Research funding awarded in FY23-24 or earlier

Chief Investigator

Dr Jonathan Chee

Organisation

University of Western Australia

Awarded Funding

 $271,389 (3 years)

Australia has one of the highest incidence rates of asbestos-related cancer, mesothelioma. The expected survival time is around 12 months with standard chemotherapies. Treatment options for mesothelioma have not improved in the past 10 years; however, a promising recent breakthrough is checkpoint blockade immunotherapy.

These immunotherapies enhance the immune system's ability to identify and destroy cancer cells. Clinical trials report average survival times of 18 months for patients with mesothelioma, a substantial improvement over standard dual chemotherapies. Yet, only 20-30% of treated patients benefit from immunotherapy. Dr Chee and his research team aim to develop copper-binding drugs as a novel way to increase the number of responders.

Copper is essential for healthy cells, but it accumulates in many cancers, including mesothelioma, contributing to tumour growth, cancer spread, and chemotherapy resistance. Dr Chee's collaborative team is the first to show that copper helps tumours evade the immune response. Treatment with copper-binding drugs has been found to slow mesothelioma growth.

Using these copper-binding drugs, the team aims to reduce the amount of copper available to the cancer and to understand how this improves the function of anti-cancer immune cells in mesothelioma. Dr Chee's research team will also investigate whether copper-binding drugs are suitable to combine with immunotherapy for treating mesothelioma.

As these copper-binding drugs are already clinically approved for other diseases and are safe to use, they represent ideal candidates for re-purposing to enhance immunotherapy outcomes for patients with mesothelioma.

Chief Investigator

Associate Professor Yuen Yee Cheng

Organisation

University of Technology Sydney

Awarded Funding

$248,720 (3 years)

Pleural mesothelioma (PM) is a highly aggressive tumour for which there is currently no specific early diagnosis biomarker. The current gold standard for PM diagnosis is laparoscopy and biopsy with multiple immunohistology staining.

However, these procedures are invasive and often inaccessible for elderly patients. A/Prof Cheng's research team at UTS has studied cancer cell-derived sEV circular RNA (exo-circRNAs), which are likely to be detected in bodily fluids such as pleural effusion. These could serve as powerful, less-invasive early diagnosis biomarkers.

The team believes that exo-circRNA may play an important role in epithelial to mesenchymal transition (EMT)-related processes, which lead to tumour progression and metastasis. A/Prof Cheng's project aims to study a novel approach to suppress exo-circRNA and, consequently, EMT progression using miRNA replacement.

Preliminary studies have indicated that exo-circRNAs could serve as novel less-invasive biomarkers for PM. The proposed experiments seek to validate these candidate biomarkers using PM cell lines and clinical pleural effusion samples, employing the highly specific and sensitive droplet digital polymerase chain reaction (ddPCR) technique.

The team will also explore the suppression of exo-circRNA using miRNA, which has the ability to halt tumour progression and metastasis. Leveraging their experience in translating bench discoveries to clinical applications, A/Prof Cheng's team anticipates that this project will yield specific and sensitive early detection biomarkers for PM diagnosis. Additionally, the suppression of exo-circRNA by miRNA could become a potent treatment option for inhibiting EMT in mesothelioma.

Chief Investigator

Associate Professor Yuen Yee Cheng

Organisation

University of Technology Sydney

Awarded Funding

$249,520 (3 years)

Mesothelioma is an aggressive cancer for which there are currently no effective treatment options. Responses to existing treatments among patients are generally short-lived, and despite recent advances, average survival times remain poor. Novel treatment agents and approaches are critically needed to improve outcomes for mesothelioma patients. A/Prof Cheng's team at UTS has recently developed a small molecule named IR1Gd. This molecule has the capability to identify mesothelioma cells and inhibit their growth using near-infrared light (NIR). For the first time, IR1Gd presents an opportunity to apply photodynamic therapy (PDT) to mesothelioma treatment. This molecule leverages the deep penetration essential for tackling mesothelioma tumours, taking advantage of both the NIR biological transparent window and the properties of lanthanide elements.

The NIR dye employed by the team inherently targets tumour sites. They have synthesised this molecule and demonstrated its anti-mesothelioma activity in animal models. In the proposed project, A/Prof Cheng's team will validate the molecule's anti-cancer properties in vitro, examine its staining capabilities in mesothelioma cell lines in both 2D and 3D models, and evaluate its anti-cancer functions in two different animal models, along with conducting sample histology analyses.

Successful completion of these comprehensive in vitro and in vivo experiments will lay the groundwork for a clinical trial focused on mesothelioma treatment. Utilising the results from these proposed experiments, the team aims to demonstrate the efficacy of IR1Gd in treating mesothelioma, leading to early-stage clinical trials. The investigators involved in this project have extensive experience in translational research and are building upon previous successful research funded by icare.

