The evaluation of the avb6 integrin as a biomarkers and therapeutic target for idiopathic pulmonary fibrosis

Lead Research Organisation: University of Nottingham
Department Name: School of Life Sciences

Abstract

Idiopathic pulmonary fibrosis (IPF) is a disease where the fine, delicate structure of the lungs is replace by a hard, concrete-like substance called fibrous matrix. This prevents the normal functions of the lung, such as the transfer of oxygen from the air to the body, it also leads to irritation and persistent cough. The speed at which this concrete-like matrix is deposited in the lung varies between different people, but ultimately leads to death. Unfortunately it is difficult to predict who will get worse quickly, and who will get worse slowly. Furthermore, there are no treatments that can improve the outlook for people with IPF at the current time. The aim of this study is to develop a biological test that can predict which people with IPF are going to have slowly progressive disease compared with rapidly progressive disease. More importantly these biological tests will hopefully be able to be used to show whether a current, or new treatment, is working in an individual patient. This information will help patients plan their future when the receive a diagnosis of IPF and will help in the development of new treatments for this condition, which are so urgently sought.

Technical Summary

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown aetiology. The pathogenesis of IPF is thought to be due to abnormal repair following alveolar epithelial injury within the lung. Current estimates suggest 4500 new cases of IPF each year in the UK, with median survival around 3 years. Furthermore, there has been a progressive increase in the incidence of IPF since the early 1980s. Considerable disease heterogeneity exists both in terms of clinical presentation and survival. However, there are no treatments that reduce the mortality or morbidity, although candidate treatments are emerging.
The aim of this proposal is to evaluate the alphavbeta6 integrin, which has an established role in the pathogenesis of fibrogenesis, as a potential biomarker in IPF. We will use immunohistochemistry from historical and prospective data sets as well as serum and lavage studies to evaluate alphavbeta6 integrin expression and downstream TGFbeta activation. We will develop a radiolabelled imaging strategy to permit real-time assessement of alphavbeta6 integrin expression which can then be followed longitudinally to assesss disease progression or response to therapy.
Specifically we aim to: 1) immunotype (alphavbeta6; alphaSMA, PAI-1, HGF) histological samples from patients undergoing surgical biopsies, to accurately determine patients with a poor prognosis compared with other fibrotic lung diseases; 2) develop non-invasive radioimaging (PET/CT and SPECT/CT) of pulmonary alphavbeta6 integrin levels to monitor the presence and progression of pulmonary fibrosis; 3) evaluate bronchoalveolar lavage and serum makers of alphavbeta6 integrin mediated TGFbeta activation in patients with IPF.
Initial studies will be performed in historical samples from patients with a diagnosis of lung fibrosis to determine whether . The cohort will be recruited within the established clinical network of centres in the whole Trent region, and will aim to recruit up to 225participants. At the time of diagnosis participants will be phenotyped in detail and the cohort will be followed for an average of 2.5 years (range 1 to 4 years). During this time we expect nearly 50% of our cohort to die. We will then determine which factors most accurately predict survival.
The results of this study will provide information regarding prognosis and disease progression in IPF. This information will be used to help plan the timing of therapeutic interventions such as lung transplantation as well as design of efficient clinical trials to alleviate the suffering of patients who suffer from this devastating disease.
 
Description ERS/ATS Clinical Guideline Committee for the Diagnosis of IPF
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description Editor in Chief Thorax
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact As Editor-in-Chief of Thorax (the official journal of the British Thoracic Society and 4th highest Respiratory Journal) we have completely revised the instructions for authors to emphasise scientific rigour with explicit guidelines for research of many disciplines.
URL http://thorax.bmj.com/pages/authors/
 
Description MILD Fibrosis Meeting
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact No particular change in practice but dissemination of the information regarding the benefits of participating in Clinical Trials.
 
Description MILD Fibrosis meeting
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Wide ranging update to a range of health care practitioners regarding the diagnosis and treatment of IPF
 
Description NICE Nintedanib Scoping Workshop
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
 
Description NICE PAS
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
Impact Pirfenidone is currently prescribed with under a patient access scheme for which my evidence formed part of the review.
 
Description Specialist Respiratory Clinical Reference Group
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact Advising on reorganisation of Specialised Respiratory Services for NHS England
 
Description Workshop on the Future Directions of Pulmonary Fibrosis Research
Geographic Reach North America 
Policy Influence Type Participation in a national consultation
URL http://www.atsjournals.org/doi/abs/10.1164/rccm.201602-0254ST?url_ver=Z39.88-2003&rfr_id=ori:rid:cro...
 
