Pancreatic Cancer Theme

At the CRUK Scotland Centre, we take on cancers that profoundly affect the people in Scotland – such as pancreatic cancer, currently ranked 5th for cancer mortalities. Within the next decade it is predicted to be the second most common cause of cancer deaths in Scotland and the UK.

While overall survival for most cancers has improved over the past 30 years, this has not been replicated for patients with pancreatic ductal adenocarcinoma (PDAC), where prognosis is mostly woeful and only 6-7% of patients survive five years from diagnosis. When most patients present, the tumour is not amenable for surgery, has spread to distant sites and chemotherapy has limited effects. Previous work from the CRUK Precision-Panc initiative and the Centre teams has identified subtypes within PDAC that are characterised by different transcriptional profiles. But how these subtypes relate to treatment response, and if this can be exploited for targeted therapeutics is not well understood.

Advance disease classification and develop new therapies

Over the next five years, we aim to understand the signalling networks between tumour and surrounding microenvironment, and how these might drive subtype development. Our overall ambition is to facilitate a platform – representative of human disease, encompassing multiple subtypes and stages of disease – for therapeutic testing. This, we approach through three strategic avenues:

At the Centre, we have considerable expertise in multi-omic studies and access to state-of-the-art technology and equipment. Through spatial proteomic and imaging analysis, we are developing a comprehensive molecular map of human pancreatic cancer samples (tumour and metastasis) which we aim to overlay with information on genomics, gene expression and the immune cell landscape. While boosting our understanding of the tumour microenvironment specific to pancreatic cancer, our target is to identify signatures that are linked to disease progression and that can form the basis for new treatment options.

Another focus is to advance pre-clinical models of pancreatic cancer, implementing new findings from the patient cohorts. We already layered additional mutations onto pancreas-specific models which are driven by Kras and p53. Within the next few years, we will develop the next-generation of models that will allow the induction of genetic alterations over time and tissue-space. This work is crucial to our agenda to model human disease accurately while simultaneously forming a key component for our pre-clinical testing pipeline.

We are also looking to model genetic variations of the KRAS oncogene. Our sequencing efforts on late stage patients have revealed the spectrum of KRAS mutations in these tumours, including the KRASG12R mutation which appears to have unique metabolic features. Partnering with the SPECIFICANCER Grand Challenge team, we will carry out tissue and mutation specific screens to identify targetable vulnerabilities within KRAS-mutant cancer whilst using pre-clinical models to drive forward proof-of-concept and functional interrogations of metabolic and transcriptional targets.

Theme Members