Chief Investigator

Dr Tracy Hoang

Organisation

University of Western Australia

Awarded Funding

$260,674 (3 years)

Mesothelioma is an incurable cancer that occurs exclusively after asbestos exposure. Immunotherapies, which enhance the immune system's ability to combat cancer cells, are now approved for treating mesothelioma. However, these treatments are effective only in a subset of patients. Dr Hoang's research team is focused on understanding and developing methods to more accurately predict a patient's likelihood of benefiting from immunotherapy.

Previous studies have indicated that immunotherapies tend to be more successful in patients whose cancer cells exhibit high levels of PD-L1, a protein that inhibits the immune system's ability to attack cancer cells. Consequently, accurate measurement of PD-L1 levels within tumours may provide insight into the selective efficacy of immunotherapies.

In this project, Dr Hoang's team aims to develop a Positron Emission Tomography (PET) imaging protocol for detecting and measuring PD-L1 levels in mice with mesothelioma tumours. The first step involves creating a radioactive tracer that will specifically bind to PD-L1 and can be detected by PET imaging. Subsequently, using mice with mesothelioma tumours, the team will utilise this imaging tool to monitor changes in PD-L1 levels during tumour growth and after administering various existing cancer therapies.

The team seeks support for this pioneering project, which will be the first to explore the application of PD-L1-specific PET imaging in mice with mesothelioma. This study aims to complement a clinical trial that they are currently initiating. If both investigations prove successful, there is potential to more precisely predict which patients will respond favourably to immunotherapy.

Chief Investigator

Scientia Professor T. David Waite

Organisation

The University of New South Wales (UNSW Sydney)

Awarded Funding

$334,957.10 (3 years)

Work-related dust-induced lung dysfunction remains a pressing issue both in Australia and globally. Major etiological agents include asbestos, coal mine dust (CMD), and crystalline silica, which have been widely used in various industries—ranging from building materials and coal mining to construction, tunnelling, and engineered stone manufacture. Since 2015, Australia has seen a resurgence of coal mine dust lung disease and a concerning uptick in predicted silicosis rates. Additionally, a legacy of asbestos-related diseases persists, with the peak in diagnoses expected to occur within this decade due to the latency characteristics of the disease. Although these inhalable particulates possess different elemental compositions and vary significantly in their rates of progression, they share critical pathological features such as pulmonary inflammation, pneumoconiosis, and lung carcinoma.

Scientia Professor Waite and his research team aim to deepen the understanding of factors that contribute to the considerable variations in latency periods and rates of disease progression. Utilising a novel co-culture technique along with advanced 3D organoid models, the successful completion of this project is expected to offer substantial insights. These could include targeted interventions—such as the regulation of exogenous/endogenous metals, identification of specific cytokines or chemokines, or variations in immune cell numbers—as early-stage disease biomarkers and/or treatment targets. This improved understanding of the fundamental biochemistry of dust-induced lung diseases will hold significant value for future clinical investigations. It will also be crucial for policymakers when revising regulations and formulating guidelines for effective workplace dust management.

Chief Investigator

Jane Bourke

Organisation

Monash University

Awarded funding

$322,500

Silicosis is a fatal chronic inflammatory disease of the lungs, most commonly caused by exposure to inhaled silica particles during unsafe cutting of engineered stone benchtops. Despite best efforts to avoid exposure and enforce safe work processes, silicosis remains a major health problem, with a concerning rise in cases in Australia.

There are no effective treatments for silicosis, apart from lung transplant. There is a strong need to develop drugs that reduce the scarring of the lungs (fibrosis) that causes severe respiratory symptoms and death. One of the reasons that anti-inflammatory and anti-fibrotic drugs have not reached the clinic for silicosis patients as readily as for other lung diseases such as asthma and lung cancer, is that human-based models for laboratory drugs testing of potential silicosis therapies have not been developed.

We will directly address this need by adapting a model drug testing system that we have already developed for asthma drugs, to a model for specifically testing silicosis drugs. Briefly, we will take microscopic slices of tissue from human lungs, donated but not used for transplantation. We will expose them to silica and inflammatory protein cocktails found in the lungs of silicosis patients to cause lung damage and scarring. The project will hone this disease-relevant model by characterising and mimicking the environment in the silicotic lung and then, excitingly, test two anti-fibrotic drugs (already approved and shown to be effective in other lung disease) and two promising novel in-house drugs to target inflammation and fibrosis in silicosis.

 

Chief Investigator

Philip Hansbro

Organisation

University of Technology Sydney

Awarded funding

$352,879

This project aims to improve health and care outcomes for sufferers of accelerated silicosis (AS) by taking a three-pronged approach to discover effective therapies. First, we will deepen the understanding of how silicosis develops by defining the early pathogenesis of silica-induced lung disease in an innovative murine model of chronic, low-dose exposure to respirable crystalline silica (RCS), representative of human exposure.

