Ideas to action

Chief Investigator

Professor Richard Lake

Organisation

University of Western Australia

Awarded funding

$249,100 (3 years)

Immunotherapy works exceptionally well in a minority of cancer patients. As immunotherapy is expensive, and can cause severe side effects, it is important to accurately predict which patients will benefit from therapy.

Immunotherapy acts by improving the patient's immune cells (in particular T cells) to clear the tumours. Each patient has a different combination of unique structures on their T cells called T cell receptors, which are able to recognise tumour cells. We believe that these unique receptors are a reason why only some patients respond to therapy.

We have the technology to study millions of these receptors at the same time, unlocking the code to understand why an individual may benefit from immunotherapy. We will study T cell receptors in our established models of mesothelioma, investigate how they change after immunotherapy, and find out whether these changes affect the outcome of therapy.

These findings will be important for developing novel predictors that will inform therapy decisions for mesothelioma patients.

Chief Investigator

Professor Gary Lee

Organisation

University of Western Australia

Awarded funding

$299,871 (3 years)

Most cancers (especially mesothelioma and lung cancer) can spread to the lining of the lung (pleura) causing fluid build-up, distressing breathlessness and impair daily life.

Fluid (often many litres) usually recurs and requires drainages in hospital that are painful, costly and with potential harms. Surgery is conventionally seen as the definitive option to stop fluid forming, but is invasive with known operative complications. Indwelling pleural catheter (IPC) is a novel implanted device inside the chest that allows patients to drain fluid at home when needed.

The Chief Investigators of this study are world leaders whose work have established the use of IPC in Australasia, Europe and America. Our recent studies showed that IPC significantly reduced repeat pleural interventions and hospitalization in these patients.

The Australasian Malignant Pleural Effusion (AMPLE) Trial 3 is a multicentre randomised clinical trial, and the first, to compare surgery vs IPC in providing lifelong cancer fluid control and improving quality of life. The results will impact global practice.

Chief Investigator

Dr Alison McDonnell

Organisation

University of Western Australia

Awarded funding

$232,926 (3 years)

The average survival from mesothelioma and lung cancer is only nine to 12 months. New treatments are being developed that combine chemotherapy with drugs designed to activate the immune system; however, successful combination of these treatments requires an understanding of how chemotherapy affects immune cells in humans.

This study will examine how chemotherapy alters immune cells at the tumour site compared with those in the blood of mesothelioma and lung cancer patients.

Chief Investigator

Professor Gary Lee

Organisation

University of Western Australia

Awarded funding

$295,224 (3 years)

Mesothelioma is an asbestos-induced cancer of the lining of the chest and lung (the pleura). Mesothelioma has no cure and the average survival of patients is 12 months post diagnosis.

Current standard therapy is mainly palliative and prolongs survival in only a small number of patients. There is a desperate need to find innovative and novel therapies. One such potential therapy involves the use of bacteria as novel anti-cancer agents.

There is strong evidence to suggest that the development of an infection in the space where the tumour develops (pleura) may increase survival in patients with mesothelioma. Studies that capitalize on this phenomenon are urgently needed to determine whether bacteria can be used as effective anti-mesothelioma agents.

We have previously shown that a bacterial toxin can significantly reduce mesothelioma tumour growth in pre-clinical animal models. Our proposed study aims to test how efficiently bacteria can kill mesothelioma cells and tumours and determine how feasible it will be to implement this innovative therapy in the clinic.

Chief Investigator

Professor Bruce Robinson

Organisation

University of Western Australia

Awarded funding

$292,398 (3 years)

Cancer cells carry many mutations which should be ‘seen’ by the immune system as foreign and attacked by the host anti-cancer T cells. Combining immunogenic chemotherapy with immunotherapies induces spectacular responses in mice with MM, augmenting neo-antigen responses and curing otherwise incurable advanced tumours. But to date, clinical studies in MM are lacking.

In this study, we will study patients with MM, determining for the first time:

1. the effect of chemotherapy on T cell responses to MM tumour neo-antigens
2. the induction of new tumour mutations by chemotherapy, mutations which could be fresh targets for immune attack if such an attack could be stimulated for example by neo-antigen vaccines.

This work could be the basis for game-changing neo-antigen vaccines therapies for otherwise incurable, chemotherapy-resistant MM. Importantly, this approach could also become applicable to other chemotherapy-resistant cancers.

Chief Investigator

Dr Yuen Yee Cheng

Organisation

Asbestos Diseases Research Institute (ADRI)

Awarded funding

$300,000 (3 years)

Malignant pleural mesothelioma (MPM) is an aggressive tumour with nine to 12 months median survival for patients. Most patients receive chemotherapy, but almost every patient will be confronted with recurrence of disease and drug resistance. Finding more effective treatment strategies is urgently needed for MPM.

