Investigating transcription factors in development

Fast facts

• Official title: Alterations of oncogenic transcription factors as therapeutic targets in paediatric gliomas
• Lead researchers: Dr Rameen Beroukhim; Professor Chris Jones
• Where: Dana-Farber Cancer Institute, Boston, USA; The Institute of Cancer Research, London, UK
• When: January 2021 – December 2025
• Cost: £1,444,811 over five years
• Research type: Paediatric, High and Low grade, Academic
• Award type: Quest for Cures

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What is it?

Gliomas are the most common group of brain tumours in childhood. Researchers believe that childhood cancers are caused when mistakes happen in the normal programmes of development. This is especially so for gliomas, which are often characterised by mutations in a group of proteins called transcription factors. Transcription factors have important roles in the regulation of normal brain development.

In this project, Dr Beroukhim and his team at the Dana-Farber Cancer Institute, along with Prof. Chris Jones at The Institute of Cancer Research, will investigate how, in children’s brain tumours, two specific transcription factors switch on developmental pathways that would normally be switched off. They will also determine how to switch off these transcription factors using new treatments.

Additionally, Dr Beroukhim and Professor Jones are collaborating with other leading researchers to develop new drugs that can specifically destroy these transcription factors as another way to treat paediatric gliomas.

This collaboration brings together investigators with diverse areas of expertise, including glioma and developmental biology, genomics and epigenomics and chemistry. They will use sophisticated model systems of paediatric gliomas to understand how mutations in transcription factors affect developmental pathways. The researchers will also use genetic and epigenetic methods to understand how these changes affect the other regulatory structures of cells, and the team’s chemists will develop strategies to degrade these proteins as a way to therapeutically ‘switch them off’.

Our goal is to perform true bench-bedside-bench research, translating research findings into the clinical trials arena, while in turn, leveraging clinical trial experiences (and samples collected on the trials) to inform our basic science research.

Dr Rameen Beroukhim

Why is it important?

Brain tumours are the leading cause of cancer-related morbidity and death in childhood. While children with low grade gliomas are more likely to survive, they can be left devastated by both the tumours themselves and the treatments required to cure them. Children diagnosed with high grade gliomas face a fight for life, with a dismal prognosis. Better treatments for all gliomas are desperately required. This research will be directed to understanding how cancers hijack normal developmental processes and how this can be targeted in new treatments for children diagnosed with gliomas.

Who will it help?

This work is driving us towards a future where children diagnosed with a brain tumour, regardless of grade, have more effective, less harmful treatments available.

Milestones

• By creating models of tumours in the lab and preclinical models, the team have investigated two families of transcription factors known as MYB and PLAG.
• Their research has highlighted the important role that the family of PLAG proteins play in the formation of brain tumours in children. This discovery will help focus their research to investigate ways to counter the effects of these PLAG proteins to help prevent tumour growth.
• For some specific proteins within the MYB family, they have successfully identified genes that seem to be crucial for the growth of cells with those proteins. This means they have identified new potential targets for treatments to be developed that can kill the tumour cells without hurting healthy cells. They are now performing similar work for the PLAG proteins.