Through examining early-stage transcriptional and cellular changes in the lungs, as well as gene expression and protein changes in the blood, plasma and bronchioalveolar lavage fluid (BALF), we will identify early biomarkers of silicosis onset and progression.

Secondly, we will determine if early treatment with inflammasome-directed therapies can reduce progression to fibrosis in experimental murine silicosis, and if the selected biomarkers can predict response to these therapies.

Finally, we will perform in vitro, qPCR-directed AS drug screening using macrophages isolated from whole-lung lavage (WLL) of AS patients. One hundred putative therapeutics will be screened for their effect on seven master regulator genes, including FABP4 and FCN1, and the three most effective drugs will be progressed to in vivo investigation using our murine model of AS.

 

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

Steven Kao

Organisation

Asbestos Disease Research Institute

Awarded funding

$249,000

Malignant pleural mesothelioma (MPM) is an aggressive thoracic malignancy with poor prognosis and no standard treatment options currently available to patients beyond the first-line setting. Natural products provide key substrates in the production of anti-cancer drugs, and there is growing interest regarding their potential utility as new anti-cancer therapies for MPM.

However, despite preclinical evidence of anti-cancer activity, natural products are yet to be successfully tested in human studies to assess their potential as an improved alternative to conventional cancer therapy for MPM. 

Manuka honey is a mono-floral honey produced by bees from the nectar collected from Leptospermum species. Both manuka honey and the essential oil from Leptospermum species have been used in supportive care trials as topical agents for radiation mucositis. The potential for products derived from Leptospermum species to have anti-cancer benefit for MPM is yet to be determined. 

We have conducted preliminary studies of a specific extract from Leptospermum polygalifolium (QV0) which demonstrated anti-proliferative activity in vitro, and anti-tumour activity in in vivo animal studies. Importantly, there was no clinical, biochemical or anatomical evidence of toxicity in the tested animals. 

This project is a Phase 1 study of QV0 to determine its potential utility as a monotherapy agent for patients with MPM. This will involve a determination of a safe dose, identification of potential toxicities and characterisation of the pharmacokinetic profile of this product. We intend to further investigate the safety of combining QV0 with standard of care chemotherapy or checkpoint inhibitors in dose expansion safety cohorts.

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.

Chief Investigator

Anne Holland

Organisation

Monash University

Awarded funding

$195,377

People living with silicosis face many uncertainties and stressors. Prognosis and future healthcare needs are often unclear, and changes to work roles may impact on psychosocial and financial wellbeing. Many people with silicosis were born outside Australia and may have limited access to health information due to language barriers. Little is known about the lived experience of younger people with silicosis, or their preferences for long-term supportive care. 

The aims of this study are to (1) understand the experiences and care needs of younger people with silicosis; and (2) identify key components of a long-term supportive care model.

We will recruit people with silicosis aged under 65 years old who have worked with manufactured stone. We will include people with varying disease duration, geographic location (metropolitan and regional) and cultural background. In Stage One, individual interviews will be conducted by telephone or videoconference, to gain an in-depth understanding of experiences and needs.

Questions will explore lived experience of silicosis, including physical and psychosocial wellbeing, health literacy and information needs, and preferences for long-term support. Analysis will be conducted using the principles of grounded theory. In Stage Two, online focus groups will be used to confirm or refine Stage One results and identify key components of a long-term supportive care model.

This project brings together researchers with expertise in dust diseases, respiratory medicine, qualitative research, supportive care and consumer engagement. A key outcome will be a proposed model of supportive care that reflects the experiences, needs and priorities of young people with silicosis.

Chief Investigator

Dr Anna Yeung

Organisation

Woolcock Institute

Awarded funding

$55,200 (3 years)

Silicosis is an incurable lung disease caused by the inhalation of crystalline silica dusts. It affects multiple industries where workers quarry, process and use mineral materials including mining, construction, ceramics, glass manufacturing, and even in textiles.

However, the rapid rise in silicosis cases over the past decade has been attributed to working with artificial stone, a composite material made of more than 90 per cent silica, pigments and polymer resins. Alarmingly we are observing more accelerated and acute forms of silicosis with shortened onset times for fibrosis after exposure to high concentrations of silica dusts. As there are currently no effective treatments for silicosis, our focus is on preventative measures to reduce hazardous exposures to silica dust when working with artificial stone.

This project proposes to monitor and collect environmental data from factories to understand the exposure levels faced by workers during artificial stone processing. We will also evaluate the effectiveness of a number of relatively inexpensive N95/P2 grade face masks in protecting against respirable silica dusts and determine best practices for working with artificial stone when engineering controls are not accessible.

Finally, we recognise that artificial stone work may be carried out by untrained personnel from non-English speaking backgrounds who may not know about silicosis. As such we will produce a multi-language pamphlet based on the results of the study to warn and educate workers on the dangers of working with artificial stone.

