Research

Research

Pancreatic ductal adenocarcinoma (PDAC) has been deemed a ‘silent killer’, as it is asymptomatic at an early stage; more than 80% of patients therefore present with already disseminated disease, when curative surgery is not possible any more. Current treatments for such patients are largely inefficient, and their median survival is only 3-6 months. Overall five-year survival for pancreatic cancer patients is less than 5%.

We have therefore set ourselves a goal of making a difference for pancreatic cancer patients by developing a non-invasive test for early detection of PDAC. This is based on a thorough understanding of developmental biology of this malignancy, stemming from analysis of the most common precursor lesions, PanINs, as a key source of potential early disease markers (PLOS One, 2013).

In addition, we performed an in-depth proteomics analysis of easily obtainable biofluid, urine (Proteom Clin Appl, 2008), and described a panel of three protein biomarkers that can detect stage I-II PDAC with >90% accuracy (Clin Cancer Res, 2015).

See video for more info here

We have subsequently further validated this urinary biomarker panel in additional retrospectively collected samples (PLoS Medicine, 2020), and developed a PancRISK score (BCJ, 2020) which enables us to stratify the patients into having a high or an average risk of developing PDAC (BCJ, 2020). Recently, we have also shown that our biomarker panel can detect PDAC up to two years before clinical diagnosis (IJC, 2023).

With funding support from Pancreatic Cancer Research Fund (PCRF), we are now running UroPanc study (https://www.pcrf.org.uk/uropanc-study/), a large observational trial. The aim of this trial is to establish the accuracy of our biomarker panel and the affiliated PancRISK in two cohorts at risk of developing pancreatic cancer: individuals with hereditary predisposition to pancreatic cancer (familial history and genetic syndromes), and patients with vague, but suggestive of pancreatic cancer, symptoms. If the urine test proves to be able to accurately stratify the patients, it would be implemented into a ‘new’, improved diagnostic pathway for pancreatic cancer patients. In addition and importantly, within the UroPanc we will also assess the economic and social impact of the test.

Highly accurate, non-invasive test for early detection of PDAC, we believe, will make a true impact on currently exceptionally poor prognosis of pancreatic cancer patients.

See video for more info here

We are now working towards developing and manufacturing of a standardised, clinical-grade kit that will be submitted for CE-marking before it can be ready for real time application for the benefit of patients at risk for developing pancreatic cancer.

In addition to proteins, we have also interrogated urinary ctDNA for mutation detection, profiled urinary miRNAs (Am J Cancer Res, 2015), volatile organic compounds (Gastroenterology, 2018; Talanta, 2021), as well as metal elements in urine (Metallomics, 2020), demonstrating the utility of urine as an excellent completely non-invasive biofluid source for an array of different biomarkers.

In addition to biomarker work, we are also interested in understanding of the roles in pancreatic cancer of additional proteins, AGR2 and S100P, as well and S100P- binding partner S100PBP, which we discovered in our laboratory. Both AGR2 and S100P are highly expressed in PanINs, primary PDACs and metastatic lesions, and also facilitate dissemination of pancreatic cancer cells both in vitro and in vivo (J Pathol 2003; Cancer Res, 2007; Cancer Res, 2011; Clin Exp Metastasis, 2013; Oncogene, 2017, Am J Ca Res, 2021), and are therefore potentially promising therapeutic targets. Our recent study demonstrates that S100PBP is regulated by mutated KRAS and plays a tumour suppressor role in pancreatic cancer (Oncogene, 2023).

Finally, we are also studying EOPC - early onset pancreatic cancer, in order to decipher why this subgroup of patients is developing PDAC when they are around 20 years younger than the typical, aged PDAC patient population. We started with EOPC epidemiology (BMC Gastroenterology, 2018) and have recently completed the mutational profiling of primary and matched metastatic EOPC samples (Molecular Oncology, 2024).

Finally, we are continuing to explore further potential biomarkers to complement our urinary proteins. We have recently evaluated C-reactive protein (CRP) in samples of PDAC patients and demonstrated feasibility of measuring this traditional blood biomarker also in urine (Frontiers in Oncology, 2024).

Patents

1. Patent Number: GB1501930.0: covers anti-SPAG1 antibody that was raised and validated in collaboration with CR-UK. It has now been commercialised by Cancer Research Technology Limited, UK.
2. A worldwide patent (WO2005062055A2 with Prof N. Lemoine) titled: “Methods for detecting neoplasia and markers thereof”. This patent is based on three proteins (S100P, AGR2 and SPAG1) that can aid diagnosis of pancreatic cancer in tissue biopsies/cytology material.
3. Patent (No 10001596.5 – 2404/ US 2013/0045884) with Dr C. Schroder and Prof J. Hoheisel, from University of Heidelberg, Germany: “Means and methods for diagnosing pancreatic cancer”. This patent is based on nconstruction and testing of the antibody array. Dr Schroder is now a CEO of spin out company Sciomics.
4. The PCT application “PCT/GB2016/050277: Biomarkers for pancreatic cancer” was published on 11th August 2016. In July 2017, the patent was filed within Europe and US and in additional 12 countries (Australia, Brazil, Canada, Chile, China, Israel, Japan, Europe, Korea, Mexico, New Zealand and Singapore).
5. ROC Patent I643869, 2018 on “The Preparation Methods of Molecularly Imprinted Materials” with Profs Hung-Yin Lin and Mei-Hwa Lee, National University of Kaohsiung (NUK), Kaohsiung, Taiwan. The patent is based on the construction of molecularly imprinted polymer for REG1 that will enable design of biosensor for detection of this protein in urine.