To facilitate drug screening that can be fast tracked into the clinic, we have developed a model using porcine lung as a 3D scaffold. One of the major advantages of this scaffold is that it provides a biocompatible adhesive architecture for cells to grow. Our recent publication showed this 3D model resembled the conditions of cells in the natural tumour microenvironment, compared to 2D culture.

Most current drug screening systems rely on 2D culture system where cells are grown as a single layer attached to a plastic surface. This is not an adequate model, as the behaviour and characteristics of cells can be very different to the actual morphology and behaviour of cells in a natural tumour microenvironment.

To create a microenvironment akin to that of a tumour, we developed a novel 3D tumour model using decellularised porcine lung seeded with cancer cells. When compared to 2D culture, cells grown in this 3D model exhibited markers and expression levels that were like real tumours. We therefore plan to further characterise the cancer biology and drug responses of this 3D model.

Chief Investigator

Professor Jenette Creaney

Organisation

University of Western Australia

Awarded funding

$276,734 (3 years)

Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-induced cancer with limited therapeutic options and poor prognosis. Understanding the underlying genetic changes that occur in MPM may improve patient outcomes. Three genes are commonly altered in MPM; BAP1, CDKN2A/p16 and NF2. How these alterations affect mesothelioma cell biology is not fully known. These genes play important roles in normal cells to stop tumour formation, their role in MPM development is thought to be significant.

This study aims to evaluate if clinical benefit can be achieved based on knowledge of these common MPM genetic alterations. Firstly, the frequency of BAP1, CDKN2A/p16 and NF2 loss will be determined in more than 200 clinical samples. The diagnostic value of these new markers, compared to standard-of-care markers, will then be determined in an independent set of more than 250 consecutive, prospectively-collected clinical samples.

Correlation of tumour marker status with clinical data, specifically overall survival and treatment response will enable the prognostic and predictive significance of marker expression to be evaluated. In parallel, tumour cell growth and response to therapy will be evaluated using cell lines with different marker phenotypes. In light of recent interest in immunotherapy for MPM, the association of these genetic alterations on the immune-microenvironment will be examined.

Chief Investigator

Dr Jonathan Chee

Organisation

University of Western Australia

Awarded funding

$264,653 (3 years)

Malignant mesothelioma is an incurable cancer caused by asbestos. The standard treatment for mesothelioma is chemotherapy, but outcomes remain poor. Because immunotherapy is an exciting option to improve mesothelioma treatment, and our laboratory work supported combining chemotherapy with immunotherapy, we recently completed a clinical trial in which 54 patients with mesothelioma received this novel combination (chemo-immunotherapy).

We observed deep and durable responses, suggesting that immunotherapy may work better when combined with chemotherapy. However, the treatment did not work for everyone. This project aims to understand the mechanisms behind why some individuals respond to chemo-immunotherapy but others do not, to develop novel methods of predicting these responses, and to identify ways to enhance responses.

We have collected blood samples from patients before and during trial treatment and will compare individuals who responded well to those who did not. We will characterise millions of genes from these samples, apply cutting-edge mathematical methods to visualize and identify the patterns of change over time that can predict successful treatment outcomes.

This combination chemo-immunotherapy is so promising for mesothelioma that we are initiating a 480-person randomised phase 3 trial. However, understanding who will respond well to treatment, and who may need additional or different strategies, will be key to improving patient outcomes further.

This project will identify early markers of treatment outcomes, which we will be able to validate in the randomised phase 3 trial. Eventually, we may be able to better understand how to alter or add to treatment to improve patient survival.

Chief Investigator

Dr Yuen Yee Cheng

Organisation

Asbestos Diseases Research Institute (ADRI)

Awarded funding

$232,500 (3 years)

Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with poor prognosis and limited treatment options. MPM is especially difficult to diagnose as a surgical procedure is required to obtain a biopsy. Such a procedure has a long associated recovery period and is not often a feasible option for elderly patients with declining health. Hence there is an urgent requirement to develop less invasive blood-based biomarkers to facilitate an improved MPM-specific diagnostic technique.

Circular RNAs (circRNAs) are an emerging type of blood-based biomarker that possess desirable biochemical properties for early detection of disease. A deregulation of blood-based circRNAs correlates with tumorigenesis in a range of cancer types, with some circRNAs having been established as useful biomarkers for detection of cancers such as acute myeloid leukaemia and lung adenocarcinoma.

