Molecular and pharmacological validation of rationally-designed combination treatments in pancreatic cancer

Pancreatic cancer is a leading cause of cancer-related death, with a 5-year survival rate that remains below 10%. Few therapeutic options are opened to patients beyond chemotherapy-based standard-of-care regimens. Despite extensive molecular characterization of this disease, the response of pancreatic tumours to recently proposed therapies remains underwhelming. A contributor to this is the suboptimal nature of approaches employed to identify clinically robust targets.

We are using a rational and robust sequential approach to identify and validate novel targets that demonstrate synergy with chemotherapeutics, in order to develop combination therapies that will significantly improve patient survival. Using a CRISPR-Cas9 screening approach combined with chemotherapy exposure on pancreatic cancer organoids, we have identified genes that appear essential for pancreatic cancer cells to survive treatment.

In this project, some of the identified candidates will be validated using gene-specific CRISPR-Cas9 invalidation and pharmacological inhibition, including in a mouse model of pancreatic cancer. Characterisation of the mechanism that underpin the role of these targets will also be performed using a combination of RNAseq, biochemical and imaging techniques. This project will thus contribute to the characterisation of new drug targets that most efficiently synergise with chemotherapy to eradicate pancreatic cancer cells, allowing the development of robust drug candidates to improve clinical outcome for patients with this disease.