Targeting SRC in childhood glioma

Fast facts

• Official title: Targeting SRC as a driver for CNS Group 4 Medulloblastoma and glioma
• Lead researcher: Professor Louis Chesler
• Where: The Institute of Cancer Research, London, UK
• When: December 2020 – January 2025
  
• Cost: £1,430,968 over five years
• Research type: Paediatric, High grade, Academic, Medulloblastoma, Glioma
• Award type: Quest for Cures

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Inside cells are complex communication networks that involve hundreds of proteins that interact with each other to relay messages and make cells behave in a certain way. Discovering a link between SRC activation and Group 4 medulloblastomas (MBs) and glioma is a major breakthrough in the field, and highlights a potential opportunity to disrupt the communication network that’s telling these tumours to grow. However, blocking the activity of a single protein in the network rarely stops tumours in their tracks (although it may slow them down), as they quickly find ways to reroute the message.

What is it?

Many of the complex events that underlie the development of brain tumours are ‘invisible’ if you only look at the genetic (DNA) makeup of tumour cells. Recently, Professor Louis Chesler and his team from The Institute of Cancer Research in London, used a technology called ‘proteomics’ to directly measure thousands of cancer proteins (which are the targets of cancer drugs) in brain tumours. They discovered changes in a cancer protein called SRC that appears to drive the formation of Group 4 MBs and gliomas in preclinical brain tumour models.

Professor Chesler and his team aim to build on this work to understand the role SRC plays in the development of aggressive MB and glioma in more detail, and to test whether or not blocking SRC activity can halt the growth of these tumours.

Understanding how tumour cells work

Together with colleagues from Paris, Toronto and Dusseldorf, Professor Chesler will perform multi-omic analysis (which means looking at the activity inside cells at multiple levels i.e. from DNA to RNA and proteins) on Group 4 MBs from over 110 children. They have already started to analyse a small number of tumours, and have been able to measure 8000 – 9000 proteins for each one.

Looking at protein interactions
They will elaborate on this by investigating which proteins SRC interacts with and how those interactions drive tumour development. By doing this, the team aims to identify additional proteins that could potentially be targeted with drugs to block tumour growth.

Making new lab models
Current brain tumour research is hindered because there are very few laboratory models that accurately represent the disease in humans. These models are essential for properly assessing potential new drugs before they progress to clinical trials.

Professor Chesler and his team will use the information they gather about how SRC and other proteins drive tumour growth, to develop accurate preclinical models of SRC-driven Group 4 MB and glioma. Advanced preclinical drug trials, using these sophisticated models, will incorporate surgery, imaging and other treatments, similar to the treatment pathway in children.

Testing SRC drugs
Finally, the team have access to a drug that has been developed to block SRC activity and has been shown to cross the blood brain barrier. They will use their complex models to test this drug alongside other drugs designed to disrupt other parts of the SRC communication network. In this way the researchers aim to get enough evidence to test 1-3 new potential treatments in clinical trials.

A substantial cross-disciplinary effort is required to advance knowledge of the molecular dependencies of MB and to translate them to clinical benefit. This programme will not only aim to improve fundamental knowledge of the cellular origins of MB and the signalling pathways that sustain MB development but identify clinically relevant treatment approaches.

Professor Louis Chesler

Why is it important?

Medulloblastoma is the most common aggressive primary brain tumour occurring in children. While advances in genetic technologies have improved the accuracy of clinical diagnosis, they’ve failed to identify new treatments, meaning increases in survival have stalled.

Four different molecular subgroups of MB have been identified – SHH, Wnt, Group 3 and Group 4. Group 4 is the largest but also the least biologically understood subgroup – researchers don’t yet know which cells within the brain change and become tumour cells, or fully understand the specific changes that happen in those cells to trigger tumour growth in the first place. This information is critical for developing new and targeted drugs for children with this type of tumour.

Who will it help?

This programme of work aims to increase the depth and breadth of our knowledge of children’s MB. At a minimum it will offer up new areas of investigation for Group 4 MB, but, along with the researchers, we hope it will be the starting point for new, better treatments for children with medulloblastomas in the future.

Milestones

• Completed analysis of SRC protein in 200 medulloblastoma samples and confirmed it is present in children with aggressive brain tumours.
• The team have developed new cell lines and pre-clinical models for Group 4 medulloblastoma. In particular, the new patient-derived model of Group 4 medulloblastoma could offer the potential for use in pre-clinical trials.
• The experiments have indicated the potential origins of SRC-driven medulloblastoma and will explore this further.
• The team have seen promising early results in multiple different models with a dTAG they have developed, which is a molecule that degrades the SRC protein.