The involvement of aberrant circRNA expression in MPM is an uncharted research area, however our preliminary microarray study has revealed that there are approximately 300 circRNAs that are up-regulated in MPM cell lines; indicating their potential to be exploited as biomarker candidates for detection of MPM.

This proposed project will employ a novel circRNA-specific quantitative droplet digital polymerase chain reaction (ddPCR) technique to detect and validate the top ten up-regulated circRNAs (identified from our microarray data), using an extensive cohort of biobanked cell lines and patient biospecimens.

We anticipate that the successful completion of the project will provide a statistically powered indication of the reliability and validity of the circRNA biomarker candidates in relation to their specificity and sensitivity for MPM. 

Chief Investigator

Dr Elham H Beheshti

Organisation

University of Sydney

Awarded funding

$470,213 (3 years)

Mesothelioma is a rare and very aggressive type of cancer affecting the mesothelial cells in the linings of the lungs, abdomen or heart. The disease is very slow to progress and often develops decades after exposure to asbestos. Malignant pleural mesothelioma (MPM) is the most common type and accounts for about 90% of all mesotheliomas.

The disease is often diagnosed at an advanced stage with limited treatment options. Due to the lack of robust diagnostic-biomarker, biopsy remains the only definitive diagnostic test for MPM. Therefore, there is an urgent need for the discovery of robust biomarkers to replace the existing tests for a better, less aggressive, and earlier diagnosis.

Extracellular vesicles (EV) are nano-sized vesicles released from all cells and present in all biological fluids. These nanovesicles carry cell-specific cargos including proteins, lipids and genetic material, thereby acting as novel intercellular messengers. In this research proposal we will comprehensively characterize the EV derived from MPM cell lines and patients' samples for their novel potential in MPM diagnosis via a less invasive procedure. We also will investigate the changes in the EV cargo upon immunotherapy with Pembrolizumab, in our clinical samples.

The association between changes in EV PD-L1 expression and clinical outcome will also be studied as part of our biomarker discovery. Finally, the role of MPM-derived EV in modulating invasion into neighbouring tissues and secondary-tumour formation will be investigated in the light of discovering novel preventive therapeutic strategies contributing to the field of precision medicine.

Chief Investigator

Dr Steven Kao

Organisation

Asbestos Diseases Research Institute (ADRI)

Awarded funding

$277,800 (3 years)

Malignant pleural mesothelioma (MPM) is an aggressive tumour with 9-12 months median survival. Most patients receive chemotherapy, but almost every patient will be confronted with progression of disease and drug resistance. In recent years, immunotherapy has become a focus in MPM research, however, with disappointing patient survival improvement.

We believe finding predicative biomarkers of efficiency to immunotherapeutic agent is urgently needed. In this project we have collected 75 samples from our recent pembrolizumab review and aim to investigate whether epigenetic alteration has any implication in treatment response of pembrolizumab in MPM.

We plan to study any alteration of DNA methylation and microRNA epigenetic biomarkers in these samples and to study epigenetic biomarkers contributing to biological response in MPM. The successful outcomes in this project will provide a) epigenetic biomarkers to predict pembrolizumab response, b) biomarkers to monitor and c) discovering disruption of biomarkers to enhance immunotherapeutic agents in MPM.

Chief Investigator

Dr Maggie Davidson

Organisation

Western Sydney University

Awarded funding

$78,100 (2 years)

The association of occupational exposure to stone dust and lung disease has been well established for hundreds of years. Respirable crystalline silica (RCS) exposure and occupational lung disease silicosis thought to be well controlled and on decline in the late 20th century.

In the 21st century with the increased demand for artificial stone (AS) for use in interior decorating, there has been a increase in cases of accelerated silicosis, a severe form of silicosis, among stone masons.

Contributing factors include a lack of awareness of the high silica content (more than 90 per cent) in some AS types, and the failure in some workplaces to implement appropriate controls such as banning dry cutting to reduce RCS exposure. Regulators and the stone industry have been working to reduce occupational exposure to RCS, including the adopting the lower Australian workplace exposure standard (WES) of 0.05 mg/m3 for RCS.

However, silica is only one component of AS, which is a conglomeration of silica, resins, pigments, glass and natural stone that is superheated under pressure to produce the desired textures and colours. Therefore, cutting and grinding of AS will produce a more complex airborne mixture, that may be more toxic, in comparison to natural stone.

This project aims to evaluate the toxicity of artificial and natural stone dusts using human lung cells exposure to AS dust in a purpose-built exposure chamber that mimics occupational exposure. The outcome of this research will assess the suitability of the current WES for use in the AS industry.

