RESEARCH PROJECTS 2015

Transcription

1 RESEARCH PROJECTS 2015 Queen Elizabeth II Medical Centre Unit School of Medicine and Pharmacology Address: Harry Perkins Institute of Medical Research Building, QQ Block, Queen Elizabeth II Medical Centre, Nedlands Western Australia Postal Address: School of Medicine and Pharmacology M503, University of Western Australia, 35 Stirling Highway, Crawley Western Australia 6009

2 UWA School of Medicine & Pharmacology QEII Medical Centre Unit RESEARCH PROJECTS 2015 Contents Introduction to the QEII Medical Centre Unit School of Medicine and Pharmacology Bone and Vascular Research Group... 3 Centre for Cell Therapy and Regenerative Medicine... 4 Genetic Epidemiology & Molecular Genetics... 8 Respiratory Medicine Other Groups Offering Research Projects... 14

3 Nothing is more exciting than making a discovery, or testing your own original hypothesis. The efficiency of modern research has increased so much that creative people will find it a fantastic and fast moving career choice. Professor Barry Marshall AC Nobel Laureate Introduction to the QEII Medical Centre Unit School of Medicine and Pharmacology. The Queen Elizabeth II Medical Centre Unit (QEII Unit) in the School of Medicine and Pharmacology, made up of clinicians, scientists and educators, offers unique opportunities for students, scientists and doctors interested in pursuing careers in biomedical research and training across a wide range of fields in the health sciences. This booklet outlines the research and education activities within the School and with adjunct staff at SCGH and the opportunities for students and collaborators to work and study within this vibrant group. Unit Profile: Originally based around clinical academics, who work for part of their time as medical specialists at SCGH, and researchers and educators for the rest of their time, the SCGH Unit has now expanded to include a large number of research scientists. The mix of Clinical Academics, in current clinical practice, along with highly trained and motived researchers from science backgrounds offers research opportunities from basic science through to clinical research, along with intervention, translational, epidemiological and educational research projects. In addition, proximity to the hospital has allowed collaboration with adjunct academics who are active researchers. Areas of Research: The School offers opportunities for students to study in many of the disciplinary areas in clinical practice, and researchers bring skills from the sciences to humanities and clinical practice. Expertise in a wide range of areas (statistical, scientific, clinical) can be found within the School or with close collaborators. SMP researchers are closely linked to research organisations and Universities sited locally, nationally and internationally, including the Lung Institute of Western Australia (LIWA), the Centre for Cell Therapy and Regenerative Medicine (CCTRM), the National Centre for Asbestos Related Disorders (NCARD), the Cancer Council and Arthritis and Osteoporosis Western Australia. Facilities: The SCGH Unit is based in the new Harry Perkins North Building on the QE11 site, a purpose built research facility developed by UWA, the Health Dept and the Harry Perkins Research Institute of Medical Research. School researchers have access to world class laboratories in an environment designed to ensure mixing of researchers and ideas, and sharing of equipment, to enhance collaboration and success. Opportunities: SMP members play a major role in the teaching for the professional practice Doctorates with a focus on the newly commenced Doctor of Medicine. As is laid out subsequently, there are many opportunities to participate in research in the School through Honours, higher degrees including Masters or a PhD, or research projects which are a required part of the MD program. 1.

4 Funding: Scholarships to cover student living are available through UWA, the Unit, linked Institutes such as LIWA, NCARD and CCTRM and external bodies such as the Heart Foundation and the Asthma Foundation Further Information: Interested people are encouraged to contact any individual academic, researcher or research group to discuss research and funding opportunities. Contact details for specific research areas or projects are listed in the following pages. You can also contact the School of Medicine and Pharmacology s Graduate Research Coordinator to get related to the specific area of research and availability of supervision within the proposed field of study before lodging a formal application. Assistant Professor Jane Allan jane.allan@uwa.edu.au Other useful links: Graduate Research Office for about admission requirements, fees and the application process. Scholarship UWA International Office for overseas students considering postgraduate research at UWA Faculty of Medicine, Dentistry and Health Sciences See what research current Medicine and Pharmacology students are undertaking profiles School of Medicine and Pharmacology s research programs 2.

