Professor Doug Brooks

Professor Doug Brooks is the leader of the Mechanisms in Cell Biology and Disease Research Concentration in Clinical and Health Sciences Academic Unit and the Cancer Research Institute at the University of South Australia. Doug has over 30 years experience in medical research and is a Research Professor in Molecular Medicine at UniSA and Affiliate Professor of Cancer Pathology at Trinity College Dublin (TCD).

Doug had his initial research training in Immunology with a focus on cancer research, involving the immunochemistry of cell surface antigens and involved the translation of cancer biomarkers for B-cells into clinical practice (Becton Dickinson).

For 24 years Doug worked in the Lysosomal Diseases Research Unit at the Women’s and Children’s Hospital, on a group of genetic diseases called lysosomal storage disorders. The Lysosomal Diseases Research Unit has been responsible for significant health outcomes for this group of disorders, with the development of strategies for early screening, diagnosis and treatment (technology commercialised by BioMarin and Genzyme). This research reflects Doug's strong interest in lysosomal cell biology and a desire to develop practical applications in biochemical medicine that benefit patients and the wider community.

The Mechanisms in Cell Biology and Diseases Research Group has two main research themes involving basic and applied medical research on cancer (major theme) and immunity (collaboration involving RMIT and TCD). These project areas are heavily aligned with the national research priorities of Promoting and Maintaining Good Health, A Healthy Start to Life, Aging well and Preventative Health Care. The Mechanisms in Cell Biology and Disease Research Group's primary objective is to facilitate technological advances that result in research outcomes that can be translated into clinical practice to directly benefit cancer patients and their families.

Current research projects include:

1. ENDOSOME-LYSOSOME CELL BIOLOGY AND VESICULAR TRAFFIC.  Investigate basic endosome-lysosome cell biology and developing innovative technologies: Facilities that build capacity in cell biology have been established through competitive ARC LIEF grant funding, UniSA infrastructure support, and commercial/philanthropic funding. State of the art infrastructure has been acquired to establish: Biophysical Characterisation Facility (CD spectrometer; calorimeter; and Biacore), Advanced Intravital Imaging Facility (Zeiss 710 META NLO confocal with FLIM, multiphoton, pulsed laser and spectral capacity; Vivascope with FLIM and Horiba Raman capacity), Non-invasive Analysis technology (2 specialised IRMS); A complete histopathology facility with tissue cutting, processing and digital imaging capacity; Live cell and automated imaging facilities. These facilities directly support cutting edge cell biology research projects. There are challenges in the diagnosis, prognosis and treatment of cancer that necessitates further research into the pathogenic process. The endosome-lysosome compartments are often abnormally located in cellular periphery of cancer cells and this is involved in progression of the cancer to metastasis. Retrograde and anterograde traffic facilitates homeostatic localisation of endosomes-lysosomes in cells and we are studying how vesicular traffic aligns with the development of cancer metastasis.

2.   DEVELOPMENT OF BIOMARKERS FOR PROSTATE CANCER, COLORECTAL CANCER (CRC), MELANOMA AND OTHER CANCERS. Involves the study of altered endosome biogenesis in prostate, CRC and other cancers. Every year approximately 20,000 Australian men are diagnosed with prostate cancer and more than 3,000 die of this disease. This makes prostate cancer the second largest cause of male cancer deaths and a significant health care issue, particularly in Australia where the incidence of this disease is high. We will investigate a novel aspect of endosome-lysosome cell biology in prostate cancer to identify new biomarkers. The end stage objectives for this project are therefore to develop effective methods for the early detection and prognosis of prostate cancer, which are important as this will have a major impact on patient outcome and survival. There is mounting evidence for a central role for endosome-lysosome compartments in cancer cell biology. Endosomes and lysosomes are directly involved in the critical processes of energy metabolism, cell division and intracellular signalling, and will therefore have a direct role in cancer pathogenesis. The endosome-lysosome system has a specific capacity to respond to environmental change, acting as an indicator of cellular function and will consequently be altered in cancer. Moreover, the endosome-lysosome system has a critical role in controlling the secretion of proteins into extracellular fluids, making it an ideal system to identify new biomarkers that are released from cancer cells. We therefore performed a comprehensive study of endosome-lysosome proteins in a panel of prostate cancer and non-malignant prostate cells and have demonstrated that endosome biogenesis is significantly altered. These changes in vitro have been confirmed with patient data, and we have established that the early endosome vesicular machinery is altered in prostate cancer, showing: 1. Significant increases in early endosome gene expression and protein amount, in multiple prostate cancer compared to non-malignant control cells 2. Altered distribution of early endosome organelles in prostate cancer cells 3. Altered cancer-specific early endosome gene expression in multiple prostate cancer patient datasets 4. Altered histology for early endosome proteins in prostate cancer specimens 5. Significant increases in early endosome protein secretion and concomitant decreases in late endosome protein secretion, from prostate cancer compared to non-malignant cell lines. Endosomal proteins therefore have the capacity to discriminate between prostate cancer and controls, in both cell lines and patient data bases, and none of the previously described prostate cancer biomarkers have this capacity/specificity. We are currently doing clinical trials of biomarkers in patient tissue, developing blood tests for diagnosis/prognosis, developing targeted therapeutics, developing PET imaging technology for patient imaging. We are commercialsiing this technology through Envision Sciences and also expanding our research program to focus on the primary pathogenesis in other cancers.

