Dr Lucy Oldfield MSc., PhD., AFHEA

Aim
To identify protein biomarkers that distinguish type 3c diabetes (which includes PDACassociated) from type 2 diabetes, paving the way for the development of diagnostic tools capable of selecting individuals for PDAC screening at the point of diagnosis of diabetes.

We are undertaking the deepest interrogation of the human plasma proteome for biomarkers of PDAC to-date. Using a state-of-the-art aptamer-based platform (SOMAscan) we will measure ~7,000 proteins in individual plasma samples from disease groups selected to address early diagnosis of PDAC in NOD. SOMAscan’s deep-multiplexing will reveal differentially expressed proteins and enable pathway analysis which will inform candidate
selection. We will validate the three best-performing candidates in an independent cohort, providing proof of concept of the process and generating the requisite data for future application of candidates and/or the SOMAscan platform to pre-diagnostic cohorts of NOD individuals.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common cancer (five-year survival is 5-7%). For ~80% of patients, PDAC is detected after disease spread, limiting treatment options. At the time of diagnosis, ~65% of PDAC patients have diabetes mellitus (DM). In ~15% of cases, DM is longstanding, however for >50% of PDAC patients DM is new–onset, with the DM diagnosis coming, on average, 13 months prior to PDAC being identified. Thus, new-onset DM (NOD) is an early warning sign of the presence of PDAC, and individuals with NOD are the largest high-risk group for PDAC. Approximately 1% of adults diagnosed with type 2 DM (T2DM) actually have PDAC-associated DM, a form of type3c DM (T3cDM). The scientific/medical community currently cannot distinguish PDAC-associated DM from T2DM and individuals with NOD are not screened. The US Consortium of Chronic Pancreatitis, Diabetes and Pancreatic Cancer is launching a collection of individuals with NOD. Similar initiatives in Europe are underway. Additional contributions are required; a UK component of the international NOD cohort will ensure that future biomarker-driven screening is relevant to the UK population/healthcare system, and will increase national awareness of the link between NOD and PDAC.

With programme funding from Cancer Research UK, the aim of our work at Liverpool is to develop a diagnostic test for use in individuals newly diagnosed with DM which will identify those most at risk of a diagnosis of PDAC, allowing them to be screened.

Individuals >50 years, newly diagnosed with DM are being recruited (target 2,500) from UK hospitals and general practice. Biosamples and questionnaire/clinical data are being collected to GCP and standardised to US and European collections. While recruitment is ongoing, further biomarker development for the high-risk NOD group is being undertaken. The specificity of biomarkers with potential to distinguish T3cDM (which harbours PDAC-associated DM) from T2DM will be tested in existing high-risk cohorts, including a pilot-scale collection of individuals with NOD (PANDIA) and the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). Protocols for biomarker discovery using NOD will be developed/refined. The sensitivity/specificity for the detection of PDAC by combined biomarker and epidemiological/clinical feature analysis will be evaluated in the international NOD cohort. The cost-effectiveness of diagnosing PDAC earlier will be assessed. UK-NOD samples will be made available for research on early PDAC detection.

It is anticipated that our work will enable stratification of individuals with new-onset DM for PDAC risk, making it feasible in future to screen for PDAC in individuals with new-onset DM.