Defining the Functions of EGFR Variants in Glioblastoma Heterogeneity

Primary Supervisor: Paulo Ribeiro, Queen Mary University of London

Secondary supervisor: Alex Gould, Francis Crick Institute

Project

Glioblastoma is a common and aggressive brain tumour, which has a very poor prognosis, in part due to high tumour heterogeneity and nearly complete recurrence with chemotherapy-resistant disease. Glioblastoma primary treatment includes surgery and chemotherapy with the current standard of care drug, temozolomide. However, virtually all glioblastoma patients develop recurrent tumours that are resistant to temozolomide, which contributes to a dismally low 5-year survival of ~5%. Epidermal Growth Factor Receptor (EGFR) is commonly amplified or mutated in cancer but, in glioblastoma, displays variants that are uncommon in other cancer types. The importance of EGFR in glioblastoma is reflected by the fact that 40-60% of patients carry EGFR amplification or mutations. These EGFR variants can often co-occur in a single tumour and dramatically influence resistance to chemotherapy. However, it is challenging to study their functional effect in vivo, due to a lack of adequate models. Despite the prevalence of EGFR alterations and the existence of efficient therapies, to date, attempts at targeting EGFR in glioblastoma have been largely unsuccessful and the reasons for this failure remain unclear. Therefore, a better knowledge of how different EGFR mutations influence glioblastoma tumour growth in the context of tumour heterogeneity will provide new avenues to targeting EGFR in glioblastoma.

This project aims to define the functional role of EGFR variants in the development and progression of glioblastoma in the context of tumour heterogeneity. For this, we will combine our newly generated genetic systems to create and study tumour heterogeneity with in vivo and in vitro models of glioblastoma, including the fruit fly Drosophila and mammalian 3D culture models. Firstly, we will generate genetic models that allow us to create cell populations carrying different combinations of EGFR variants. Then, we will characterise the effect of specific combinations of EGFR variants on tumour development and progression using in vivo fly models and mammalian models. Moreover, we will characterise the downstream signalling and determine if specific variants elicit distinct responses. Our experimental approaches will rely on the use of sophisticated imaging systems to monitor tumour behaviours in vivo and in vitro, which will form the basis for the development of a computational model to describe tumour development and the contribution of each EGFR variant to tumour growth and progression. We will reveal mechanisms underlying the impact of EGFR heterogeneity in glioblastoma that will aid the development of future therapies.

Candidate background

The project is a collaboration between laboratories in the Barts Cancer Institute and The Francis Crick Institute and involves a multi-disciplinary approach to study the functional role of EGFR mutations in glioblastoma. Both Barts Cancer Institute and The Francis Crick Institute have state-of-the-art equipment and all the conditions to develop this project. Extensive training opportunities are available in both sites. We seek highly motivated prospective students, who should have a degree in cell and molecular biology or related subject (minimum degree of a 2:1). Previous experience of working with Drosophila and/or mammalian 3D models is not essential but would be advantageous.

Potential Research Placements

1. Alex Gould, Francis Crick Institute
2. Kurt Anderson, Advanced Light Microscopy Science Technology Platform, Francis Crick Institute
3. Richard Grose, Barts Cancer Institute, Queen Mary University of London

References

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5. Furnari et al. Nat Rev Cancer 2015; 15:302-10.