Chief Investigator

Professor Fraser Brims

Organisation

University of Western Australia

Awarded funding

$103,551 (1.5 years)

The recent introduction of artificial stone into Australia has resulted in workers being exposed to extremely dangerous levels of silica dust. This has caused more than 330 cases of silicosis in Australia so far.

Screening for the early signs of silicosis is vital, however, the best way to identify silicosis is not known. In Australia we are using chest X-rays (CXR) to try to identify silicosis. The CXR has been used for over 100 years and now doctors more commonly use a CT scan to look for chest disease because they are far more accurate. For instance, in Queensland, doctors think that up to four in 10 CXRs have missed early silicosis.

Therefore, CXR may not be the best way to find early silicosis. But, standard CT scans use a lot more radiation than a CXR, and doctors are worried they may cause harm by using CT scans too much.

In Western Australia, we have access to the latest technology of CT scanner that gives almost the same dose of radiation as a CXR, and yet we get a much better picture of what is happening in the lungs. We believe that this ‘low dose CT’ scan will be better than a CXR at finding silicosis and at a much safer radiation level.

Our project aims to compare chest x-rays with low dose CT scans to find which is more accurate for diagnosing early silicosis. The results may change the way we look for silicosis in Australia and other countries.

Chief Investigator

Dr Sharyn Gaskin

Organisation

University of Adelaide

Awarded funding

$224,872 (2 years)

The introduction of engineered stone products has led to incidence of silicosis following shorter exposure periods and shorter latency periods than with natural stone. This project will aim to compare the physical, chemical and toxicological properties of the emissions of engineered stone with those of natural stone, and to identify dust control measures best able to eliminate the risk of silicosis from these products.

Dust samples from machining of engineered stone and natural stone will be examined for differences in particle size, electrostatic charge, elemental composition, and VOC emissions. Emissions from cutting, polishing and grinding will be measured using a range of wetting techniques and dust control technologies to identify best practice control measures.

Finally, using a hydroxyl free radical assay, the toxicological properties of freshly-generated emissions of engineered stone will be compared with those of natural stone, and with aged engineered stone samples to determine whether toxicity decays with time.

A report with recommendations for stakeholders will provide evidence on dust toxicological and morphological profiles and also advice on risks and control measures. Ultimately, the project should assist in reducing respiratory health risks for workers, and add to scientific knowledge.

Chief Investigator

Dr Matthew Soeberg

Organisation

Asbestos Diseases Research Institute (ADRI)

Awarded funding

$57,000 (1.5 years)

Understanding the total impact of dust diseases in a community requires information about when a person was diagnosed or treated with the disease and when they died. Unlike diseases such as malignant mesothelioma, silicosis does not have a historic disease register to measure incidence and mortality. An alternative and novel approach is needed.

In this project, we will collect national data about the number of hospitalisations and deaths due to silicosis. For mortality data, we can track this data back to 1997. We will also request the data for NSW only. Importantly, we will collect these data held by the Australian Institute of Health and Welfare where silicosis is either the primary reason for hospitalisation or death or an associated reason for hospitalisation or death. For example, it is possible to identify people where silicosis was an associated cause of death but the main reason could have been another (respiratory or other) disease.

This approach allows a much more comprehensive estimate of the silicosis burden in the community. We will then sort and analyse these data by age group (A), the period when the silicosis was treated or diagnosed (P), and the cohort in which someone with silicosis was born in (C). This age-period-cohort (APC) approach will allow researchers and policy makers to understand the risk of silicosis by these three different factors.

Chief Investigator

Dr Amber Louw

Organisation

Institute for Respiratory Health

Awarded funding

$120,000 (3 years)

Malignant pleural mesothelioma (MPM) is an aggressive cancer caused by asbestos that is universally fatal. Two of the most frequently mutated genes in MPM are BRCA1-associated protein 1 (BAP1) and cyclin-dependent kinase inhibitor 2A (CDKN2A). My research aims to evaluate the biological and clinical consequences of these genetic changes commonly seen in MPM through three avenues.

1. Understanding the biological consequences of these genetic changes: Up to 76 per cent of MPM have BAP1 loss while more than half demonstrate homozygous deletion of CDKN2A. The biological consequences of these losses have not been fully characterised. We will use established primary MPM cell lines from clinical samples with different BAP1 and CDKN2A expression profiles to determine: the cell proliferation and migration rates of these cell lines, determine the sensitivity of these cell lines to chemotherapeutic agents routinely used clinically (in other words pemetrexed, cisplatin and gemcitabine) and agents previously reported to be effective in the absence of BAP1 expression (in other words the PARP inhibitor olaparib in combination with a PI3K-mTOR inhibitor).
2. Understanding the frequency of BAP1 and CDKN2A loss in an Australian cohort: Since January 2015 to December 2018, 200 patients have been diagnosed with MPM at PathWest, Nedlands. The average age of patients is 72 years and 80 per cent are male. BAP1 protein expression by immunohistochemistry (IHC) and CDKN2A status by fluorescence in-situ hybridisation (FISH) has been assessed for a subset of these cases. We propose to determine the frequency of BAP1 loss of protein expression by IHC and homozygous deletion of CDKN2A by FISH in this cohort where sufficient material is available.
3. Correlating these genetic changes with clinical and epidemiological data: For MPM cases where tumour BAP1 and CDKN2A status has been determined (in 1 and 2) we will correlate expression profiles with patient survival from diagnosis; cancer history; asbestos and tobacco–exposure data; and clinical response to chemotherapy. Survival data and the incidence of other cancers in this population is available through the Western Australian Mesothelioma Registry (WAMR) which maintains a comprehensive, validated record of MPM cases for the State. Asbestos and tobacco exposure data is available for a subset of MPM cases enrolled on the Genetic Understanding of Asbestos Related Disease (GUARD) study, (Prof Creaney is a CI on this study). Clinical response to chemotherapy data is available for a subset of cases who have previously consented to be part of the Tumour Immunology Group – National Centre of Asbestos Disease biobank (managed by Prof Creaney).

Results from this research will provide valuable information regarding the frequency of these genetic changes in an Australian cohort. Preliminary data examining BAP1 IHC and CDKN2A FISH in the pathological assessment of difficult cases suggests that these may be valuable in the diagnostic pathway. Results may also have clinical significance for patients, in that predicting prognosis impacts treatment selection. Additionally, molecular profiling of patients likely to respond to a given agent may improve treatment planning. Improved understanding of the underlying genetic events in MPM may lead to development of new treatment strategies.

Chief Investigator

Mr Joel Kidman

Organisation

University of Western Australia

Awarded funding

$120,000 (3 years)

Malignant mesothelioma is an aggressive and incurable cancer caused by asbestos. Standard treatment of chemotherapy is predominantly palliative with patients having a median survival of approximately 12 months. This poor prognosis highlights the need to develop new therapies. Immunotherapies, such as immune checkpoint blockade (ICPB, anti-PD-L1/CTLA-4) have transformed the treatment modalities of other cancers such as melanoma and non-small cell lung cancer, with long-term tumour regression observed in approximately 20 per cent of treated patients.

ICPB treatments for mesothelioma are currently being assessed by other research groups and ourselves, with responses similarly observed in a small proportion of treated patients. It is unknown why only a minority of patients respond to ICPB, but others do not.

The project aims to understand mechanisms that underlie successful responses to ICPB by characterising features of the immune system in responding and non-responding individuals. To achieve this, Joel will utilise unique preclinical models, novel technologies such as immuno-sequencing, network biology and machine learning to help me unravel this complex question.

This project is significant because they will develop a predictor of response to treatment outcomes for mesothelioma patients. There is currently no single accurate biomarker that will predict immunotherapy response. Having a biomarker will aid clinicians in tailoring treatment plans, saving time, costs and preventing side effects. Furthermore, in-depth understanding of therapy mechanisms will help develop novel ways of converting non-responders into responders.

Joel's focus is on T cell receptors (TCR), as T cells are a group of immune cells pivotal in CPB responses. The hallmark of T cell function is antigen-specificity, which is determined by a diverse set of antigen receptors. Notably, the collection (repertoire) of TCRs in any given individual is highly different, and Joel hypothesizes this difference is why some patients respond to therapy but others do not, and novel network analysis of TCRs provides a biomarker of response to therapy.

The project aims are:

1. To characterise features of the T cell repertoire that change over time in responding and non-responding animals to ICPB.
2. To develop novel computational analyses of T cell sequencing data that will generate a biomarker of response to ICPB. Joel will utilise an established preclinical model that closely mimics ICPB responses observed in the clinic.

Joel will use cutting-edge sequencing technology to exhaustively characterise the T cell repertoire. Data sets produced by T cell repertoire sequencing require novel analysis methods beyond the standard methods that are currently used. Joel will apply novel network analysis, machine learning, and mathematical modelling in my analysis workflow to provide a rigorous understanding of nuanced differences in T cell repertoire over time.

These methods may provide insight that were not previously obtainable from traditional data modelling. Joel will subsequently validate my approach using serial blood samples from mesothelioma patients undergoing ICPB and chemotherapy. All patients outcomes are blinded, and Joel will determine if TCR analysis can reliably differentiate patient outcomes, and if so, at what time point can the effect a mesothelioma patients treatment be known.

Chief Investigator

Dr Paris Clarice Papagianis

Organisation

Monash University

Awarded Funding

$240,000 (3 years)

Dr Papagianis and her research team will screen for early signs of silicosis, using a non-invasive, portable device which analyses exhaled breath. Early detection will limit hospital presentations, encourage individuals to better mitigate their workplace risk and reinforce safety regulations when working with silica-containing products.

