Professor Eithne Costello B.Sc., Ph.D., SFHEA
Professor of Molecular Oncology Molecular & Clinical Cancer Medicine
- +44 (0)151 706 4178 / +44 (0)151 795 8032
- Work email Ecostell@liverpool.ac.uk
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 Grants
Dissecting the biology underpinning pancreatic cancer-associated diabetes
PANCREATIC CANCER UK (UK)
September 2021 - September 2024
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
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 2020
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 & SOCIAL CARE (UK)
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
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 & SOCIAL CARE (UK)
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.