Investigating the role of epigenetic remodelling in glioblastoma in response to therapy

Glioblastoma (GBM) is the most common and most deadly form of brain cancer. GBM tumours are solid but many of the cancer cells break away and invade the surrounding normal brain tissue, making complete surgical removal impossible. After surgery, patients commonly receive radio- and chemo-therapy but GBM tumours typically grow back within 6 to 9 months and are fatal. This is why brain tumours kill more people aged under 40 than any other cancer. New drugs that were developed to target the DNA mutations that are commonly found in GBM tumours have failed to increase patient survival. It is now thought that this is because, although such mutations may have caused the tumour to form, they are not responsible for its continued growth and ability to resist treatment. To specifically identify what properties of GBM cancer cells do enable them to resist treatment, I have collected, characterised and compared paired GBM tumours from multiple patients i.e. the first tumour that was diagnosed and removed and the post-treatment recurrent tumour from cases where the latter also underwent surgery. I have found that a specific set of genes are universally altered in GBM by treatment, but whether they become more switched on or more switched off after therapy is patient dependent and enables them to be split into two classes. I will determine whether assignment to one class versus another alters the likely survival for GBM patients or can be used to better predict the likely benefit of treatment with one type of therapy versus another. Furthermore, if the changes that I have observed in the specific genes are actually required by the GBM cells in order for them to survive treatment, then developing drugs to inhibit the changes may provide a more effective treatment for GBM. I plan to use my fellowship to test just that. I will use both computational analysis of patient datasets to reveal the biology underpinning the observed gene changes and further profiling of GBM tumour pairs to confirm whether the changes are driven by a single master regulator protein. I will then grow GBM tumours in the laboratory and use experimental approaches to stop them being able to undergo the observed changes, before administering the same radio- and chemo-therapy that patients receive to see if more cells die versus tumours where the changes are allowed to take place. Finally, I will determine whether drugs can be adapted or developed that restrict the gene changes in patients, making their GBM tumours more susceptible to killing as part of more effective treatment strategies.