Getting ahead of drug resistance in diffuse midline glioma (including diffuse intrinsic pontine glioma)

Diffuse Midline Gliomas (DMGs) are aggressive childhood brain tumours, which include diffuse intrinsic pontine gliomas (DIPG). There is currently no cure. A class of cancer drugs, called MEK inhibitors, have shown early promise in treating some DMGs but there is a risk that these tumours could develop resistance to these drugs. Prof. Chris Jones and his team aim to work out the mechanisms by which DMG cells become resistant to MEK inhibitors and come up with new combination treatments to overcome this.

Project Details

  • Project Title

    Evolutionary dynamics of MEK inhibitor sensitivity and resistance in diffuse midline glioma

  • Lead Researcher

    Prof. Chris Jones

  • Research Centre

    Institute of Cancer Research

  • City & Institution Postcode

    Sutton, SM2 5NG

  • Start Date

    1 April 2021

  • Duration

    30 months

  • Grant Amount

    £349,393

Chris Jones pic

Overview

Diffuse Midline Gliomas (DMGs) are aggressive childhood brain tumours, which include diffuse intrinsic pontine gliomas (DIPG). There is currently no cure and effective treatments are desperately needed.

A class of cancer drugs, called MEK inhibitors, are currently being tested in children with low-grade gliomas, raising optimism for a therapeutic strategy that can be readily translated to DMGs. Prof. Chris Jones and his team have developed laboratory models of DMGs using cells taken from patients with these tumours and found that MEK inhibitors may act as effective treatments in some cases. However, MEK inhibitors have been found to have limitations when used to treat other types of cancer. In other tumours, MEK inhibitors can quickly stop working as the cancerous cells develop resistance by a variety of mechanisms. To date, this has not been explored in DMG.

Prof. Jones and his team aim to work out the mechanisms by which DMG cells become resistant to MEK inhibitors and come up with new combinations treatments to overcome this. They have unique resources of patient DMG tumour samples from their ongoing BIOMEDE clinical trial in children and young people. These tumour samples show markers of sensitivity to MEK inhibitors and have then been cultured to act as laboratory models of the disease for this study. These models will be used in cutting-edge techniques to mark individual cells with a genetic ‘barcode’ which will allow Prof. Jones and his team to track them over time. They will treat the cells with MEK inhibitors and find out which ones survive the drug, and how they have managed to become resistant to the drug. They will then look for these mechanisms in the original clinical samples.

Prof. Jones and his team will also carry out large-scale drug-treatment experiments where they ‘delete’ every gene present in the tumour cells one-by-one and find out which combination of drug and gene ‘knock-outs’ causes the cells to die. From these ‘hits’ they will develop combined drug treatments to test in the laboratory models, and hopefully overcome the resistance than can develop when using MEK inhibitors alone.

Potential impact

DMGs are currently incurable. Although Prof. Jones and his team have identified a potential novel treatment, it is highly likely the tumour cells will become resistant, and the gliomas will grow back. Rather than wait for this to happen over many years in clinical trials, they want to work out how this will happen in advance, so that they can instead test sensible combination treatments in these patients.

About the research team

Prof. Chris Jones, based at the Institute of Cancer Research, is the UK biology lead of the BIOMEDE clinical trial, which is testing targeted therapies for children and young people with DMG (DIPG). He has developed laboratory models from tumour samples taken from patients in this trial and identified the possible use of MEK inhibitors in some of these tumours. He is an expert in the molecular analysis of these kinds of childhood brain tumours and has considerable experience in testing new drugs in the laboratory.

Prof. Jones will be working with Dr Pratiti Bandopadhayay, who is based at the Dana-Farber Cancer Institute at Harvard University. She has developed cutting-edge screening techniques that allow for large-scale, high-throughput analysis to identify individual cancer cells which evade drug treatment, as well as genetic deletion screens. Dr Bandopadhayay has applied these techniques successfully to other brain tumour types and is an expert in childhood brain tumour biology.

This project joins up the world-leading academic drug development expertise at the ICR in London and the unparalleled cancer biology facilities at the Dana-Farber in Boston.

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