Research
Research Projects
Lung Cancer Whole Genome Sequencing
Lung cancer is the biggest cause of cancer deaths in Western countries including Australia with smoking accounting for 85-90% of lung cancers. In the remainder, the specific aetiology is uncertain with passive smoking, asbestos, cooking fumes and other carcinogens implicated in some cases. Never smoking lung cancers are enriched for specific somatic gene mutations such as EGFR exon 19 and 21 sensitising mutations, EML4/ALK fusion mutations and both represent effective therapeutic targets. We collaborated with the International Cancer Genome Consortium and The Cancer Genome Atlas (TCGA) is to identify other relevant driver mutations by interrogation of the genome by supplying high quality resected lung cancer tissues (adenocarcinoma and squamous cell carcinoma). We seek to complement this work by undertaking genomic analysis of never smoking adenocarcinomas in order to identify other therapeutic targets.
Epigenetic Profiling of Lung Adenocarcinoma from Never Smoking Patients
Lung cancer is thought to be due to the accumulation of insults to cells. Lung cancer in patients who have never smoked may have different causative cellular changes from those demonstrated in tumours that develop under the influence of a specific carcinogen, such as tobacco cigarette smoke. This study examines the genetic code of cancers from patients who have never smoked. DNA will be obtained from samples available from both The Prince Charles Hospital Tissue Bank and international collaborators, and processed by new techniques available to study the human genome. This will provide a list of changes to the gene code that may contribute to lung cancer development in never smokers. A second processing technique will be used to confirm these findings. Subsequent studies will determine the effects of these changes, and whether they are useful in diagnostic tests for lung cancer or as targets for treatment.
Genetic Mutation Testing in Clinical Practice
Lung cancer is the biggest cause of cancer deaths in Australia and the world. Scientific advances are allowing us the technically measure these genetic mutations that lead to lung cancer with relative ease and accuracy, but lagging behind is the clinical translation to actual patient benefit. Here we address the challenge in translating these innovations to practice, by testing genetic mutations in samples obtained during diagnostic testing, compared to lung cancer surgery specimens.
Treatment-Responsive Mutation Testing in Lung Cancer
Lung cancer is a leading cause of cancer death and disease burden in many countries including Australia. Understanding the biological pathways involved in lung cancer is required to identify key biomolecules that could be of significant clinical value, either through serving as predictive, prognostic or diagnostic markers, or as targets for the development of novel therapies to treat this disease.
It is well-recognised that 'EGFR' mutation testing is a biomarker that has direct clinical relevance to patients with lung cancer. Patients who have demonstrated EGFR mutations in their lung cancer tissue are eligible for specific treatments that target these mutations i.e. treatment with specific inhibitors, that potentially improve survival when used. This study will therefore test the feasibility and diagnostic accuracy of undertaking biomarker mutation testing during routine treatment of patients.
Low Dose CT Screening for Lung Cancer
Lung cancer is the biggest cause of cancer deaths globally including Australia. Patients often present at a late stage when curative intent treatment is no longer applicable. Lung cancer screening efforts by CXR and sputum testing are ineffective. NLST, the US National Lung Screening Trial, compared low-dose computed tomography (LDCT) and standard chest X-ray, found that low-dose computed tomography screening statistically significantly reduced lung cancer mortality by 20% in high-risk individuals.
In Queensland, our current LDCT observational screening study based on the NLST design, has identified 10 lung cancers in 256 high-risk participants. All cancers occurred in participants with impaired lung function in addition to the inclusion criteria set by the NLST. CIs MT, SL and AM also found that lung cancer risk increased with decline in FEV1% in a British Columbia Cancer Agency study of high-risk individuals enrolled and followed prospectively. Using data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial PLCO, CI MT has developed and validated 2 lung cancer risk prediction models.
These studies collectively indicate that accurate lung cancer risk prediction using patient information and lung function tests can more precisely identify the population most likely to benefit from LDCT screening. In this way, both the efficiency and cost-efficiency of LDCT screening programs can be improved and possible harms from false positive screens be reduced. In this 2nd phase of our LDCT research program, we will collaborate with our Canadian colleagues to prospectively validate these models in a multicentre study.
A Novel X-ray Technique to find Lung Nodules
Spots on the lung are an increasingly common finding, whether intentional or incidental, due to the widespread use of computed tomography (CT) scanning and renewed interest in screening for lung cancer using low dose CT. Many of these spots are too small to biopsy or be seen on chest X-ray. There is a small possibility that these spots represent early lung cancer.
Digital tomosynthesis (DT) is a new X-ray technique that exposes patients to approximately 2% of the radiation of a CT scan and is at least 50% cheaper. Research indicates that DT may be as good as CT, and significantly better than CXR, at detecting lung spots. This project aims to formally compare the nodule detection ability of CXR and DT, using CT scan as the reference standard. We predict that DT will detect nodules and measure their dimensions as accurately as CT scan.
Cost Impact of Electromagnetic Navigational Bronchoscopy (ENB) for Lung Cancer
Currently people with distant lung cancer are often diagnosed with invasive method due to the inability to reach the lesion and take lung tissue samples. Electromagnetic navigational bronchoscopy (ENB) could potentially provide a similar effective, but less invasive, way for obtaining lung tissue samples thus is safer than the current methods.
Before introducing ENB into the healthcare system in a large scale, it has to be proven to be, firstly, useful and safe in detecting lung cancer. Secondly, the cost of using ENB has to be justified when compared with the current methods used, whether with an increased cost, similar cost or decreased cost. This project aims to evaluate value for money of ENB by looking at the cost of using ENB for diagnosis of distant lung cancer taking into consideration of its usefulness in detecting distant lung cancers.