Chief Investigator

Associate Professor W. Alexander Donald

Organisation

University of New South Wales, Sydney

Awarded funding

$480,817.80 (3 years)

Work-related lung disease from dust exposure including silicosis is an emerging epidemic in Australia and globally, impacting workers at the peak of their lives. Internationally, 45,000 deaths have been attributed to silicosis alone and, based on a recent government audit in Australia, the rate of disease development exceeds 12 per cent in engineered stone (ES) workers.

Although there are preventative measures that can be taken by ES workers to mitigate disease (e.g. exposure limits and PPE), these actions are of variable efficacy. Without known, established treatments, silicosis and silica-related diseases will continue to strain the resources of the health and medical sector. However, by developing approaches to identify such diseases early and prevent further exposure, the rate of progression of silicosis can be slowed, and treatments (once established) potentially implemented.

Early detection has enormous potential to improve survival rates and disease burden. Our proposed solution is to use state-of-the art chemical analysis methods to identify and improve understanding of the pathophysiology of silica-related lung diseases. We aim then to apply such approaches in routine respiratory surveillance of workers. Such a technique could yield substantial economic opportunities and benefits to the medical and health sector.

This project brings together an interdisciplinary team of international leaders in occupational dust-related lung diseases and chemical analysis to develop a rapid, sensitive and portable device to enable early detection and treatment of silicosis.

Chief Investigator

Dr Edward Fysh

Organisation

University of Western Australia

Awarded funding

$224,867 (3 years)

Mesothelioma is an asbestos-induced cancer of the lining of the chest wall and lung (the pleura). It often presents as multiple small nodules or areas of thickening. It is notoriously challenging to diagnose, often needing multiple invasive biopsy tests, making this first step of the patient journey stressful and unpleasant. Computed tomography (CT) forms part of the workup but often fails to detect pleural nodules. Many patients ultimately need open-chest or key-hole surgery to find the nodules for biopsy.

This study explores a novel method to make pleural nodules visible on CT, by instilling air into the chest to create an air­pleura interface. Once located, the nodules can then be biopsied with a small needle (like a blood test) under CT guidance. Our pilot data are promising.

Our team includes world leaders in pleural medicine and radiology and has strong track record in clinical trials. This study aims to prove the safety and clinical utility of this exciting approach which can save many mesothelioma patients from invasive surgery, its risks (pain and tumour spread) and costs.

Chief Investigator

Professor Patrick Brennan

Organisation

University of Sydney

Awarded funding

$300,000 (3 years)

Accurate diagnosis of dust diseases of the lung are essential for optimum patient treatment and outcomes, yet between 30-40 per cent of subtle thoracic lesions are missed by clinicians.

We present a novel platform that will transform disease detection and identification - CHEST: Chest diagnosis: a High level Educational Strategy. This rapidly translatable, innovative infrastructure will be based on a previous 10-year program of work where we have developed similar solutions for other domains such as breast, which has improved cancer detection by 34 per cent, is voluntarily used by 85 per cent of clinicians in Australia, is mandatory in some jurisdictions and has been implemented across five continents.

Such a tool is currently not available for diagnosing dust disease, but our solution will enable 24/7 access where each clinician can diagnose chest radiographs and lung CT images (with known truth), will receive instant detailed assessment of diagnostic skills, is provided with tailored interactive feedback and can examine benchmark performance data.

The project described within will collect robust sets of radiographs and CT scans, develop the software tool for insertion of the images, validate the tool with 10 expert radiologists and provide a clear route for clinical translation. In three years time diagnosis of dust diseases will be transformed.

Chief Investigator

Associate Professor Lauren Breen

Organisation

Curtin University

Awarded funding

$32,207 (1 year)

Mesothelioma is an aggressive cancer with no cure; palliation is the key. Care of the psychosocial aspects of mesothelioma patients and their family is a neglected area, with minimal prior research.

Practice guidelines emphasise the importance of evaluating psychosocial factors for people with mesothelioma and their family carers. However, there is very little research on these psychosocial factors for people living with mesothelioma and even less is known about carers.

Addressing these aspects first requires a detailed understanding of the psychosocial experiences, needs, and priorities of care for people living with mesothelioma and their family carers, as mesothelioma has unique demands on patients (e.g., long lag time, historical view as a horribly distressing cancer, compensation issues) separating it from other malignancies.

The idea for the project emerged from the Pleural Medicine Unit Consumer Reference Group and the study uses a cross-sectional, mixed-methods design. Currently, we have recruited a sample of 20 and the funding will enable us to increase this to 50, making the study the largest comprehensive investigation of the psychosocial factors relevant to the care of people with mesothelioma and their family carers.

The identified areas of need and priorities of care will be used to design future intervention strategies/studies that will achieve the implementation of practice guidelines for this vulnerable group.