5 Research Projects Bone and Vascular Research Group Bone and Vascular Research Group Meta analysis of effects of calcium and vitamin D on falls Professor Richard Prince Hons or PhD Background: Falling is a major cause of disability as women and men age. The incidence is 30% per year in older women and somewhat less in older men. As a result of the huge expansion in clinical research there are many publications based on controlled trials of interventions to prevent falling. Exercise interventions and nutritional interventions, especially calcium and vitamin D, have been the basis of many studies. To provide overviews or syntheses of these studies in a more objective way the statistical techniques of meta analysis have been developed Hypothesis: Specific combinations of calcium and vitamin D reduce falls risk in older individuals. Techniques and skills: This project will develop skills of searching the medical data base using search terms. Second it will develop skills of understanding the differences in study design and its implications on outcomes. Next it will develop skills in understanding study implications including outcome assessment. Finally it will develop skills in understanding and implementing the statistical aspects of meta analysis. Prerequisites: 1) An interest in understanding the basis of clinical research design and implementation 2) An interest in developing skills in statistical evaluation of research output Outcomes: A publishable scientific paper Professor Richard Prince Ph: richard.prince@uwa.edu.au 3.

6 Research Projects Centre for Cell Therapy and Regenerative Medicine Centre for Cell Therapy and Regenerative Medicine Elucidating the cellular mechanisms driving STAT3 mediated lung fibrosis Associate Professor Cecilia Prêle and Professor Steven Mutsaers Hons or PhD Project description: Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown aetiology that is unresponsive to current therapy. It is characterised by excessive deposition of extracellular matrix (ECM) proteins within the pulmonary interstitium, leading to impaired gas transfer, a loss of lung function and death. What drives the development of IPF is unknown but a widely accepted hypothesis is that repeated injury to the epithelium leads to dysregulated healing, initiating a cascade of processes resulting in fibroblast/myofibroblast accumulation and overproduction and deposition of collagen. Our lab has pioneered studies identifying the STAT3 signalling pathway as pivotal in the development of lung fibrosis. The mechanisms regulating STAT3 mediated fibrosis are unclear, but our preliminary data suggests that STAT3 regulation is impaired in IPF and that STAT3 mediated effects require epithelial cell and immune cell activation. Hypothesis: STAT3 mediates its pro fibrotic effects via epithelial cell activation and altered B cell mediated immune regulation. To address this hypothesis, we propose two related, yet independent aims, and each aim constitutes a separate Honours project. Aim 1: STAT3 induced changes in lung epithelium modulates epithelial cell and fibroblast proliferation, migration, cytokine and chemokine production driving fibrogenesis. Aim 2: B cells mediate STAT3 induced lung fibrosis by regulation of T cell responses. These studies will provide fundamental on the role of STAT3 signalling pathways in regulating matrix synthesis and may elucidate for the first time effective ways to develop novel therapies to treat patients with IPF. Techniques: Immunohistochemistry, real time PCR, ELISA, Western blot analysis, FACS analysis, confocal laser scanning microscopy, tissue culture, animal models. Please note that several potential projects exist within this broad programme of research and we welcome all enquires. Associate Professor Cecilia Prele Ph: cecilia.prele@uwa.edu.au The role of Bard1 in pulmonary fibrosis Professor Irmgard Irminger Finger and Associate Professor Cecilia Prêle Hons or PhD This project will be undertaken in a new Centre for Regenerative Medicine in the new state of the art research facility and with a dynamic team who produce high quality publications. Project description. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with no effective treatment. The pathogenesis of IPF is poorly understood but, TGFβ is recognised to be downstream of key pro fibrotic cascades. We have recently discovered evidence suggesting that BRCA1 associated RING domain1 (BARD1) may be an effector molecule for TGFβ s actions. It is highly expressed in the fibrotic regions of lungs of patients with IPF, and Bard1 over expression in an animal model of lung fibrosis appears to enhance the fibrotic response. BARD1 exists as several isoforms with different functions. Full length (FL) BARD1 is essential for BRCA1 function as an E3 ubiquitin ligase and for apoptosis signalling. However, isoforms lacking the BRCA1 binding domain have been associated with cancer progression. In particular BARD1β has essential pro proliferative functions in mitosis. Altered cellular apoptosis and proliferation are recognised to be central to 4.