Description Biogen Idec contract
Amount £200,000 (GBP)
Organisation Biogen Idec 
Sector Private
Country United States of America
Start 02/2014 
End 01/2016
 
Description Clinical Fellowship
Amount £279,483 (GBP)
Funding ID MR/P001327/1 
Organisation MRC-UK 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 11/2016 
End 10/2019
 
Description MRC Case Award
Amount £100,000 (GBP)
Organisation MRC-UK 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2016 
End 09/2020
 
Description Medical Research Foundation Respiratory Disease Call
Amount £250,000 (GBP)
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 07/2016 
End 06/2019
 
Description Medical Research Foundation Respiratory Disease Call
Amount £250,000 (GBP)
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2016 
End 09/2019
 
Description Molecular Pathology Node
Amount £2,400,000 (GBP)
Organisation MRC-UK 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2015 
End 09/2020
 
Description Refining Radiation Models of Fibrosis
Amount £48,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 04/2014 
End 03/2016
 
Description Research Grant G1100564
Amount £553,341 (GBP)
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Private
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2011 
End 04/2015
 
Title Beta6 integrin imaging 
Description We can now perform whole lung imaging of avb6 integrin expression 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This technology is being used by us for commercial groups and would be made available to other groups if requested. Studies are ongoing to translate it into a clinical tool. 
 
Title Biological samples from patients with IPF 
Description We have begun collecting blood and lavage from patients with IPF. Some will be stored for sharing after primary analysis 
Type Of Material Biological samples 
Provided To Others? No  
Impact These biological samples are at an early stage of collection and therefore no impcts have resulted as yet. 
 
Title Lung specific G protein null mouse 
Description As part of the program to assess integrin mediated TGFbeta activity in mice we have developed a lung epithelial specific Gq/11 double and G12/13 double knockout mouse. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact These mice are currently being characterised and no notable impacts have yet been reported. 
 
Title PROFILE Study database 
Description We have a collection of over 330 biological samples with matched clinical data from patients with incident IPF 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact First paper is under review at Lancet and further papers are planned. A number of lectures describing the PROFILE cohort have been delivered and two articles have cited the development of the PROFILE cohort. 
 
Description MedImmune MRC-CASE awards 
Organisation AstraZeneca
Department MedImmune
Country United States of America 
Sector Private 
PI Contribution I am supervising a PhD with input from MedImmune having successfully submitted an MRC CASE award.
Collaborator Contribution MedImmune will be co-supervising the award.
Impact None yet
Start Year 2015
 
Description Nottingham Molecular Pathology Node 
Organisation Galecto Biotech
Country Sweden, Kingdom of 
Sector Private 
PI Contribution I am supervising a PhD jointly funded by the MRC and Galecto Biotec
Collaborator Contribution Galecto part funding the PhD
Impact None yet
Start Year 2015
 
Description UK Interstitial Lung Disease Consortium 
Organisation Imperial College London (ICL)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Coordinated the genotyping and data analysis of genotype with outcome of patients with Idiopathic Pulmonary Fibrosis
Collaborator Contribution Provided patient samples and data Provided data analysis Undertook genotyping
Impact Data analysis still ongoing
Start Year 2012
 
Description UK Interstitial Lung Disease Consortium 
Organisation University College London (UCL)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Coordinated the genotyping and data analysis of genotype with outcome of patients with Idiopathic Pulmonary Fibrosis
Collaborator Contribution Provided patient samples and data Provided data analysis Undertook genotyping
Impact Data analysis still ongoing
Start Year 2012
 
Description UK Interstitial Lung Disease Consortium 
Organisation University of Bristol
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Coordinated the genotyping and data analysis of genotype with outcome of patients with Idiopathic Pulmonary Fibrosis
Collaborator Contribution Provided patient samples and data Provided data analysis Undertook genotyping
Impact Data analysis still ongoing
Start Year 2012
 
Description UK Interstitial Lung Disease Consortium 
Organisation University of Cambridge
Department Department of Medicine
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Coordinated the genotyping and data analysis of genotype with outcome of patients with Idiopathic Pulmonary Fibrosis
Collaborator Contribution Provided patient samples and data Provided data analysis Undertook genotyping
Impact Data analysis still ongoing
Start Year 2012
 
Description UK Interstitial Lung Disease Consortium 
Organisation University of Edinburgh
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Coordinated the genotyping and data analysis of genotype with outcome of patients with Idiopathic Pulmonary Fibrosis
Collaborator Contribution Provided patient samples and data Provided data analysis Undertook genotyping
Impact Data analysis still ongoing
Start Year 2012
 
Description UK Interstitial Lung Disease Consortium 
Organisation University of Hull
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Coordinated the genotyping and data analysis of genotype with outcome of patients with Idiopathic Pulmonary Fibrosis
Collaborator Contribution Provided patient samples and data Provided data analysis Undertook genotyping
Impact Data analysis still ongoing
Start Year 2012
 
Description UK Interstitial Lung Disease Consortium 
Organisation University of Leicester
Department Genetic Epidemiology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Coordinated the genotyping and data analysis of genotype with outcome of patients with Idiopathic Pulmonary Fibrosis
Collaborator Contribution Provided patient samples and data Provided data analysis Undertook genotyping
Impact Data analysis still ongoing
Start Year 2012
 
Description UK Interstitial Lung Disease Consortium 
Organisation University of Sheffield
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Coordinated the genotyping and data analysis of genotype with outcome of patients with Idiopathic Pulmonary Fibrosis
Collaborator Contribution Provided patient samples and data Provided data analysis Undertook genotyping
Impact Data analysis still ongoing
Start Year 2012
 
Title Humanised PET Ligand 
Description This is a methodology study to examine the quantification of GSK2634673F binding in humans, with the aim of characterising a robust, non-invasive method to quantify the specific binding signal for the alpha(V)beta6 protein in human tissues. This will be the first time that this micro-dose ligand is administered to humans. The study will consist of three parts; Part A, Part B and Part C. Healthy subjects will be recruited into Parts A and B of the study in order to gain experience with the GSK2634673F positron emission tomography (PET) ligand and to optimise the scanning procedures prior to administration to IPF patients in Part C. 
Type Diagnostic Tool - Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2017
Development Status Under active development/distribution
Clinical Trial? Yes
Impact This study will identify whether the avb6 integrin can be used as a PD biomarker for interventional clinical trials. 
URL https://clinicaltrials.gov/ct2/show/NCT02052297
 
Title Nordic Biomarkers 
Description The Nordic biomarkers that we identified in our Lancet paper Jenkins et al 2015, are now been assessed as theranostic biomarkers in an interventional clinical trial sponsored by Boehringer Ingelheim. NCT02788474 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact These biomarkers are now being assessed in a large number of interventional clinic trials. 
URL https://clinicaltrials.gov/ct2/show/NCT02788474
 
Description American Thoracic Society Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talk sparked questions and discussions afterwards

International collaborations developed
Year(s) Of Engagement Activity 2013
 
Description British Inflammation Research Association 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Talked sparked discussion afterwards

Networking opportunites
Year(s) Of Engagement Activity 2014
 
Description Cambridge respiratory Group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Talk sparked discussion

Collaborative opportunnities
Year(s) Of Engagement Activity 2013
 
Description Fibrosis Conference (Rhodes) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 90 researchers from across organ systems and across the world attended the conference and my talk sparked discussion and debate afterwards.
Year(s) Of Engagement Activity 2016
URL http://www.aegeanconferences.org/src/App/conferences/view/112
 
Description ICLAF 2014 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talk sparked discussion

Numerous collaborative requests and possible review
Year(s) Of Engagement Activity 2014
 
Description London Matrix Group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Talk sparked discussion

Collaborative requests
Year(s) Of Engagement Activity 2013
 
Description Munich International Autumn School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Large international meeting to the largest Respiratory Research group in Germany that also attracted an audience from access Europe and the world, I delivered two lectures and participated in group workshops with a number of post docs.
Year(s) Of Engagement Activity 2015
URL https://www.helmholtz-muenchen.de/en/press-media/press-releases/.../index.html
 
Description Nordic Respiratory Society meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talk sparked questions and discussions afterwards

International contacts developed
Year(s) Of Engagement Activity 2013
 
Description Patient Day 2013 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact 100 patients and carers attended, sparking discussion.

Formation of the national IPF Charity Action of Pulmonary Fibrosis
Year(s) Of Engagement Activity 2012,2013
URL http://www.actionpulmonaryfibrosis.org/
 
Description Patient Priority Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact 110 patients or patient relatives attended a one day conference informing them about their disease (IPF)

Formation of Pulmonary Fibrosis Association Patient Group
Year(s) Of Engagement Activity 2012
 
Description Royal College of Physicians Advanced Medicine Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact talk sparked discussion afterwards

Talk lead to an invited review
Year(s) Of Engagement Activity 2014
 
Description Royal College of Physicians Update 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Approximately 200 physicians around the west midlands attended and I had discussions about the diagnosis and management of pulmonary fibrosis subsequently
Year(s) Of Engagement Activity 2016
URL https://www.rcplondon.ac.uk/events/regional-update-medicine-west-midlands
 
Description Royal College of Physicians and Surgeons Glasgow 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk sparked discussions afterwards

After my talk slides were requested
Year(s) Of Engagement Activity 2013
 
Description Summer BALR meeting in 2013 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Me and my team organised a two day scientific meeting and accompanying Patient Support day in July 2013. The feedback from the days was outstanding, there was a huge amount of discussion and the attendance at the conference was a record.

Increased collaborations, videos of patient day posted on the pulmonary fibrosis foundation website.
Year(s) Of Engagement Activity 2013
URL http://www.pulmonaryfibrosis.org/life-with-pf/pff-educational-resources/webinars
 
Description Tissue Fibrosis: State-of-the-Art 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Widespread discussions of future collaboration

Tissue Fibrosis Website to be generated
Year(s) Of Engagement Activity 2014