Background: Pancreatic cancer is one of the most lethal cancers in humans. There is a high unmet medical need to develop new therapies for the treatment of this disease. Drugs which engage the immune system (immunotherapies) have shown a survival benefit in lung cancers and melanoma, but there remains no approved immunotherapy for the treatment of pancreatic cancer. Developing preclinical models of pancreatic cancer, particularly fully human models that can replicate the interactions between cancer cells, stromal cells and the immune system has the potential to aid understanding of the biological mechanisms that propagate pancreatic cancer as well as support the development of candidate drugs more likely to provide an overall survival benefit to patients.
Aim: To develop methods for the co-culture of patient derived pancreatic organoids and human immune cells for use in drug sensitivity testing. Identify optimal combinations of drugs that result in tumour cell death.
Year 1 objective: Characterisation of pancreatic organoids. Culture pancreatic organoids for in depth analysis. Profiling using qPCR, flow cytometry, fluorescence microscopy and western blot to identify biomarkers that are predictive of sensitivity to candidate drugs for example, PAK, KRAS, PI3K and define HLA type.
Skills in molecular biology and cell biology.
Year 2 objective: (First 3 months at Immunocore) Establish methods to co-culture pancreatic organoids with immune cells. T cell activation and tumour cell killing of pancreatic organoids cocultured with T cells will be measured using Immunocore’s established assays. Expand work to include live cell /multiplex immunofluorescence imaging.
Skills in cell biology, microscopy, pharmacology & cell-based assays.
Year 3 objective: Test best combination of Immunocore specific T- cell treatments inhibition of PAK/KRAS signalling pathway to deliver pancreatic organoid cell death.
Skills: pharmacology, high resolution Imaging and cell biology
Year 3.5 – 4 Complete outstanding experiments, Write thesis, prepare paper for publication