Project Description
Glioblastoma (GBM) is the most common primary malignant brain tumour in adults and is associated with an extremely aggressive clinical course and poor prognosis. Recently, immune checkpoint inhibitors (ICPIs) targeting programmed cell death 1 receptor (PD-1) and its ligand (PD-L1) have been approved and licensed in multiple tumour types. Regrettably, for GBM patients only modest and unpredictable responses have been reported so far. This is most likely due to a relatively immune-depleted (“cold”) GBM microenvironment. However, recent findings have demonstrated that pronounced infiltration of pre-existing CD8+ cytotoxic T-lymphocytes (CTLs) into the tumour microenvironment (TME) can render GBM more responsive to ICPIs. Therefore, in a clinical context, a desirable outcome would be to restore the immunological environment of GBM to improve the response of these tumours to ICPIs. We hypothesise that targeting PI3K/AKT with brain penetrable inhibitor not only directly impact cancer cells but also has the capacity to affect immune cell effector functions and to modulate immune TME improving the efficacy of ICPIs. Furthermore, we postulate that PET imaging will non-invasively measure these changes. Last but not least, given previous reports demonstrating that apart from the tumour cell-intrinsic mechanisms that cause constitutive PI3K/AKT pathway activation, also factors secreted from CAFs can maintain this pathway, we will assess whether a transmembrane fibroblast activation protein (FAP) can affect the GBM cells sensitivity to PI3K/AKT inhibition. The role of FAP within the glioma microenvironment is still unclear. However, it has been recently revealed that subpopulations of GBM and stromal cells with mesenchymal features overexpress FAP. Now it is also well recognised that GBMs with mesenchymal features (FAP+) have elevated levels of PD-L1 and highest presence of TAM, CD8+, CD3+ and FOXP3+T cells, which suggests they may be more immunoreactive in nature, and therefore, more amenable to immunotherapy. However, little is known about the relationship between FAP+ mesenchymal GBM cells and PI3K/AKT signalling in this complex phenotype.
This PhD project aims to discover novel imaging biomarkers of GBM, which can be translated into the clinic for treatment management.
Objective 1. To investigate the response to PI3K/AKT inhibitors in combination with anti-PD-L1 mAbs in PTEN deficient and PTEN wild type GBM models (2D and 3D).
Objective 2. To assess by PET imaging whether PI3K/AKT inhibition in vivo modifies tumour TME toward promotion of an effective anti-cancer immune response.
Objective 3. To determine whether targeting PI3K/AKT signalling in combination with ICPIs in vivo enhance the immune cell infiltration prolonging the survival. To evaluate whether PET imaging biomarkers will quantitatively measure tumour response induced by these therapeutic intervention.
Keywords
- Glioblastoma (GBM)
- PET imaging
- PI3K/AKT inhibition
- Immuno-Oncology
- Immune Checkpoint Inhibitors
Links
Preclinical Molecular Imaging
Preclinical Molecular Imaging (@PETImagingICR) / Twitter
Candidate profile
Candidates must have a First class or Upper Second class BSc Honours/MSc in medicine or biological sciences.
How to apply
To view the full project proposal and details on how to apply using our online recruitment portal, please go to icr.ac.uk/phds. Please ensure that you read and follow the application instructions very carefully.
Please note we only accept applications via the online application system apply.icr.ac.uk.
Applications close at 11:55pm UK time on 14 November 2021.
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