Glioblastoma is an aggressive, incurable type of brain tumour that strikes around 2,500 people every year in the UK. Even after successful surgery, some tumour cells are always left behind, and these cells eventually grow back into a recurrent tumour that is more resistant to treatment. Only a quarter of patients survive more than a year from diagnosis.
In many cancers, tumours evolve by acquiring new genetic mutations that allow cancer cells to survive treatment. However, there is little evidence to support this type of genetic ‘clonal evolution’ in glioblastoma.
Dr James Nicholson has been awarded a Brain Research UK Fellowship to test a new idea called “epi-clonal evolution”, whereby cancer cells survive treatment because of inherited ‘epigenetic’ states that control which genes are switched on or off. He will also test whether combining drugs that target different resistant cell populations improves treatment response.
Funded in our second round of fellowship funding, James was considered an outstanding researcher working on a highly innovative idea in an area in which new understanding and treatments are urgently needed.
Glioblastoma is the most aggressive and lethal type of brain tumour. Despite many years of research, treatments developed in the laboratory have failed to improve patient outcomes and glioblastoma remains incurable. Only a quarter of patients survive more than a year from diagnosis, and just 5% survive five years.
The current treatment strategy includes surgery to ‘debulk’ the tumour, followed by radiotherapy and chemotherapy to destroy the remaining tumour. This prolongs survival but is not curative; the tumour always grows back.
New treatments are desperately needed.
Read more: About brain tumours
Recent advances in single-cell profiling and gene sequencing now allow us to study thousands of individual cancer cells from the same tumour, giving us a much clearer picture of how different they are and how they behave. If ‘epi-clonal evolution’ occurs, we would expect primary brain tumours to contain tiny groups of cells that are already resistant to treatment. During chemotherapy and radiotherapy, these resilient cells would survive while other more sensitive cancer cells die, slowly increasing in number until they dominate the recurrent tumour.
To test this idea, James and his colleagues will study tumour samples taken from both the first and the recurrent surgeries of glioblastoma patients. They will also treat tumour cells from primary tumours in the laboratory with the same types of chemotherapy and radiotherapy used in the clinic, and track how the cells’ characteristics change over time.
By comparing laboratory-treated cells with real recurrent tumours from the same patients, James and his colleagues aim to determine whether the changes they see truly reflect what happens inside the human brain.
Finally, they will identify existing medicines that are able to target treatment-resistant cells and test whether adding these medicines to standard therapy makes treatment more effective.
Dr James Nicholson was awarded his PhD in 2019 and has since been a post-doctoral researcher at Cornell University and QMUL.
His long-term ambition is to lead a translational research group that combines advanced brain tumour modelling with cutting-edge computational biology to understand how epigenetic variation drives disease progression and treatment resistance, especially in glioblastoma.
James’s mentor, Professor Silvia Marino, is an internationally recognised leader in brain tumour biology and precision medicine. As Director of the QMUL Brain Tumour Research Centre of Excellence, she leads a highly integrated programme spanning patient tissue, clinically annotated disease models, and translational pipelines focused on glioblastoma and therapy resistance.
This research will use cutting-edge technology to test a new explanation for why existing glioblastoma treatments fail. By identifying epigenetic states that allow tumour cells to survive therapy, this work could open new strategies for designing more effective, targeted treatment combinations.
In addition, this project will generate new computational tools for analysing single-cell epigenetic data, which will be made freely available to the research community.
Together, these outcomes have the potential to advance understanding of glioblastoma recurrence and support the development of better treatments for patients facing this devastating disease.
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