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

  • Full or part time
    Dr C Jones
    Dr O Rossanese
  • Application Deadline
    Sunday, November 17, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

The Institute of Cancer Research, London, is one of the world’s most influential cancer research institutes. We are committed to attracting and developing the best minds in the world to join us in our mission—to make the discoveries that defeat cancer.

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

Project Description:
We have identified distinct genetic alterations activating the MAPK pathway to be present in different subgroups of diffuse midline glioma (DMG) with H3K27M mutation. These mutations confer sensitivity to MEK inhibitors in our model systems. Such inhibitors are currently undergoing evaluation in phase II trials for children with low-grade gliomas, raising optimism for a therapeutic strategy that can be readily translated to DMGs. However, DMGs exhibit heterogeneity in the mechanisms through which the MAPK pathway is activated, including subclone mutations in the pathway and transcriptional processes, all of which can confer differential sensitivity of DIPG cells to MEK inhibition. Using state-of-the-art molecular barcoding techniques and high-throughput CRISPR-Cas9 screens applied to samples from a co-clinical trial of DMG, we aim to map the evolutionary dynamics of subclones harbouring these alterations in patients and patient-derived models, and to identify novel combination therapies to increase efficacy of MEK inhibition for future clinical trials. Specifically, we will first determine the frequency of such alterations and characterise novel patient-derived models of such tumours prospectively via a biopsy-stratified clinical trial. We will then use these models to test the prediction that DMGs harbor distinct populations of cells that are predetermined to exhibit tolerance to MEK inhibition through high complexity barcoding. Finally, we hypothesise that treatment of DMG cells with MEK-inhibitors will induce novel genetic dependencies that can be targeted in combination therapies, and we will leverage genome-scale CRISPR-Cas9 screens to identify such combinations for validation and clinical translation in this devasting disease.

Keywords /Subject Areas:
DIPG / midline glioma
Childhood brain tumours
CRISPR screening
Cancer evolution

Funding Notes

Students receive an annual stipend, currently £21,000 per annum, as well as having tuition fees (both UK/EU and overseas) and project costs paid for the four-year duration. We are open to applications from any eligible candidates and are committed to attracting and developing the best minds in the world.
See to apply
Applications close 11:55pm UK time on Sunday 17th November 2019
Candidates must have a first class or upper second class honours BSc Honours/MSc in a relevant biological science

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