Blocking hypersensitive Glioblastoma growth

Fast facts

• Official title: Preventing activation of EGFR in glioblastoma
• Lead researcher: Dr Pim French
• Where: Erasmus Medical Centre, Netherlands
• When: January 2021 – December 2022
• Cost: £199,792 over two years
• Research type: Adult, High Grade, Academic
• Award type: Expanding theories

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What is it?

Dr Pim French and his team at the Erasmus Medical Centre are taking testing a new way to stop the growth of glioblastomas (GBMs) that have specific changes in a protein called epidermal growth factor receptor (EGFR).

Receptors, like EGFR, act like the first domino in a set; if you hit it, a cascade of effects will follow through activation of other proteins within a cell. The effects of the EGFR cascade can be: increased cell proliferation (growth), cell migration (movement within the brain) or cell survival.

In healthy brain cells, EGFR is activated when the right naturally-occurring chemicals initiate the cascade. In brain tumour cells EGFR can have a number of variants/mutations that mean it’s more easily activated than normal, or even that it’s permanently activated.

The focus of this work is a particular type of EGFR variant, those with substitution mutations. This is where just one small change in the DNA code of the EGFR changes how it behaves. The researchers have early data that these variants may be ‘hypersensitive’ i.e. activate more easily than normal EGFR.

The three ways that this project will investigate this hypersensitivity are to ask:

1. Which EGFR variants are activated most easily?

• The team will use a technique called CRISPR to create the most common mutations in cells grown within laboratories. They will then assess how easy each variant is to activate.

2.Does the type of EGFR variant in a GBM change between diagnosis and any recurrence?

• Using data from a large clinical trial, the researchers will compare 180 paired GMB samples collected at first occurrence and at recurrence. They will look for any changes in the EGFR variants, and the chemicals that activate them.

3.Can the growth of tumour cells in a lab be slowed/stopped by preventing EGFR activation?

• Tumour cells grown in laboratories will be used to test whether drugs, called monoclonal antibodies, can block the mutant EGFRs to stop activation, and hopefully to stop cell growth.

If positive, our research can lead to a much needed novel treatment option for patients.

Dr Pim French

Why is it important?

Because of the success of drugs against the EGFR vIII mutation in lung cancer, there’s been a lot of research into GBMs with EGFR vIII mutations. Unfortunately, these drugs don’t work the same way in brain tumours, so a new approach is needed.

That’s why this study is so important. It’s redirecting efforts to confirm how distinct EGFR mutations are driving brain tumours, as well as working to see how they can be targeted for new treatments.

Who will it help?

According to the researchers about 24% of GBMs have variants of EGFR that may be hypersensitive to activation. This project aims to provide more evidence of this hypersensitivity, and we hope it will lead to new research towards a cure for GBM.

Milestones

• Experiments to date have shown that some specific EGFR mutations make the receptor more sensitive (easier to activate).
• Analysis of data on primary and recurrent glioblastoma samples indicates that the types of cell in a tumour changes when progresses compared to when first diagnosed. The team are examining the consequences of these changes of EGFR expression.
• They have seen that withdrawal of EGFR activators doesn’t affect the ability of tumour cells to live, but that it does change where in the cell the EGFR receptors are located.
• Next steps:
• The focus for the next 12 months is to further analyse the changes of EGFR and its activators over time. This is done to model the EGFR changes in glioblastomas.
• In addition, the team will continue to examine the role of EGFR activation and its corresponding effects in glioblastoma cells from human tumours. Ultimately these data will indicate whether stopping EGFR activation (and by which means) is a valid treatment option for glioblastomas.