3. THERAPEUTIC SOLUTIONS FOR INFLUENZA AND OTHER RNA VIRUSES. We live in a world of unprecedented vulnerability with the current pandemic COVID-19 outbreak and imminent similar outbreaks due to influenza A viruses (IAV). Seasonal IAV infection continues to claim millions of lives annually and costs health care systems billions of dollars worldwide. The pathogenesis of IAV spans multiple livestock industries, which act as primary pathogenic reservoirs for the virus (e.g. birds and pigs), and given their zoonotic potential results in very significant human infection and pathogenesis. Human IAV infections cause a wide range of disease and complications encompassing acute uncomplicated disease, severe hospitalization with secondary bacterial infection, and severe hospitalization with chronic complications such as in pregnancy. However, there is neither an immediate or effective strategy to treat epidemic and pandemic IAV outbreaks nor an effective program to eradicate the virus from within the critical livestock reservoirs. The critical knowledge gaps that have hindered development of pan viral therapeutics are centred on a general lack of understanding of how the immune system both spatially and temporally regulates the disease process. In this regard, we have made 3 pioneering discoveries recently published in Nature, Cell and Nature Communications. We have demonstrated: 1) That IAV evades the immune system by promoting the production of reactive oxygen species in endosomes via a novel TLR7-NOX2 oxidase signalling axis that drives viral replication and the ensuing pathology. 2) That infection promotes a switch in cellular metabolism in immune cells, like macrophages from oxidative phosphorylation to glycolysis that drives inflammation and key intermediates for virus replication. 3) A novel powerful anti-inflammatory and anti-bacterial mediator called itaconate to be generated by the TCA cycle of metabolic pathways within immune cells. These findings have unravelled a 3-stage disease process that will ultimately necessitate a combination of therapeutic interventions. This work has also been patented: PCT/AU2018/050667 (Australian Provisional Patent Application No. AU 2017902545): Selemidis S, O’Leary J, Brooks D. “A method of treatment for viruses” and a company has been established to commercialse this technology; ViraLok Therapeutics. The therapeutic device being evaluated relates endosome biology and to the field of immunomodulation and a common conserved pathway derived over 500 million years ago.  We have developed an agent for inhibiting the heightened immune stimulation mediated by Toll-like receptor 7, which is useful in the treatment of all RNA viral pathogenesis. The inhibition of this aberrant inflammation pathway is reliant on a lead compound which is currently in pre-clinical trial. Pharmaceutical compositions are proposed and lead compound development will involve the production and formulation of mimetics. The dampening down of this immune pathway with the inhibitor results in an enhanced adaptive immune response (humoral) towards RNA and ssDNA viruses and reduced pathogenesis.

• Australian Society of Biochemistry and Molecular Biology
• Australian Society of Medical Research

Qualifications

• Doctorate in Philosophy Flinders University

• Bachelor of Science (Honours) Flinders University

• Bachelor of Science Flinders University