Current Research
The ADDRI conducts biomedical (preclinical), clinical and public health research into asbestos-related diseases with findings enabling improved methods of prevention, diagnostic, therapeutic procedures, and treatments. As one of the smallest independent medical research institutes (iMRI) in Australia, ADDRI aims to create momentum by crossing disciplines internally and collaborating externally.
Our biomedical (preclinical) research focuses on a variety of molecular and biological techniques and utilises the invaluable biological specimens stored in the ADDRI Biobank to further research into asbestos-related diseases. Our patient support reaches out to mesothelioma patients who are undergoing therapy or post-therapy in the community, thereby integrating clinical and public health approaches. Biomedical (preclinical) research is conventionally conducted in the context of translational research, i.e. “from bench to bedside” to which ADDRI gives a major emphasis. At ADDRI, we aspire to add another dimension to translational research with public health/preventative. We call this “from bench to the public.”
Aim
Pulmonary diseases related to human exposure to asbestos are becoming an increasingly common major health concern, both in Australia and worldwide. It is now widely understood that asbestos fibres are highly pathogenic, capable of causing several different asbestos-related diseases in humans, including asbestosis, lung cancer and malignant pleural mesothelioma (MPM). MPM is an aggressive asbestos-related disease, with global incidences rising steadily over the past decade. Due to the long latency period from exposure to the onset of symptoms, and with no distinctive biomarkers to differentiate it from other lung diseases, it is challenging to diagnose MPM at an early stage. Consequently, prognosis is typically poor, with median survival ranging from just 9 to 12 months once a patient has been diagnosed with MPM.
There is a combination of factors that can be attributed to the inadequate diagnosis and treatment of MPM in the clinic. These include a lack of existing knowledge of the molecular mechanisms that leads to the development and progression of the disease, a lack of existing biomarkers to facilitate an early and accurate diagnosis, as well as a lack of effective treatment strategies. Therefore, the main aim of pre-clinical research undertaken in ADRI’s laboratories is to improve the following key areas in relation to ARDs; 1) knowledge of disease mechanisms, 2) biomarker discovery and development, and 3) development of novel treatment strategies.
Impact
The biomedical research being carried out at ADRI utilises cell lines and patient-derived biospecimens sourced from ADRIs continually expanding and extensive biobank; which includes (but is not limited to) over 130 cell lines, and more than 250 matched MPM tumour tissue and blood samples. Conducting experiments on these valuable biospecimens ensures that the data gained from our investigations are biologically relevant and provides us with a reliable indication of how the novel biomarkers and treatment strategies would perform when translated to the clinical setting. By successfully addressing the three key objectives (mentioned in our aims above), in combination with the biospecimens procured from ADRIs extensive biobank, it is hoped that ADRIs pre-clinical research will lead to novel diagnostic and treatment strategies that have the potential to progress to the clinical setting.
Additionally, we have established a genetic testing laboratory. Currently we are in the process of seeking NATA accreditation for this laboratory and have successfully fulfilled the requirements for the first advisory visit and external quality assessment; both of which are important milestones towards receiving full NATA accreditation. We are looking forward to completing the NATA accreditation process this year. The successful attainment of NATA accreditation with an ISO standard will ensure the quality, safety, and efficiency of the genetic testing to enable biomarkers that are developed to be fast tracked into the clinic, and in doing so will broaden ADRIs network within Australia’s public healthcare system.
Current Research Projects
The development of a novel 3D model for drug screening in mesothelioma. To accelerate drug screening for the treatment of malignant mesothelioma into the clinic we have developed a 3D scaffold using porcine lung. Currently most drug screening systems rely on a 2D culture system where cells are grown as a single layer attached to a plastic surface. With the novel 3D scaffold, one of the major advantages is that it provides a biocompatible adhesive architecture for cells to grow. When compared to 2D culture, cells grown in this 3D model exhibited markers and expression levels were comparable to that of real tumours. Over the next three years we plan to further characterise the cancer biology and drug responses of this 3D model. This project is funded by the Dust Diseases Board.
Epigenetic variations are the biological mechanisms that switch genes on and off, the key processes of cellular development and carcinogenesis. These modifications are considered a hallmark of cancer and have attracted considerable attention over the past decade for developing biomarker detection methods and therapeutic discovery for various malignancies. Epigenetic variations could potentially be used to identify biomarkers in blood samples for cancer due to their accuracy, specificity, and ease of collection, or as targets for therapeutics in the treatment of mesothelioma. Over the coming years we will continue our research in this area.
Circular RNAs (circRNAs) are noncoding competitive endogenous RNAs (ceRNAs) that originate from within and interact with microRNAs as ‘sponges’ via direct binding, subsequently leading to their repression. CircRNAs are dysregulated in cancer and are cell-type specific, thermodynamically stable, and highly conserved; therefore, we will continue our research on circRNA expression as potential blood-based biomarkers for the detection of MPM. This project is funded by the Dust Diseases Board.
The discovery of circulating RNAs, a genetic marker which can be found in the blood, is an also an attractive and innovative option to be considered in asbestos-related cancer (ARC) research due to their stability and substantially in blood circulation. This will potentially allow for the identification of mesothelioma at an early and potentially treatable stage. To study circulating RNAs in ARC patients we will utilise ADRI’s biobank collection, one of the largest collections of ARC biospecimens available in Australia. We anticipate that this project will lead to the discovery of early biomarkers for identification of ARC.
There is an urgent need to identify highly specific and sensitive biomarkers for the detection MPM via a less invasive method. Currently there are more than 15 biomarkers used in the clinic to differentially identify MPM, but none are highly specific or sensitive. The co-deletion of the genes CDKN2A and MTAP, have been shown by researchers to be a highly specific characteristic of MPM, which can potentially be utilized in the development of a less-invasive method to diagnose MPM. In this project we will ultilise ADRI’s extensive biospecimen collection to validate the detection of both CDKN2A and MTAP loss by droplet digital PCR (ddPCR), which in turn could potentially be used in developing a less-invasive method of biomarker detection for malignant mesothelioma from cell-free tumour DNA.