The problem:

Silicosis is an incurable but preventable lung disease, whereby inhalation of silica dust causes irreversible lung fibrosis. Silicosis is predicted to impact 100,000 Australians, of which 10,000 will develop cancer (ACTU, 2022). Screening of stone-workers in Victoria identified 1-in-4 with silicosis (OccupEnvironMed. 2021). The only effective treatment is lung transplant at end-stage disease.

Silicosis screening is invasive and time-consuming, involving multiple hospital visits for lung function tests, blood sampling and X-rays; all with direct costs to employers and employees. Furthermore, early detection is complicated by vague symptoms, including fatigue or shortness of breath. Currently, silicosis cannot be diagnosed without hospital visits.

Easy, early screening is urgently needed to identify at-risk workers.

Solution:

Dr Papagianis research team’s non-invasive screening device for silicosis will rely on detection of volatile organic compounds (VOC) in breath, as reported in lung cancer and fibrosis. In 2023, the DDB funded team’s collection of lung fluid from people with silicosis through invasive bronchoscopy. Preliminary analysis has identified silicosis-specific compounds that may also be present in breath. Research team’s easy to apply, non-invasive screening device collects breath in 10 minutes and can be used at worksites, with no costs to employees. Based on differences the research team has detected in blood (Respir, 2022) and lung fluid (unpublished), they are confident of identifying different VOCs in early and established silicosis for rapid workplace screening.

Study design for analysis of VOCs in exhaled breath:

Study A: Engineered stone-induced silicosis

• N = 150; 50 silica-exposed but no fibrosis, 50 silicosis, 50 healthy age-matched controls

• Our pre-established, well characterised cohort will identify different VOC profiles.

Study B: Analysis in workers from alternative occupations

• N = 400; 100 mining-induced, 100 quarry-induced, 100 tunnelling-induced, 100 controls

• This will highlight different VOC profiles with silica source and environment.

For initial studies, VOCs will be analysed using gas chromatography-mass spectrometry in specialised labs at Monash. Dr Papagianis's research team's portable screening device for workplace testing will then be fitted with detectors that reveal silicosis markers in exhaled breath immediately. The device will use a traffic light system: red means 'remove yourself,' amber means 'proceed with caution,' and green means 'safe.

Benefits to patients:

Identifying silicosis before lung function decline, will: 1) reduce hospital presentations, 2) reduce employer costs, 3) increase time at work, 4) provide better health management for longevity, and 5) prevent escalating silicosis cases. Early screening will allow individuals to manage workplace risk and to continue, rather than cease work.

National implications:

In 2023, the National Dust Disease Taskforce and the Federal Government announced their priority for a national silicosis registry and early screening. Dr Papagianis research team is targeting the construction and manufacturing industry, which make up the highest number of serious illnesses from workplace claims (Work Safe Aus.). Their timing with this project is highly relevant at a state and national level.

Chief Investigator

Dr Chandnee Ramkissoon

Organisation

The University of Adelaide

Awarded Funding

$240,000 (3 years)

The re-emergence of silicosis associated with engineered stone (ES) fabrication work is an occupational health disaster. Recently, the Australian Government agreed to consider prohibiting or banning ES to reduce workplace exposure to silica dust and prevent further disease. The government also emphasised the need for better risk awareness concerning silica exposure in occupational settings.

In anticipation of a potential ban on 'traditional' ES products, alternative 'new-generation' low-silica (10-40%) ES products are being marketed as 'safer' options, comparable to natural stones such as granite (which contains up to 40% silica). However, there is limited evidence to support a cut-off content for silica in ES that would be considered 'safe' for processing. In fact, natural stone benchtops like granite and marble are not commonly processed to the same extent as ES products, so little is known about health outcomes in comparable exposure scenarios.

The project's purpose is to provide scientific validation for policy changes aimed at reducing workplace exposure to silica in dust-generating industries. The research outcomes will help establish a critical cut-off level of silica in ES and other silica-containing materials, thereby raising awareness of silica risks in occupational settings. These efforts align directly with the 2020-2024 Dust Diseases Board Grant Strategy.

Characterising Low-Silica ES Dust Emissions

Using existing industry links, Dr Ramkissoon will first source current 'low-silica' ES products that are commercially available. She will then generate and capture respirable dust particles by cutting, grinding, and polishing these stones under real-world conditions in an Australian-first custom-made test chamber. Finally, Dr Ramkissoon will forensically characterise the physical (particle size, surface area) and chemical (mineral, elemental, organic) properties of the dust particles, aiming to correlate these characteristics with biological responses.