7 Research Projects Centre for Cell Therapy and Regenerative Medicine pulmonary fibrosis leading us to investigate the role BARD1 isoforms in the development and progression of this disease. This project will dissect the molecular mechanisms by which BARD1 isoforms contribute to pulmonary fibrosis. Hypothesis: Modulation of BARD1 isoforms by TGFβ is central to the pathogenesis of pulmonary fibrosis. Aim 1: Assess BARD1 expression profiles in various lung cell types and delineate their association with inflammatory or fibrotic forms of IPF. Aim 2: Determine the role of BARD1 in the development of lung fibrosis in vivo using Bard1 Transgenic and knockout mice. Aim 3: Dissect the mechanisms by which the TGFβ BARD1 axis drives fibrosis. Techniques: Immunohistochemistry, real time PCR, ELISA, Western blot analysis, FACS analysis, confocal laser scanning microscopy, tissue culture. Please note that several potential projects exist within this broad programme of research and we welcome all enquires. Professor Irmgard Irminger Finger Ph: Irmgard.irminger finger@uwa.edu.au; Irmgard.Irminger@unige.ch Therapeutic potential of combined chemotherapy and targeted inhibition of the hedgehog signalling pathway in treating malignant mesothelioma Associate Professor Cecilia Prele and Professor Steven Mutsaers Hons or PhD Project description: Malignant Mesothelioma (MM) is an aggressive asbestos associated tumour predominantly of the pleura, with a very poor prognosis. Current treatments are ineffective, therefore novel therapeutic approaches are required. Increasing evidence is pointing to the reactivation and aberrant expression of developmental signalling pathways, such as the hedgehog (Hh) pathway, as critical to the pathogenesis of certain cancers. Blocking this pathway may be a novel therapeutic approach to treat MM. Our laboratory has shown that blocking the Hh pathway using the inhibitor GANT61 inhibits MM cell proliferation and in preliminary studies, GANT61 synergises with the first line MM chemotherapeutic agent cisplatin to induce cell death. Hypothesis: The Hh signalling pathway plays a critical driving role in the pathogenesis of MM and that combined with first line MM chemotherapy, blocking this pathway will be a novel therapeutic approach. Aim 1: Examine the effect of combining GANT61 with first line MM chemotherapeutic agents cisplatin, pemetrexed and gemcitabine on cell death in 2 D and 3 D cultures. Aim 2: Examine preclinical efficacy of combining GANT61 with fist line MM chemotherapeutic agents in mouse tumour xenograft models. Techniques: Tissue culture, spheroid cultures, cell transfection, real time PCR, western blot analysis, FACS analysis, cell proliferation, cell viability and apoptosis assays, animal models. Please note that several potential projects exist within this broad programme of research and we welcome all enquires. Associate Professor Cecilia Prêle Ph: cecilia.prele@uwa.edu.au 5.

