Title: Systems Oncology
Funder: Cancer Research UK

Abstract: Pancreatic cancer, and specifically Pancreatic Ductal Adenocarcinoma (PDA), is a dismal disease with a median survival below six months and an average five-year survival rate below 5%. This is due to the aggressive nature of the cancer, a lack of effective therapy as well as late diagnosis. Consequently, while PDA is only the 11th most common occurring cancer in the UK, it is currently the 4th largest contributor to cancer related deaths. The most frequent occurring genetic mutations have been identified with activating mutations in the oncogene KRAS and inactivation of the tumour suppressor CDKN2A in more than 90% of all cases and loss of SMAD4 and TP53 function occurring in 55% and 85% of all cases respectively. Treatments targeting tumour cell dependencies on these mutations are not currently available in the clinic. Less frequent mutations can be grouped according to the deregulated pathways, where DNA repair mechanisms are inactive in ~20% of all PDA. This offers novel ways to treat PDA in the clinic, some of which will be tested through the PRECISION-Panc framework. A hallmark of PDA is an extensive stromal infiltrate that makes up 80% of the tumour volume. This desmoplastic reaction consists of a pathological remodelled extracellular matrix and influx of fibroblasts and immune cells. The microenvironment has been shown to contribute to therapeutic resistance, immune tolerance and tumour progression. Importantly, very little is still known about the mechanisms whereby the tumour cells co-opt hosts cells to establish this hostile environment. Delineating these mechanisms is therefore important and may lead to the identification of novel therapeutic targets in both the tumour and stromal cells. In order to define interdependencies between tumour and stromal cells it is critical to map the cellular and extracellular component in the microenvironment. We have therefore started tocatalogue, isolate and characterise individual stromal elements (including both cellular and extracellular components). The critical aim of these analyses is to determine whether individual stromal cell populations (or extracellular matrix components) differentially alter the tumour cell phenotype and whether this results in a differential sensitivity to therapy. Using a combination of proteomics and transcriptomics analyses we are defining the key pathways regulating tumour cell resistance. In parallel we are identifying targetable pathways in the tumour stroma and optimising their use for combination therapy. We are currently working closely with the Drug Discovery Unit at CRUK Manchester Institute, directed by Professor Caroline Springer, to develop this further. In an effort to improve treatment options and patient selection in PDA, we are involved in establishing a national infrastructure where individual tumours are subjected to molecular profiling such that patients can be matched with selected treatments (PRECISION-Panc). These clinical trials are underpinned by the development of biomarkers and preclinical research to further refine treatment strategies targeting specific dependencies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS