Malignant Pleural Mesothelioma (MPM) is an incurable cancer in the lining of the lung caused through the inhalation of asbestos particles. Fatally, it appears decades after exposure, with most patients dying within a year. At present, there are few effective treatments for mesothelioma, and patients often experience diagnostic delays and difficult symptoms. In Glasgow, we are uniquely placed to study the disease, as the West of Scotland has amongst the highest number of cases in the world – a legacy of our shipbuilding past and previous use of asbestos in heavy industries along the Clyde estuary.
Awarded in 2019, the PREDICT-Meso (PRE-malignant Drivers Combined with Target-Drug validation in Mesothelioma) Network brings Glasgow scientists together with mesothelioma researchers from around the UK, Spain and Italy, as well as Belgium and Brazil. The initiative is funded through CRUK’s Accelerator scheme together with the Fondazione AIRC and the Fundación Científica de la Asociación Española Contra el Cáncer for a period of 5 years. The research programme – led by clinician scientist Professor Kevin Blyth (University of Glasgow (UoG)/NHSGGC) – aims to close the gap on identifying key molecular events in the early stages of disease by focussing on understanding how asbestos-driven inflammation develops into MPM. Clinicians, pathologists, research scientists, bioinformaticians and clinical trial experts within PREDICT-Meso are working to translate these findings into effective diagnosis and early treatment for patients.
AIMING TO IMPROVE PATIENTS’ QUALITY OF LIFE
Global cases of MPM are expected to rise rapidly in the coming years, particularly in BRIC (Brazil, Russia, India and China) countries, where asbestos mining and its use in construction is heaviest. As MPM develops through decades of chronic pleural inflammation, it provides a unique window of opportunity for precision prediction and early treatment. With treating patients more effectively at its heart, the PREDICT-Meso Network aims to integrate the study of the development of pre-malignant inflammatory phenotypes into MPM, with state-of-the-art pre-clinical work-flows dedicated to target identification, in vitro & in vivo models, drug-screening, target-drug validation, multi-omics risk-profiling and response tool validation.
Building a large patient cohort and Research Tissue Bank
A key aim of PREDICT-Meso is to build the matched benign/MPM tissue cohorts, technologies and infrastructure needed to design effective MPM therapies and evaluate these in future human trials.
At the core of this lies our clinical study Meso-ORIGINS (supported by the Cancer Research UK
Clinical Trials Unit (CTU) Glasgow led by Professor Rob Jones), developed following a successful recruitment feasibility study. Meso-ORIGINS is an ambitious study that hopes to define in vivo the key biological events that drive or permit evolution of MPM, and subsequently allow development of more effective treatments and earlier interventions for the disease.
Meso-ORIGINS will recruit patients from across 25+ UK sites with benign asbestos associated pleural inflammation and follow their progression over 2 years, collecting repeat tissue samples in the minority who develop MPM, and a sample of those who do not.
Creating these unique matched benign/MPM tissue pairs and aligning these with world-class pre-clinical research, will allow us to define the driving (oncological) and/or permissive (immunological) events involved in the development of MPM.
This cohort will be supplemented with samples from the NHSGGC Biorepository (supported by Clare Orange and Dr Craig Dick) and MesobanK– a bioresource for pleural mesothelioma founded by co-Investigator Dr Robert Rintoul (University of Cambridge).
Furthermore, the NHSGGC Biorepository will support establishment and operation of a PREDICT-Meso Research Tissue Bank which will store samples from Meso-ORIGINS (and future studies) and allow mesothelioma researchers to apply for access to samples and data for their own investigations. This helps to maximise the yield of knowledge and data gathered from individual sites, samples and studies to better inform the overall understanding of MPM.
Leveraging expert Omics to generate state-of-the-art models
The collection of patient-derived samples is crucial for understanding what specific processes are driving the evolution of MPM. A multi-national team of omics-researchers are focusing on the identification of molecular targets and vulnerabilities by applying:
- Genomics – Professor Andrew Biankin (UoG/Glasgow Precision Oncology Lab (GPOL))
- Epigenomics – Professor Manel Esteller (Josep Carreras Leukaemia Research Institute (IJC), Barcelona)
- Transcriptomics -Dr Susana Cedres and Dr Enriqueta Felip (Vall d’Hebron Institute of Oncology (VHIO), Barcelona)
- Complemented by Immune Landscape Mapping – Dr Seth Coffelt (CRUK Beatson Institute/UoG).
Computational analysis of multi-omits data arising from this project will be supported by Professor Crispin Miller (CRUK Beatson Institute/UoG) and his team.
The omics-derived insights will be used to design pre-clinical models, crucial for the detailed study of early events and testing new drugs. Co-Investigators Professor Marion MacFarlane (MRC Toxicology Unit, Cambridge) and Professor Marco Bianchi (Vita-Salute San Raffaele University, Milan) are leading the translation into patient-derived cell lines, 3D organoid culture and patient-derived xenograft models.
Building on local expertise, Professor Daniel Murphy (CRUK Beatson Institute/UoG) will validate genetically engineered mouse models (GEMM) that integrate target gene studies with asbestos exposure – creating model systems similar to human disease as it is recognised in the clinic. Rigorous drug screening and target drug validation using the GEMM models is supported by the teams led by Professor Murphy, Professor Anne Willis (MRC Toxicology Unit, Cambridge) and Professor Ioannis Psallidas and Professor Sam Janes (both University College London).
Bringing findings into the clinic – risk profiling and response markers
Professor Kevin Blyth (UoG) and Professor Klaus Irion, with support from Dr Matthew Evison (both Manchester Royal Infirmary), are leading investigations into imaging and radiomics to investigate risk-profiling and imaging biomarkers that signpost patients who are in urgent need of treatment.
In addition, Breathomics research, led by Professor Jan Van Meerbeeck in Antwerp (Antwerp University and University Hospital) and supported by Dr Kevin Lamote (University of Antwerp) has shown promising results in discriminating at risk asbestos-exposed patients from MPM patients based upon Volatile Organic Compounds (VOCs) in breath. This opens opportunities to be used as non-invasive screening tool which, hopefully, could induce an earlier detection and better survival of MPM patients.
Together with Professor Fergus Gleeson (Oxford) and partners at National Consortium for Intelligent Medical Imaging (NCIMI) and Canon, PREDICT-Meso is also developing artificial intelligence (AI) to assist clinic trial teams in monitoring treatment response through CT imaging.
ASSESS-meso, led by Professor Anna Bibby at Bristol with support of Professor Nick Maskell (University of Bristol Medical School), is a prospective, multicentre, observational cohort study that collects data and biological samples from mesothelioma patients, from the point of diagnosis until death. PREDICT-Meso is collaborating with the ASSESS-Meso team to expand their recruitment and evaluate the role of serial mesothelin as a response marker and prognostic indicator. Funding from the Accelerator grant will rapidly shorten the projected recruitment period of ASSESS-Meso from 10-years to 5-years and create a blood bank for subsequent analyses by the network and wider community.
Training and sustainability
Further to the project work above, the Network also aims to train the next generation of mesothelioma experts – developing them through a series of seminars, teaching and PhDs including two in Brazil.
A focus of PREDICT-Meso is development of a Network and sharing of samples, data and knowledge. This is supported by the Research Tissue Bank and a formal Network Membership process that encourages cross Network collaboration and building of sustainable relationships and practices.
The Network invites new members and is already expanding to include new members from Canada and the USA. If you are interested in joining the Network, or have any questions about the project, please contact the PREDICT-Meso Project Manager, Dr Alexandrea MacPherson, at Alexandrea.firstname.lastname@example.org