8 Research Projects Centre for Cell Therapy and Regenerative Medicine Targeting the oncogenic isoforms of the breast cancer gene BARD1 in melanoma Professor Irmgard Irminger Finger Hons or PhD This project will be undertaken in a new Centre for Regenerative Medicine in the new state of the art research facility and with a dynamic team who produce high quality publications. Project description: Australia has the highest incidence of melanoma worldwide. Although most melanomas can be detected early and treated successfully, current diagnostic approaches are unable to identify aggressive melanomas that are likely to become invasive and fatal. It is therefore important to identify at risk patients during the early stage of disease pathogenesis. We have recently identified BARD1δ, a differentially spliced form of the tumor suppressor BARD1, as the predominant BARD1 isoform expressed in melanoma. We propose that BARD1δ is a novel melanoma biomarker and a novel target for treatment providing a potential for future targeted therapy to be combined with early detection. BARD1δ is specifically expressed in cancer cells, and its inhibition should therefore not affect healthy cells. Such targeted therapy could be applied locally in cases of melanomas that are too much advanced for surgery or where surgery is difficult or unwanted. Hypothesis: We hypothesise that Bard1δ is novel biomarker and target for the treatment of aggressive melanoma Aim 1. To validate Bard1δ as a biomarker of aggressive melanoma in human melanoma tissue samples Aim 2. To demonstrate that sirna knockdown of Bard1δ inhibits melanoma cell proliferation in vitro Aim 3. To demonstrate that repression of Bard1δ inhibits tumor growth in vivo. Techniques: Immunohistochemistry, real time PCR, ELISA, Western blot analysis, FACS analysis, confocal laser scanning microscopy, tissue culture. Please note that several potential projects exist within this broad programme of research and we welcome all enquires Professor Irmgard Irminger Finger Ph: Irmgard.irminger finger@uwa.edu.au; Irmgard.Irminger@unige.ch Identifying IGF 1 as a key driver of lung regeneration following pneumonectomy Winthrop Professor Geoff Laurent and Associate Professor Cecilia Prêle Hons or PhD This project will be undertaken in a new Centre for Regenerative Medicine in the new state of the art research facility and with a dynamic team who produce high quality publications. Project description: The capacity for tissue regeneration is highly variable across the species with many amphibians capable of regenerating limbs, tails and even eyes. In humans this capacity is more limited although this varies from one tissue to another. The lung s regenerative capacity is now recognized to be much more rapid than previously thought even in the adult human. Understanding the mechanisms of this growth and its capacity in human will open up transformational research programmes that may allow us to cure chronic lung diseases that are currently seen as untreatable. Professor Laurent has pioneered studies of lung regeneration and repair following injury. His group has previously shown that IGF 1 is required for fibroblast proliferation in lung growth of 6.

9 Research Projects Centre for Cell Therapy and Regenerative Medicine rodents post pneumonectomy. Furthermore, recent gene expression profile analysis of post pneumonectomy lung tissue identified IGF 1 as a central player although its exact role remains unknown. In this project the role of IGF 1 in lung regeneration will be determined. Hypothesis: We hypothesize that IGF 1 is a master regulator in post pneumonectomy lung growth and is a key activator of precursor cell differentiation within the lung. Aim 1: To identify the pattern of expression of the IGFIR, IGF 1 and IGF1BPs in postpneumonectomy and control mouse lung tissue. Archival lung tissue samples collected from peumonectomised mice will be compared to controls mouse lung tissue. Aim 2: To demonstrate IGF 1 knockdown alters repair mechanisms in vitro. The effects of IGF1 gene overexpression and knockdown will be determined on mouse lung fibroblasts and epithelial cell proliferation, apoptosis, migration and differentiation. Techniques: Immunohistochemistry, real time PCR, ELISA, Western blot analysis, FACS analysis, confocal laser scanning microscopy, tissue culture. Please note that several potential projects exist within this broad programme of research and we welcome all enquires. Associate Professor Cecilia Prêle Ph: cecilia.prele@uwa.edu.au 7.

10 Research Projects Genetic Epidemiology & Molecular Genetics Genetic Epidemiology & Molecular Genetics : : : Mutations associated with susceptibility to polycystic ovary syndrome. A/Prof Scott Wilson, Prof Bronwyn Stuckey Hons, MSc or PhD Genetic epidemiology and molecular genetics. Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting up to 10% of women of reproductive age. Despite the high prevalence of the condition, the physiological basis of the disorder is poorly understood. The syndrome is characterized by hyperandrogenism, hirsutism, menstrual irregularities, central obesity and hyperinsulinaemia. PCOS is also commonly associated with the presence of multiple subcapsular follicles and infertility. PCOS is well recognized as a genetic disorder however little progress has been made in revealing the genetic basis of the disorder. In this project the focus will be on the use of next generation sequencing technologies (Exome seq) to identify mutations in relevant genes in families with PCOS. Defining the precise nature of genetic defects that lead to PCOS is crucial for improved diagnosis and for the tailoring of specific therapies for this common condition in young women. Identification of specific gene variants associated with the disease could assist in the specification of lifestyle (e.g. dietary) modifications or particular pharmacological therapies, to aid in PCOS treatment. A/Prof Scott Wilson Ph: scott.wilson@uwa.edu.au Functional analysis of genomic copy number variants associated with bone mineral density. A/Prof Scott Wilson, Prof John Walsh Hons, MSc or PhD Genetic epidemiology and molecular genetics. Copy number variation (CNV) is a genetic structural phenomenon whereby large DNA sequences, sometimes including functional genes, may be duplicated or deleted in the genome of an individual. The gene copies are thought to be co expressed, in which case their presence would result in substantially altered amount of the gene product. Numerous research groups have produced preliminary evidence suggesting the presence of CNV is relevant to complex diseases such as osteoporosis, obesity and neurological diseases. This project focuses on osteoporosis, a heritable, prevalent disease with multiple gene and environmental factors interacting to influence bone fragility fracture susceptibility. This project will address the issue through the in vitro study of cells from subjects that have representative CNV genotypes. This research will validate the effect of the high and low bone mineral density (BMD) associated CNV genotypes on key functional endpoints, including expression of mrna and protein. A comprehensive understanding of the genetic basis of the disease is vital for improvement in the prevention and treatment of osteoporosis. This study will address this goal by providing knowledge on this important genetic mechanism. A/Prof Scott Wilson Ph: scott.wilson@uwa.edu.au 8.

11 Research Projects Genetic Epidemiology & Molecular Genetics Genetic basis of familial nonmedullary thyroid cancer. Prof John Walsh, A/Prof Scott Wilson, Dr Vijay Panicker Hons, MSc or PhD Cancer and molecular genetics Thyroid cancer is among the ten most common malignancies, and occurs more often in women than in men. Approximately 80% of all primary thyroid cancers consist of papillary thyroid carcinoma (PTC) and a strong familial association is seen with some types of PTC. The specific identities of the genes involved in familial PTC (FPTC) are as yet unknown. It has been suggested that FPTC is an autosomal dominant condition. In this project DNA from FPTC families will be examined, with ongoing recruitment for additional families. The research will use next generation sequencing (NGS; whole genome or exome), to identify disease causing germ line single nucleotide variants, insertion, deletions or structural variants in FPTC. DNA samples from affected individuals will be examined in order to identify rare mutations that may play a role in FPTC. The data will then be studied to determine the relevance of rare mutations that are shared by first degree relatives with FPTC. Based on previous work with NGS there is an expectation that mutations in novel genes can be identified from among our study participants. Identification of these rare variants will inform about the underlying cancer biology and will facilitate development of screening tests and ultimately development of a new therapy may be possible. A/Prof Scott Wilson Ph: scott.wilson@uwa.edu.au Use of induced pluripotent stem cells to study pathogenic gene mutations in familial thyroid cancer. A/Prof Scott Wilson, Prof John Walsh, Hons, MSc or PhD Cancer and molecular genetics Thyroid cancer is the commonest endocrine malignancy, and its incidence has been steadily increasing over the past decade. Causes of thyroid cancer are becoming clearer, for example environmental factors such as ionizing radiation explain some geographic clusters of thyroid cancer. Germline genetic factors are also involved in some thyroid cancers, most obviously in the Mendelian dominant syndromes of familial medullary thyroid cancer (FMTC) and Multiple Endocrine Neoplasia syndrome type 2 (MEN2) which are both associated with germline RET mutations. Outside these syndromes, papillary thyroid carcinoma (PTC) has a particularly high relative risk ( ) in first degree relatives. The genes underlying familial PTC (FPTC) remain largely unknown, but the disease has features of an autosomal dominant disorder and may be monogenic within individual families. Recent studies by our group have highlighted several potential gene mutations involved in FPTC. In this project induced pluripotent stem cells (ipscs) derived from somatic cells of study subjects will be used to provide a tool for the study of this disease. ipsc technology enables the epigenetic reprogramming of somatic cells into an embryonic stem cell like state followed by differentiation into other relevant cell types. ipsc based model systems will be used to validate and elaborate the functional role of mutations provisionally identified with a role in FPTC. A/Prof Scott Wilson Ph: scott.wilson@uwa.edu.au 9.

12 Research Projects Respiratory Medicine Respiratory Medicine Research Group Biomarkers and Discovery Unit Metabolic acquisition of pemetrexed resistance in malignant mesothelioma Prof Jenette Creaney Hons or PhD Malignant mesothelioma is an highly aggressive tumour which is largely resistant to current treatment strategies. Mesothelioma is mainly treated using a combination of two drugs, pemetrexed and cisplatin. However, only approximately a third of mesothelioma patients respond to these drugs and in nearly half of those patients that do initially respond the drugs become less effective over time as the cancer cells evolve to overcome the effects of the drugs. In order to devise strategies to overcome this chemoresistance, we need to know how cancer cells respond to drugs and how the cells change to overcome the drug effects. The proposed project will focus on the drug pemetrexed. Pemetrexed is an anti folate, which stops cancer cells dividing by reducing their ability to make the DNA building blocks (i.e. nucleotides) required to make more DNA as the cancer cells multiply. Resistance to pemetrexed is therefore likely to be due to alterations in the cellular pathways that are involved in nucleotide synthesis. We have developed a model system in which mesothelioma cells have, by being exposed to increasing quantities of the drug, become resistant to pemetrexed. In these resistant cells we have preliminary evidence of alterations in some of the cellular pathways involved with nucleotide synthesis. We propose to confirm these observation using independent techniques and extend the findings to other mesothelioma cell models not previously exposed to pemetrexed. Using blood and tumour samples from mesothelioma patients we will determine the clinical relevance of our findings, by comparison with actual patient response to pemetrexed incorporating treatments. If we can identify the cellular pathways that cancer cells use to overcome the effect of pemetrexed, we can then devise additional therapies to target these pathways such that pemetrexed maintains its effectiveness for a longer period of time. Prof Jenette Creaney Ph: jenette.creaney@uwa.edu.au Research Group Biomarkers and Discovery Unit Biological activity of mesothelin in malignant mesothelioma Prof Jenette Creaney Hons or PhD Malignant mesothelioma is a highly aggressive tumour which is largely resistant to current treatment strategies. We discovered that patients with mesothelioma have large quantities of a specific protein, mesothelin, present in their blood and pleural effusion. Subsequently the assay for mesothelin has been commercialized and is clinically available for use in mesothelioma diagnosis and monitoring. B The mesothelin protein itself was identified as a mesothelial cell differentiation antigen in 1992, but little is understood about the function or regulation of the protein in normal or malignant mesothelial cells. In this project we will explore the function of the mesothelin using mesothelioma cell lines and various genomic or pharmacokinetic methods to knock down mesothelin expression. Preliminary evidence suggests that mesothelin overexpression protects the tumour cell from apoptosis targeting therapies, this will be further explored by testing a range of clinically relevant chemotherapeutic agents. Results from in vitro studies will be correlated using biospecimens samples from our extensive patient tumour bank. Prof Jenette Creaney Ph: jenette.creaney@uwa.edu.au 10.

