Project ID iCASE2024_04_CM-HD


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer CentreWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer CentreWebsite

Additional Supervisor Dr Andrew Whale

Partner Immunocore Ltd

Developing a pre-clinical human pancreatic cancer model to test novel immunotherapies.

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

Representative Publications

1. Manuelli V, Cahill F, Wylie H, Gillett C, Correa I, Heck S, Rimmer A, Haire A, Van Hemelrijck M, Rudman S, Wells CM. (2022) Invadopodia play a role in prostate cancer progression. BMC Cancer. 22:386. doi: 10.1186/s12885-022-09424-4 Lizhou Xu, Farid N. Faruqu, Yau M. Lim, Kee 2. Y. Lim, Revadee Liam-Or, Adam A Walters, Paul Lavender, David Fear, Claire M. Wells, Julie Tzu-Wen Wang, and Khuloud T. Al-Jamal (2020) Exosome-mediated RNAi of PAK4 prolongs survival of pancreatic cancer mouse model after loco-regional treatment. Biomaterials 264: 120369
3. Anna Dart, Gary Box , William Court , Madeline Gale, John Brown, Sarah Pinder, Sue Eccles and Claire M Wells* (2015) PAK4 promotes kinase-independent stabilization of RhoU to modulate cell adhesion. J Cell Biol. 211:863-79. doi: 10.1083/jcb.20150107

1. Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial Verset, G., Borbath, I., Karwal, M., Verslype, C., Van Vlierberghe, H., Kardosh, A., Zagonel, V., Stal, P., Sarker, D., Palmer, D. H., Vogel, A., Edeline, J., Cattan, S., Kudo, M., Cheng, A. L., Ogasawara, S., Daniele, B., Chan, S. L., Knox, J. J., Qin, S., & 6 others, 15 Jun 2022, In: Clinical Cancer Research. 28, 12, p. 2547-2554
2. Upregulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and patients with cancer Hashimoto, A., Sarker, D., Reebye, V., Jarvis, S., Sodergren, M. H., Kossenkov, A., Sanseviero, E., Raulf, N., Vasara, J., Andrikakou, P., Meyer, T., Huang, K. W., Plummer, R., Chee, C. E., Spalding, D., Pai, M., Khan, S., Pinato, D. J., Sharma, R., Basu, B., & 11 others, 15 Nov 2021, In: Clinical Cancer Research. 27, 21, p. 5961-5978
3. A phase I, open-label, dose-finding study of GSK2636771, a PI3Kb inhibitor, administered with enzalutamide in patients with metastatic castration-resistant prostate cancer Sarker, D., Dawson, N. A., Aparicio, A. M., Dorff, T. B., Pantuck, A. J., Vaishampayan, U. N., Henson, L., Vasist, L., Roy-Ghanta, S., Gorczyca, M., York, W., Ganji, G., Tolson, J. & de Bono, J. S., 1 Oct 2021, In: Clinical Cancer Research. 27, 19, p. 5248-5257