Photo of Prof Eithne Costello

Prof Eithne Costello B.Sc., Ph.D., SFHEA

Professor of Molecular Oncology Molecular and Clinical Cancer Medicine

    Research

    UK Early Detection Initiative for Pancreatic Cancer

    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.

    Validating candidate biomarkers for future use in pancreatic cancer detection amongst individuals with new-onset diabetes

    Pancreatic cancer (PC) is set to become the second biggest cancer killer by 2030. Five year survival is less than five percent, largely due to late diagnosis.
    At the time of PC diagnosis, half of PC patients have diabetes. PC-associated diabetes (called type 3C) can occur up to 3 years prior to PC diagnosis, however, it is mistaken for type 2 diabetes, and general practitioners miss this vital early warning sign of PC.
    Approximately 1% of individuals diagnosed with type 2 DM have PC-associated diabetes, making new-onset diabetes the largest high-risk group for PC. Screening all new cases of type 2 diabetes (>250,000/year UK) would be prohibitively costly and mis-diagnosis would lead to dreadful consequences (major surgery/pancreas removal for cancer-free individuals).
    In work funded by North West Cancer Research, we aim is to develop a blood test by which PC-associated DM can be distinguished from type 2 DM, allowing earlier PC diagnosis. We have analysed blood from PC patients and controls, and have identified proteins that distinguish PC-associated DM from long-standing type 2 DM. We established the UK’s first collection of individuals with new-onset diabetes, and now seek to test the specificity of our markers for PC-associated diabetes versus new-onset type 2 DM. We will also test markers in additional high-risk groups, where diabetes is monitored.
    The accuracy of candidate markers, particularly their ability to give a negative result in cancer-free individuals will be established, paving the way for future testing in larger cohorts of individuals with new-onset diabetes and eventual screening of individuals with new-onset DM for PC.

    Preclinical evaluation of Nrf2 inhibition as a means to improve chemotherapeutic efficacy in patients with pancreatic cancer

    Pancreatic cancer is a devastating disease, usually causing death within one year of diagnosis. One of the reasons for this terribly poor prognosis is the failure of tumours to respond to chemotherapy. It is estimated that as few as 10% of patients respond to currently used treatments, such as gemcitabine.
    The reasons for resistance of pancreatic cancer tumours to treatment are many-fold and our group is currently investigating how the levels of proteins involved in the drug uptake and metabolism relate to outcome for patients in randomised controlled clinical trials. However, an important source of drug resistance, which has received limited attention in pancreatic cancer, is the ability of cancer cells to protect themselves from chemical stress induced by chemotherapeutic drugs. A key protein orchestrating this cellular defence against chemotherapeutic drugs is Nrf2.
    During inflammation or when our normal cells are exposed to environmental chemicals which cause the overproduction of highly damaging chemicals (such as, reactive oxygen species), the levels of Nrf2 are raised and induce the expression of genes involved in detoxification, thus protecting ourselves from chemical damage. The majority of pancreatic cancer cells have high Nrf2 and/or respond to chemotherapy by raising Nrf2 levels. In this way, Nrf2 protects pancreatic cancer cells from chemotherapy.
    In work funded by Pancreatic Cancer Research Fund, we are currently undertaking preclinical analysis of the interplay between the Nrf2 pathway and the response to chemotherapy in pancreatic cancer. We will document the activation of Nrf2 in response to gemcitabine in cultured human pancreatic cancer cells and using sophisticated clinically relevant mouse models of oxidative stress and pancreatic cancer. Crucially, we will examine how best to inhibit Nrf2, such as to increase the cellular response to gemcitabine.
    Our work will pave the way for combining Nrf2 inhibitors and chemotherapy in pancreatic cancer patients for the improved management of this disease.

    Research Group Membership
    Research Grants

    Clinical validation of a serum protein biomarker signature for the early diagnosis of pancreatic cancer

    IMMUNOVIA AB (SWEDEN)

    January 2016 - December 2020

    Understanding the function of genes driving fibrosis in pancreatic cancer

    THE TERESA ROSENBAUM GOLDEN CHARITABLE TRUST (THE ROSETREES TRUST) (UK)

    April 2016 - April 2019

    Regenerative Medicine Platform in Stem Cell Safety Science

    MEDICAL RESEARCH COUNCIL (MRC)

    June 2013 - March 2018

    Sample collection from individuals with new-onset diabetes and validation of potential blood-borne biomarkers to enable earlier detection of pancreatic cancer in this high-risk group

