News > Health > Unpredictable evolution in brain tumours – University of Leeds

When brain tumours are treated with radiation or chemotherapy their cells evolve in a way that appears to be random, according to research published today in Nature.

The findingshelp explain why diffuse glioma is one of the most difficult cancers to treatand could help to identify more effective treatment strategies for patientsworldwide.

Diffuse gliomais the most common malignant brain tumour in adults, with 2,500 adultsdiagnosed in the UK every year.

Aninternational team of 87 researchers and clinicians have published the largest timeseries database of glioma tumour profiles to date, with samples from 222patients at 35 hospitals across Europe, Asia, Australia and the USA.

Tumour samples weretaken at multiple time points during treatment so that scientists could try tounderstand how the tumours evolved in response to therapy.

The database could help predict how effective new cancer treatments might be at tackling brain tumours, enabling us to prioritise development of those that are most likely to succeed.

Co-author DrLucy Stead, from the University of Leeds School of Medicine, said: Thesefindings show why gliomas are so hard to treat. In other cancers, cells with certainmutations were found to resist treatment, and discovering those mutationsallowed new drugs to be developed. Unfortunately, in glioma, where tumourregrowth after treatment is almost universal, we have not found any suchmutations.

However, thisdatabase can now act as a reference for researchers and clinicians to studyglioma evolution in response to treatment.

The database couldhelp predict how effective new cancer treatments might be at tackling braintumours, enabling us to prioritise development of those that are most likely tosucceed.

Glioma invariablyreturns despite surgical, radiotherapeutic and chemotherapeutic interventions.But while the initial molecular characteristics have been well described ingliomas, their subsequent evolution under treatment remained unknown.

To address thisproblem, an international community of clinicians and researchers establishedthe Glioma Longitudinal Analysis (GLASS) Consortium, which is investigating thedynamics of molecular changes in gliomas over time.

Lead researcherDr Roel Verhaak, from The Jackson Laboratory in the USA, said: More data areneeded to fully understand glioma evolution, but the GLASS resource provides anexcellent foundation to more effectively study both evolution and treatmentresponse.

Collectively,these findings will help us determine what treatment approaches will result inthe greatest removal or killing of glioma cells possible.

Untilrelatively recently, cancer was viewed as a single disease with sub-types basedon where in the body it arose.

The advent ofdetailed molecular analysis has shown that the situation is far morecomplicated, and that there can be many sub-clonal cell populations even withina single tumour.

That creates asignificant problem for effective therapy: eradicating one type of cancer cellmay leave another unaffected, and it may actually confer a competitiveadvantage to it.

Pilot grants like that given to support Dr Stead are extremely important to support the world-class research that takes place here in Leeds.

In their newstudy, the international GLASS Consortium found that when glioma cells werestressed by cancer therapies such as radiation and chemotherapy, they did notevolve in a consistent manner.

They did findsome common features between patient samples, such as hypermutation - a veryhigh rate of mutation in the genome - and aneuploidy - in which entirechromosomes were lost or acquired through cell division errors.

Following earlyevents that drove cancer initiation and progression, the researchers found thatthe evolution of tumours often appeared to be random instead of proceeding downpredictable paths.

The researchersalso assessed how immune activity can shape glioma evolution.

Immunotherapy,which uses the bodys own immune system to target and eliminate cancer cells,is an exciting new field, and understanding immune interactions in the tumourmicroenvironment and glioma immune evasion is an important step for possibleimplementation.

The researchshowed that immune activity doesnt vary in glioma over time, though there werepatient-to-patient differences, and more work is needed to fully understand thevariability and what immunotherapy strategies might be most effective forgliomas.

The researchersidentified a particular mutation in the gene IDH1 that produces a neoantigen - apotential immune system target - and persists through recurrence. The findingprovides a possible opening for vaccine treatment at both initial and recurrentstages of glioma.

Dr Stead added:Other researchers are currently trying to develop IDH1 vaccines and clinicaltrials are underway.

Our resultssuggest we can have more confidence that these trials may succeed, which isparticularly important given that survival for brain tumours has not increasedfor decades.

The research carriedout at the University of Leeds and Leeds Teaching Hospitals NHS Trust wasfunded by Leeds Cares and the PPR Foundation.

Kevin Gerrie, Directorof Fundraising at Leeds Cares, said it was vital that the charity was able toinvest in research like this. He said: Pilot grants like that given to supportDr Stead are extremely important to support the world-class research that takesplace here in Leeds.

Our donors andsupporters will be delighted to know that this work will provide crucialinsights for the treatment of those with malignant brain tumours.

Further information

Header image shows glioma cancer cells. Credit:Castro Lab, Michigan Medicine, Ann Arbor

For interviewrequests please contact Simon Moore, Press Officer at the University of Leeds,on 0113 34 38059 or s.i.moore@leeds.ac.uk.

The paper,published in the journal Nature, istitled Longitudinal molecular trajectories of diffuse glioma in adults andwill be available online here: https://www.nature.com/articles/s41586-019-1775-1

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News > Health > Unpredictable evolution in brain tumours - University of Leeds