Linking Low-Si Dust Exposure to Lung Cell Response

Preliminary work with Prof Zosky from the University of Tasmania has identified specific cellular/molecular pathways that are unique to ES dust, pointing to particular components of ES that pose the highest risk to lung health. Using well-established protocols and state-of-the-art biochemical techniques, Dr Ramkissoon will evaluate the inflammatory potential of low-silica ES dust in comparison to typical high-silica ES. This will address two key gaps: the safety of low-silica ES products and the identification of a cut-off level for silica in building materials that could inform regulation and prevent disease.

Raising Risk Awareness to Silica Exposure Using Online Resources

Dr Ramkissoon will contribute directly to existing online educational platforms such as 'Breathe Freely Australia' by the AIOH® and 'Clean Air. Clean Lungs.' by Safe Work Australia. She will develop an occupational silica exposure estimating tool, allowing workplace managers to conduct more effective risk assessments and implement controls. This tool will be trialled by relevant end-users, facilitated by key stakeholders like the AIOH, and disseminated for education and training purposes across the industry.

Chief Investigator

Dr Jonathan Chee

Organisation

University of Western Australia

Awarded funding

$240,000 (3 years)

Immune checkpoint therapies (ICT) that target programmed death (PD)-1, PD ligand (PD-L)1, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 have revolutionized treatment of some advanced cancers, occasionally leading to durable responses.

ICT is changing how oncologists approach mesothelioma treatment (Baas et al. Lancet 2021). Our recent positive phase II DREAM clinical trial also showed promising activity in mesothelioma patients that received anti-PD-L1 antibody durvalumab in combination with cisplatin and pemetrexed chemotherapy (chemo-ICT) (Nowak et al. Lancet Oncology 2021). However, only a subset of patients benefit from ICT or chemo-ICT. Furthermore, there are financial costs and toxicities that come with ICT.

Dr Chee's research aims to investigate the immunological mechanisms that underlie successful anti-tumour responses in patients treated with chemo-ICT. Mechanistic understanding of therapeutic response will accelerate the development of predictive biomarkers. Not all patients benefit; an accurate predictive biomarker of response will help oncologists stratify patients, and develop new treatment strategies for those unlikely to respond. Dr Chee's research addresses this unmet need for a biomarker of response, and develops novel strategies to improve therapy responses for patients with mesothelioma.

Theme 1.  Identifying immune biomarkers of response to chemo-ICT in mesothelioma.

As ICT removes the suppression imposed on the anti-tumour immune response, I posit that changes in immune cells can act as biomarkers of response. I will characterise individual immune cells from longitudinal peripheral blood and pleural effusion samples collected from our DREAM clinical trial with high throughput single cell sequencing. Using novel network and time-series analysis of sequencing data, we previously identified biomarkers of response, and druggable targets that improved ICT responses in murine mesothelioma. I will use these established approaches to identify changes in immune cells gene expression that will be predictive of chemo-ICT response. If successful, results from my project could impact the design of biomarker studies in the 480 patient international phase 3 study (DREAM3R), which is co-led by Prof Nowak. This is an unparalleled opportunity to impact patients affected by dust related cancers both locally and internationally.

Theme 2.  Targeted epigenetic modification to improve mesothelioma responses to ICT

The second theme develops novel strategies to improve ICT responses. In collaboration with A/Prof Blancafort, I will develop state of the art Epi-CRISPR technology that precisely reprograms the epigenetic state of target genes within cells. Using Epi-CRISPR, I will upregulate or repress immune-related genes that will improve the immunogenicity of mesothelioma tumours. Targets will be identified from published studies, or from DREAM clinical data. Epi-CRISPR will be tested in vitro, and in vivo in preclinical mesothelioma models treated with ICT.

Targeted delivery of Epi-CRISPR to mesothelioma tumours in vivo can be achieved by designer liposomes and nanoparticles, which are ongoing areas of research by the collaborative team. Cancer targeting CRISPR based technologies are currently being assessed in phase I clinical trials, highlighting the feasibility of testing this approach. If successful, the NCARD team has the necessary technical and clinical trial expertise to move this precision based therapy into further preclinical studies and eventually clinical trials.

Chief Investigator

Dr Christina Begka

Organisation

Monash University

Awarded funding

$240,000 (3 years)

The problem. Silicosis is a devastating progressive fibrotic lung disease initiated by inhalation of silica dust. Although new regulations in NSW for preventing occupational exposure to silica are about to be put in place (as of July 1 2020), the burden of this disease is under-appreciated and individuals previously exposed to silica through dry-cutting practices in NSW and throughout Australia will still be presenting with lung fibrosis for years to come.

Current known cases merely reflect the “tip of the iceberg” of this emerging public health emergency. Currently, there is no known pharmacological treatment, and there is a paucity of data to help inform clinical decisions on treatment.

