to drive change for everyone affected by a brain tumour – and we’re really proud to have helped make this practice-changing research possible.
“Anyone living with a meningioma can get in touch for support and information on 0808 800 0004 or by emailing [email protected]. If you need someone to talk to, we’re here for you.”
Nurse and mum-of-two Tammy Andrews, 47, from Blandford was diagnosed with a meningioma brain tumour in 2019. She began noticing changes to her vision in February of that year and after numerous GP visits, being seen by the acute eye team at Bournemouth Hospital and an MRI scan, it was confirmed that Tammy had a meningioma brain tumour.
She underwent a seven-hour craniotomy and the majority of the tumour was successfully removed. Since then, she has supported the campaigning and fundraising work of The Brain Tumour Charity.
Tammy said:
“Initially when I was told by the neurologist that I had a brain tumour, I thought that it meant my life was over. Even after my operation I still had the same thought, because I still had some residual tumour, so I thought my life expectancy would still be limited.
“However after discovering the brain tumour support group on Facebook and signing up to ‘BRIAN’, an app to help track my journey, my outlook changed. I quickly learned that I needed to raise awareness of meningiomas and the signs and symptoms that people should be aware of and also the importance of fundraising for research, because “a cure can’t wait”.
“I knew that I had a duty to help out – I couldn’t just sit around hoping, praying and waiting for help or for a cure when I wasn’t putting any money in the pot to get that help and much-needed answers. I now have a positive outlook on life and I am truly thankful for all the support I have received in my brain tumour journey.
“This truly is a significant research milestone which will enable meningioma brain tumours to be analysed and classified, and hopefully in future targeted with an effective medical therapy that could save lives.”