Other Activities

• Module Lead for Genomic Approaches to Cancer (Masters courses, BCI, Queen Mary University of London)

Member of:

• Pathological Society of Great Britain and Ireland
• British and European Association of Cancer Research (BACR and EACR)
• American Association of Cancer Research (AACR)
• American Pancreatic Association (APA)
• EU Pancreas COST Action
• Pancreatic Cancer Europe

Major Funding

• 2019-2026 - Barts Charity, Screening and Early Diagnosis (with S. Duffy N Lemoine, H Kocher), £1,5M
• 2019-2026 -Pancreatic Cancer Research Fund, UroPanc trial, £1,59M
• 2018-2020 - Cancer Research UK, Evaluation of Early Pancreatic Cancer Biomarkers in pre-diagnostic urine specimens, £235,000
• 2018-2020 - Pancreatic Cancer Research Fund, KRAS Mutations in urinary cfDNA in pancreatic cancer patients, £95,704.69
• 2010-2016 - CRUK (with N Lemoine and C Clhelala), Molecular Pathology and Genomics of pancreatic cancer: £1,2M
• 2009-2013 - Pancreatic Cancer Research Fund, Non-invasive diagnosis of pancreatic Cancer, £280,000
• 2007-2012 - Pancreatic Cancer Research Fund, A role of S100PBP in pancreatic cancer, £98,000

Recent Publications

Analysis of urinary potassium isotopes and association with pancreatic health: healthy, diabetic and cancerous states Schilling K, Chen H, Glabonjat RA et al. Frontiers in Endocrinology 15(10) 1332895

Molecular characteristics of early‐onset pancreatic ductal adenocarcinoma Debernardi S, Liszka L, Ntala C et al. Molecular Oncology (2024) 18(10) 677-690

Complement system genetic variability shapes pancreatic cancer risk Langtry A, Rabadan R, Alonso L et al. Pancreatology (2023) 23(10) e28-e29

The protective effect of atopic diseases against pancreatic cancer is not driven by Th2-biomarkers He J, Alhamwe BA, Sabroso S et al. Pancreatology (2023) 23(10) e143-e144

S100PBP is regulated by mutated KRAS and plays a tumour suppressor role in pancreatic cancer Srivastava K, Lines KE, Jach D et al. Oncogene (2023) 42(10) 3422-3434

Nutraceuticals as Supportive Therapeutic Agents in Diabetes and Pancreatic Ductal Adenocarcinoma: A Systematic Review Mikolaskova I, Crnogorac-Jurcevic T, Smolkova B et al. Biology 12(10) 158

Non-Invasive Biomarkers for Early Lung Cancer Detection Saman H, Raza A, Patil K et al. Cancers 14(10) 5782

Urine biomarkers enable pancreatic cancer detection up to 2 years before diagnosis Debernardi S, Blyuss O, Rycyk D et al. International Journal of Cancer (2023) 152(10) 769-780

Proteomes of Extracellular Vesicles From Pancreatic Cancer Cells and Cancer-Associated Fibroblasts Pan S, Lai LA, Simeone DM et al. Pancreas (2022) 51(10) 790-799

Abstract 5077: Proteomics analysis of extracellular vesicles from pancreatic cancer cells and cancer associated fibroblasts Pan S, Lai LA, Simeone DM et al. Cancer Research (2022) 82(10) 5077-5077

Team

Postdoctoral Researchers

• Dr Silvana Debernardi

Other members

• Evelyn Kurotova
• Jayni Shah
• Lucia Pueyo Valles

Biography

I obtained the MBBS degree and completed an MD thesis at the Medical Faculty, University of Zagreb in Croatia, and my PhD at the Imperial College School of Medicine in London. After a postdoctoral experience in molecular biology at CNRS in Toulouse, France and molecular oncology at CRUK laboratory at Hammersmith Hospital, London, I joined Barts Cancer Institute in November 2004.

In addition to research, my teaching responsibilities include Problem Based Learning (PBL) and Student Selective Component (SSC) for undergraduate students. I am Module Leader for Genomic Approaches to Cancer, a core module on the MSc/PGDip Cancer & Molecular Pathology and Genomics, MSc/PGDip Cancer & Molecular and Cellular Biology and MSc/PGDip Cancer & Therapeutics courses.

In 2006 I was awarded a Postgraduate Certificate in Academic Practice (PGCAP) and became a Fellow of the Higher Education Academy in 2009.