    PANCREATIC CANCER ACTION (UK)

    January 2016 - April 2019

    Creating a rapid diagnostic pathway for patients with pancreatic cancer

    ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST (UK)

    May 2015 - March 2016

    MicroRNA profiling in pancreatic stellate cells: validation and assessment of potential to predict response to treatment

    PANCREATIC CANCER UK (UK)

    March 2015 - March 2016

    Creating a rapid diagnostic pathway for patients with pancreatic cancer

    PANCREATIC CANCER UK (UK)

    October 2014 - September 2017

    Preclinical evaluation of Nrf2 inhibition as a means to improve chemotherapeutic efficacy in patients with pancreatic cancer

    PANCREATIC CANCER RESEARCH FUND (UK)

    February 2016 - January 2020

    Targeting the tumour microenvironment to improve pancreatic cancer prognosis - EPC-TM-Net (European Pancreatic Cancer-Tumour-Microenvironment Network)

    EUROPEAN COMMISSION

    February 2011 - July 2014

    Protein expression in the pancreatic cancer microenvironment.

    ROYAL COLLEGE OF SURGEONS OF ENGLAND(UK)

    January 2004 - December 2004

    Gene therapy for G.I. cancer.

    SURGICAL RESEARCH SOCIETY (UK)

    July 2000 - June 2001

    Nuclear Factor Kappa B (NF-kB) and pancreatic cancer treatment.

    ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST (UK)

    January 2000 - December 2001

    Maintaining the capability to isolate primary pancreatic stellate cells from surgically resected pancreatic tissue

    ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST (UK)

    August 2014 - March 2015

    Research Capability Funding: post doctoral researcher support within the pancreatic unit

    ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST (UK)

    March 2013 - June 2013

    Identification of novel stromal targets for early detection and targeted therapy in pancreatic and oesophageal cancer

    CANCER RESEARCH UK (UK)

    July 2010 - September 2011

    Protein expression profiling in pancreatic ductal adenocarcinoma: Correlation with Gene Expression and Mutational Status.

    NORTH WEST CANCER RESEARCH FUND

    September 2001 - September 2002

    Targeting heat shock protein 27 in colorectal cancer

    THE ASSOCIATION OF COLOPROCTOLOGY OF GREAT BRITAIN AND IRELAND (UK)

    January 2013 - August 2016

    Crosstalk between pancreatic cancer cells and tumour infiltrating monocytes: Role in invasion and potential for therapeutic exploitation

    PANCREATIC CANCER RESEARCH FUND (UK)

    May 2008 - June 2011

    Risk stratification: modelling and accessibility

    ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST (UK)

    June 2010 - May 2011

    Liverpool Centre of Experimental Cancer Medicine.

    CANCER RESEARCH UK (UK)

    July 2007 - March 2012

    Novel molecular diagnostic tools for the prevention and diagnosis of pancreatic cancer.

    EUROPEAN COMMISSION

    August 2006 - January 2010

    Analysis of differential protein expression in normal and malignant pancreatic ductal cells.

    CANCER RESEARCH UK (UK)

    September 2002 - August 2005

    Validation of serum biomarkers for pancreatic cancer detection

    NORTH WEST CANCER RESEARCH INCORPORATING CLATTERBRIDGE CANCER RESEARCH (UK)

    October 2013 - June 2016

    Stratification of adjuvant chemotherapeutic response to allow personalised choice of pyrimidine prodrug: based on levels of transporters and enzymes involved in initial metabolism

    CANCER RESEARCH UK (UK)

    November 2013 - April 2017

    Liverpool Experimental Cancer Medicine Centre - DoH contribution

    DEPARTMENT OF HEALTH (UK) (NIHR)

    April 2007 - March 2012

    Involvement of MicroRNAs in the Activation of Cancer-Associated Pancreatic Sellate Cells

    PANCREATIC CANCER RESEARCH FUND (UK)

    May 2012 - October 2014

    GCLP manager at the Liverpool Experimental Cancer Medicine Centre

    CLATTERBRIDGE CANCER RESEARCH

    November 2008 - November 2009

    Identification and validation of serum biomarkers of pancreatic cancer.

    CANCER RESEARCH UK (UK)

    March 2009 - March 2013

    Evaluating and combining serum biomarkers for early pancreatic cancer detection

    PANCREATIC CANCER UK (UK)

    August 2011 - March 2015

    Suitability of lentiviral vectors for pancreatic cancer gene therapy.

    ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST (UK)

    April 2004 - December 2005

    Protein expression in the pancreatic tumour microenvironment.

    ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST (UK)

    March 2003 - March 2006

    Simultaneous integration of microRNA and mRNA expression in the analysis of quiescent and activated human pancreatic stellate cells

    THE TERESA ROSENBAUM GOLDEN CHARITABLE TRUST (THE ROSETREES TRUST) (UK)

    May 2014 - March 2015

    Determination of a possible role for Cap-G in pancreatic cancer cell movement and /or invasion.

    NORTH WEST CANCER RESEARCH FUND

    February 2004 - February 2005

    Combined gene therapy using monoclonal antibody genes and recombinant IL12.

    NORTH WEST CANCER RESEARCH FUND

    March 1997 - July 2002

    Quantitative high-throughput proteomics for biomedical research.

    MEDICAL RESEARCH COUNCIL (MRC)

    March 2005 - March 2008

    European Study Group for Pancreatic Cancer Trial 5F prospective sample collection - ESPAC-5FT

    CANCER RESEARCH UK (UK)

    September 2014 - December 2018

    Combined Genetic and Proteomic Screening for early Detection of Pancreatic Cancer.

    CANCER RESEARCH UK (UK)

    October 2007 - September 2011

    In vivo evaluation of S100A6 as a modulator of pancreatic cancer cell invasiveness.

    NORTH WEST CANCER RESEARCH FUND

    February 2006 - January 2007

    Identification of autoantibodies in pancreatic cancer.

    ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST (UK)

    April 2003 - March 2006

    Investigating the therapeutic mechanism of propranolol on haemangiomas

    ROYAL COLLEGE OF SURGEONS OF ENGLAND(UK)

    January 2012 - July 2014

    Evaluation of Lentiviral Vectors for Pancreatic Cancer Gene-Therapy.

    DEPARTMENT OF HEALTH (UK) (NIHR)

    January 2002 - December 2003

    Characterisation and proteomic analysis of pancreatic cancer stem cells (CSC) derived from pancreatic ductal adenocarcinoma (PDAC) cell lines

    EUROPEAN PANCREATIC CLUB (HUNGARY)

    August 2013 - November 2013

    Serum markers of stromal biology

    THE JEAN SHANKS FOUNDATION (UK)

    August 2010 - August 2011

    Proteomic Analysis of Pancreas.

    ROYAL SOCIETY (CHARITABLE)

    August 2001 - July 2002

    The comparative analysis of RNA and Protein Expression in Pancreatic Cancer.

    ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST (UK)

    April 2001 - March 2003

    Can protein profiling enable screening of newly diagnosed diabetics for pancreatic cancer?

    PANCREATIC CANCER UK (UK)

    October 2013 - November 2014

    Impact of tumour-associated myeloid cells on cancer stemness and chemotherapy-resistance

    NORTH WEST CANCER RESEARCH FUND

    March 2013 - December 2016

    Implications of the effects of pancreatic cancer protein expression in stroma.

    ROYAL COLLEGE OF SURGEONS OF ENGLAND(UK)

    August 2007 - July 2008

    Functional analysis of S100A6 in pancreatic ductal adenocarcinoma.

    CANCER RESEARCH UK (UK)

    January 2004 - December 2005

    Identification of autoantibodies in pancreatic cancer using a proteomics approach.

    ROYAL COLLEGE OF SURGEONS OF ENGLAND(UK)

    October 2003 - September 2004

    Wellcome Trust Four Year PhD Studentship with the PhD Programme in Cellular and Molecular Physiology - 2010

    WELLCOME TRUST (UK)

    October 2010 - March 2015

    ESPAC 4 Prospective sample collection - ESPAC 4T

    CANCER RESEARCH UK (UK)

    September 2010 - November 2017

    RCS Fellowship for Elizabeth Tweedle.

    ROYAL COLLEGE OF SURGEONS OF ENGLAND(UK)

    August 2007 - July 2008

    Research Collaborations

    Neil Kitteringham And Roz Jenkins

    Internal

    We collaborate on a number of proteomics-based projects

    Thomas Gress co-ordinator

    External: The University of Heidelberg

    A collaboration between 16 EU partners in a consortium headed by T. Gress, University of Ulm.

    Nick Lemoine

    External: Barts and the London Medical School

    We collaborate on projects involving molecular pancreatology.