The Journey of Rural and Urban Patients with Suspected Lung Cancer
Lung cancer is the leading cause of cancer-related mortality in Australia. We suspect that the journey of patients with suspected lung cancer referred to a tertiary hospital is different between non-urban and urban patients. To address this issue, we will follow patient journeys for people referred with suspected lung cancer, both from urban and non-urban centres. We will identify differences in logistical and psychosocial factors, and quality of life impact, of people undergoing diagnostic evaluation. We will then be able to use these observations to improve reversible factors that impact on this journey on patients.
Biomarkers of Severity, Recovery and Recurrence of COPD Exacerbations
Chronic obstructive pulmonary disease (COPD) is an incurable disease characterised by a persistent blockage of airways from the lungs. Patients with COPD are occasionally afflicted with acute exacerbations (AECOPD), which result in a worsened health status, accelerated lung function decline and reduced survival. Hospitalisation of these patients costs hundreds of millions of dollars each year and the symptoms are not adequately explained by clinical, pathophysiological or health care factors. Thus, a better understanding is needed of the factors that determine severity, rate of recovery and recurrence of exacerbations. As respiratory infections are the major trigger, it is plausible that inflammatory biomarkers are highly relevant. Early detection of these biomarkers in blood and serum can be used to predict severity, recovery and recurrence of AECOPD, which could then influence management of this disease.
Interventions against air pollution
Adverse health effects from air pollutants remain important, despite improvement in air quality in the past few decades. While it is imperative to contain rising levels of air pollution, it is also important that strategies be developed to minimise the damaging effects of air pollutant exposure on the lung, especially for patients with chronic lung disease. Diesel exhaust particles are increasingly recognised as a toxic component of air pollution, leading to inflammation and other injury in the lungs. This project will investigate interventions against the toxicity of diesel air pollutants exposed to bronchial cells tested in the laboratory.
Genetic and Epigenetic changes in COPD and Increased Susceptibility to Lung Cancer
Chronic obstructive pulmonary disease (COPD) is a potentially fatal chronic lung disease with no currently available cure. Amongst the mechanisms potentially involved with COPD, epigenetic modifications (changes to gene expression without direct alteration to the DNA sequence), including DNA methylation, in the lungs could provide the basis for many of the altered biological pathways in COPD. Environmental factors such as smoking, diet, air pollution and infection all affect DNA methylation patterns and therefore patterns of gene expression, with potential implications for the ageing lung. It is known that: 1. DNA methylation status alters gene expression; 2. Changes in DNA methylation occur with COPD; and 3. Changes in mRNA expression occur in COPD lung. We aim to discover clinically relevant alterations in gene expression that could prove useful for risk stratification and development of new therapeutic targets for COPD through correlation of transcriptome sequencing and gene methylation profiles, to identify potential targets that could be predictive and/or indicative of the development and severity of the disease. As it is well-established that COPD and lung cancer commonly coexist in smokers, and the presence of COPD increases the risk of developing lung cancer, we will also investigate changes in COPD relating to increased susceptibility to lung cancer.
Mobile health for COPD
Clinical guidelines for chronic obstructive pulmonary disease (COPD) are available for use by clinicians; however, the dissemination of these, despite systematic efforts, is still suboptimal. Similarly, educational resources for patients with COPD are widely available in hard copy and online; however, patients do not always access these appropriately in a timely manner. This project will address these gaps, by using mobile technologies to deliver medical management tools to clinicians, and self-management tools to patients, for enhanced management of COPD. The expected outcomes of this study will be enhanced uptake of COPD guidelines by clinicians, and improved self-management of COPD by patients, through application of mobile health technologies.
Characterisation of Mesothelioma Cell Lines
Mesothelioma is a deadly asbestos related cancer that may develop many years after the exposure to even a small amount of asbestos. There is no known cure but chemotherapy may prolong survival in patients who respond. Australia has the highest incidence of mesothelioma per capita in the developed world, and a strong track record in mesothelioma research. To sustain international research competitiveness and capitalize on emerging technologies with potential to discover therapeutic targets for mesothelioma, the 2011 NCARD meeting ratified the need for curated national tissue banks and cell line repositories to facilitate mesothelioma research. This project aims to establish a fully annotated tissue bank and genomic DNA source, and a fully characterized mesothelioma cell line repository.
Whole Genome Sequencing of Mesothelioma
Mesothelioma is a deadly asbestos related cancer that may develop many years after the exposure to even a small amount of asbestos. There is no known cure but chemotherapy may prolong survival in patients who respond. Whole genome sequencing has paved the way for large-scale analyses of tumour biology. The project aims to sequence complete genome of mesothelioma tumour samples and use this data to elucidate tumour biology and identify novel candidate therapeutic targets. Firstly; the cell lines (cultured from the biopsy / pleural fluid samples from patients) will be characterized and the second part will include sequencing of whole genome to reveal the deeper complexity of the disease. That will lead to identification of key dysregulated pathways, which can better inform prognosis, and enable targeting of therapies to improve outcomes.
Anti-cancer Activity of Candidate Drugs for Mesothelioma
Malignant Mesothelioma (MM) is an aggressive pleural malignancy caused by asbestos. It will be a major health threat for many years to come, but peak incidence in Australia is occurring this decade. Current treatments are of limited effectiveness with few active chemotherapy agents available. For the last two years we have been involved in discovering compounds with activity against mesothelioma by screening mesothelioma cell lines with the John Hopkins Clinical Compound Library (JHCCL) (>1500 approved drugs). After a pharmacotoxicology literature search, we have short listed 8 anti-mesothelioma compounds and now aim to confirm the activity of these drugs in mesothelioma cells derived from an independent set of individuals. Drugs with confirmed anti-mesothelioma activity can then be tested in clinical trials. If successful, this approach may result in new and more effective treatment for patients with mesothelioma.