Our goals

Utilizing a new animal model of silicosis, the goal of this project is to ascertain whether two highly translational interventions could hold potential for treatment of people suffering from silicosis, specifically:

• whether targeted broncho-alveolar lavage is effective at removing silica from the airways and consequently reducing disease progression, and
• whether removing silica-ladened macrophages and restoring healthy airway macrophage populations re-establishes lung health.

A novel model system

Dr. Begka has established a world-first mouse model of lung silicosis, where through the use of a miniaturized endoscope, equipped with a camera and irrigation channel, a dose of silica can be delivered directly to a single lung lobe. This results in the development of silica pathophysiology and fibrotic nodules only in the selected lobe, while the counter lobe remains unaffected and provides an internal control for the model and interventions to be tested.

Aim 1

Therapeutic intervention by segmental broncho-alveolar lavage (BAL) for the removal of silica dust. We hypothesize that by reducing the burden of silica in the airways we will reduce disease severity and progression. In our new model, we can perform lobe-specific lavage to remove both silica particles and “foamy” macrophages, characteristic of alveolar proteinosis and silicosis. We will wash distinct lung lobes at different stages of disease, and track the impact of this intervention on disease development, using a NanoPET/CT small animal scanner, and lung function. In addition, we have established a multi-omics (lipidome, metabolome, RNAseq) analysis pipeline that allows in-depth analysis of disease causing pathways.

Aim 2

Targeting airway macrophages to restore lung health. Dysregulated macrophage functionality in the airways could drive disease pathology in silicosis. We will induce silicosis throughout the lung, then pharmacologically remove macrophages in a single lobe, followed by repopulation of that lobe with healthy macrophages. Disease progression in the individual lobes will be monitored as in Aim 1.

Outcomes

Our evaluation of the use of lung lavages and macrophage restoration strategies is not only novel but, by design, highly translational. Clinically, lung lavage is a viable, albeit yet to be implemented therapy for lung silicosis. Similarly, restoration of macrophage populations is feasible with clinically approved drugs. Data yielded from our unique model system will provide the much-needed platform for clinical studies and holds the potential to make a substantial impact on patient care in the medium term.

Chief Investigator

Dr Anna Yeung

Organisation

Woolcock Institute of Medical Research

Awarded funding

$240,000 (3 years)

Silicosis is an incurable lung disease caused by inhaled crystalline silica dust whereby prolonged exposure manifests into nodular lesions and chronic inflammation in the lungs. Historically coal and gold miners were the most common occupations affected by silicosis, which can develop from chronic (more than 10 years) exposure to moderate levels of respirable crystalline silica (RCS).

In recent years however, Australia has seen a dramatic rise in the number of cases of acute silicosis, especially among young stonemasons and builders, which have been linked to the increase use of engineered stone – a popular material used in kitchen and bathroom benchtops. Cutting, sanding and drilling into stone materials generate large amounts of dust, such high exposure levels of RCS vastly reduces the timeframe for the onset of silicosis down to five years, and in extreme cases onset can occur after a few months.

Although safe work practices such as adequate ventilation, using wet cutting techniques and wearing protective masks are in place to reduce exposure to RCS, however may be ignored or perhaps unable to be implemented. As such, the current proposal aims to increase the understanding of how RCS cause damage to the lung epithelium using cellular models and looking at the physiological impacts. Ultimately this work aims to affect policy to reduce RCS exposure and improve the safety of workers.

The project will look at four specific aims:

Aim 1

Investigating the size of RCS particles and the duration of time that particles remain in the air following wet and dry cutting in well-ventilated and non-ventilated rooms. The project will utilise an Andersen Cascade Impactor designed to capture particles, and a laser particle counter to enumerate particle size and number generated under different cutting conditions.

Aim 2

Investigate the toxicity effects of different sized RCS particles on macrophage uptake and airway epithelial cell toxicity. Blood-derived macrophages and airway epithelial cells differentiated at air liquid interface will be exposed to different sized RCS particles. Dr Yeung will measure particle uptake by macrophages - a process thought to play an important role in silicosis disease progression, and also measure toxicity effects on airway epithelium. The outcome of this aim will show whether some particle fractions are more toxic than others.

Aim 3

Determine the effectiveness of cheaper protective masks (50 cents - $1.50) in the protection against harmful RCS particles. Dr Yeung has identified a number of N95 respirators that are inexpensive. Dr Yeung would like to evaluate their effectiveness against high-level exposures to RCS (some N95 respirators easily clog up, leading to workers removing), and then engage with major suppliers of manufactured stone products to see if such respirators could be supplied with their products.

Aim 4

Develop multi-language information pamphlets (English, Chinese, Arabic) in consultation with stonemasons and contractors. Many people with silicosis in the building industry come from non-English speaking backgrounds, and are not aware of the dangers of RCS. Therefore, much like the images placed on cigarettes we aim to produce similar warnings labels that could be placed on cutting discs.