Mesothelioma is an incurable asbestos-related malignancy. The incidence of mesothelioma is higher in the West of Scotland than in almost any other part of the world – a legacy of our shipbuilding past and the previous use of asbestos in heavy industries along the Clyde estuary. At present there are few effective treatments for mesothelioma and patients often experience diagnostic delays and difficult symptoms. Our research programme, which is led by clinicians who care for mesothelioma patients, seeks to define novel, less invasive diagnostic tools, new therapeutic targets and methods to refine and improve available treatments, particularly radiotherapy.
Aiming to achieve better outcomes for mesothelioma patients
- SYSTEMS (N Macleod, N O'Rourke, B Laird) is a single arm, phase II, multicentre observational study funded by JHMRF/BOCF. The primary aim of SYSTEMS is to assess the effect of palliative radiotherapy (20 Gy in 5#) on key symptoms in patients with mesothelioma (e.g. pain) using comprehensive and validated symptom assessment measures. The study also seeks to identify predictive biomarkers for RT response, using both blood markers and a detailed clinical examination known as Quantitative Sensory Testing. The role of PET-CT in radiotherapy planning in mesothelioma is also being explored.
- Ketamine Pain Study (B Laird) is a CRUK-funded phase III trial of Ketamine in neuropathic cancer pain in patients with mesothelioma and other cancers. In mesothelioma, pain is often neuropathic due to damage to the intercostal nerve structure and standard analgesics are often ineffective. Ketamine is a direct antagonist of the NMDA receptor in the spinal cord.
- NCRN 636 (N O'Rourke). This is a phase II randomised double-blind placebo-controlled multicentre study of VS-6063 oral maintenance therapy in patients who have completed first-line platinum based chemotherapy for mesothelioma. The study is already open in other centres and we aim to open in 2014.
- Second-line Vinorelbine (N O'Rourke). NCRI/CR-UK randomised phase II trial of oral Vinorelbine as second-line therapy for patients with malignant pleural mesothelioma. We aim to open this study in 2014.
- Nintedanib in Mesothelioma (N Steele) is a commercially funded, double-blind phase II study of Cisplatin + Pemetrexed chemotherapy in combination with oral Nintedanib or placebo, followed by Nintedanib or placebo monotherapy maintenance in patients with unresectable malignant pleural mesothelioma who have not received prior chemotherapy. Nintedanib is on orally administered triple angiokinase inhibitor. Its main known mechanism of action is to inhibit tumour blood vessel formation, which is essential for tumour growth. This study is now open to recruitment.
Diagnosis and Prognosis
- DIAPHRAGM (S Tsim, K Blyth) is a prospective, multicentre observational study funded by CSO. In DIAPHRAGM we aim to determine the diagnostic and prognostic value of novel, recently identified blood and pleural fluid biomarkers of mesothelioma. Novel MR imaging techniques are being used to quantify tumour volume, describe tumour biology and define the basis of biomarker measurements in patients who present with suspected mesothelioma.
- IPAC Study (B Laird) is a Medical Research Scotland funded multicentre study examining key inflammatory markers in prognosis in advanced cancerincluding mesothelioma, in whom improved prognostic accuracy is needed in order to direct treatments and optimise patient care.
(Anthony Chalmers, Saurabh Dayal) Mesothelioma exhibits resistance to various treatments including radiotherapy. Upon irradiation, normal cells undergo programmed cell death (apoptosis). Defects in the pathways leading to apoptosis within mesothelioma cells may explain their resistance to radiotherapy. This project aims to overcome this by using Tumour Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL), an agonist of the apoptosis pathway in combination with radiotherapy in laboratory and animal models. Once the cytotoxic effects of the combination of radiation and TRAIL have been demonstrated we will investigate the mechanisms underlying what appears to be a synergistic interaction. We also aim to identify potential predictive biomarkers of a response to radiotherapy.
(K Blyth, D Murphy). In this BLF-funded project we are constructing a mouse model of mesothelioma that incorporates the driving genetic mutations typical of human mesothelioma, while also replicating the unique macroscopic features of the disease at the appropriate anatomical site, in an animal with a functioning immune system. This model combines state-of-the-art genetic engineering with pleural access techniques derived from human thoracoscopy. Such a model is crucial to establishing a mechanistic understanding of disease progression, developing diagnostic tools and interrogating novel therapeutic approaches in a relevant pre-clinical setting.
The following funding agencies sponsor our work:
Respiratory Medicine: Kevin Blyth, Selina Tsim
Clinical Oncology: Noelle O'Rourke, Nick MacLeod, Karen Moore
Translational Radiation Biology: Anthony Chalmers, Saurabh Dayal
Palliative Medicine: Barry Laird
Medical Oncology: Nicola Steele
Cancer Models: Daniel Murphy
Imaging: David Stobo, Tracey Steedman, Rosie Woodward
Clinical Physics: Andrew Aitken