13 Research Projects Respiratory Medicine Research Group Tumour Immunology Group Identification of the dynamic cellular networks that underlie immunotherapy induced tumour regression Asst Prof Joost Lesterhuis, Prof Richard Lake, Asst Prof Scott Fisher, Asst Prof Andrea Khong Hons Background Over the last decades many studies have pinpointed oncogenic events and cellular pathways that initiate or promote thoracic cancer formation and progression. Although compounds targeting these pathways have shown initial promise and effective drugs have been developed, their clinical benefit is often modest. We propose that by focussing on what we do right as clinicians and medical scientists and investigating the molecular and cellular events associated with resolving rather than evolving cancer, we may be able to reinforce or mimic those events to increase the response rates to current treatments. Although in the past, this was not possible because full regressions were not seen in thoracic cancer, recently, immunotherapy with immune checkpoint blocking antibodies has shown remarkable success with full cure in a small percentage of patients. We have mirrored this situation in a mouse model, where mice display either full tumour regression or no response whatsoever after immune checkpoint blocking antibodies. Importantly, we are able to sample entire tumours during treatment. This model gives us the unique opportunity to create a comprehensive and detailed map of the molecular network that is associated with therapeutic success. Using a systems biology approach, we identified genetic modules that govern the response to immune checkpoint blockade and we identified drugs that reinforce those response associated modules and we could show that these drugs indeed increased therapeutic efficacy. However, we do not know which cell types are responsible for the response associated genetic modules. Aim #1 Identify in detail the dynamic, cellular networks that underlie immunotherapy induced tumour regression: the student will characterize the cellular constituents (and their phenotype/activation state) of the checkpoint blockade induced immune response in the tumour in time during treatment using flow cytometry and immunohistochemistry. Aim #2 The therapeutic relevance for cell types identified in aim 1 will be investigated using depleting or blocking antibodies. These studies will run alongside our systems biology experiments in which we map the molecular networks underlying the response to immune checkpoint blockade, using the same mouse models. This will ensure that the student will be well embedded within the work of the team. Techniques/procedures used Cell culture; immunohistochemistry; flow cytometry; inoculation of tumour cell lines; monitoring of animal welfare and tumour growth; intraperitoneal administration of immune checkpoint blocking antibodies. All these techniques are up and running in our lab, although for individual antibody staining optimization may be required. Ethical approval for all mouse studies has been obtained. We seek a motivated honours student with particular interest in cancer immunology and animal research. Please note that several potential projects exist within this broad programme of research and we welcome all enquires Asst/ Prof Joost Lesterhuis Ph: willem.lesterhuis@uwa.edu.au 11.

14 Research Projects Respiratory Medicine Research Group Tumour Immunology Group Exploiting immune checkpoint blockade to generate effective therapy for thoracic cancers. Asst Prof Scott Fisher, Prof Richard Lake, Asst Prof Andrea Khong, Asst Prof Joost Lesterhuis Hons Project description: Immune checkpoint blockade (ICPB) has demonstrated effective therapy in melanoma and is now being applied to other cancers, including lung cancer and malignant mesothelioma (MM). ICPB therapies work by using antibodies to block molecules that negatively regulate T cell activation, thus promoting and prolonging antitumour immunity. Current ICPB therapies are mostly focused on two key checkpoint molecules; CTLA 4 and PD 1. We have identified four key checkpoint molecules that have the potential to be used to specifically target and modulate anti tumour immunity. This study aims to further characterise the expression profile of these key checkpoint molecules on immune cells present within thoracic tumours and use this to identify the best combination of checkpoint blockade antibodies that generate effective therapy against mesothelioma. These findings will be fundamental to inform the rational design of future clinical trials that utilise ICPB for the treatment of lung cancer and malignant mesothelioma. Aim 1: Characterise OX40, CTLA 4, TIM 3 and PD 1 expression on immune cell subsets in mesothelioma tumour bearing mice. Hyp: Tumour resident Treg and tumour infiltrating effector T cells (Teff) can be identified (and thus targeted) by their expression of high levels of OX40/CTLA 4 and TIM 3/PD 1 respectively. Aim2: Assess efficacy of ICP molecule identified in Aim 1 to enhance immunity against MM. Hyp: Targeted ICPB therapy either alone or in combination will enhance endogenous antimesothelioma immunity. Aim 2a: Assess targeted ICPB to enhance anti tumour immunity in tumour bearing mice. Hyp: Dual ICPB using anti CTLA 4 plus anti OX40 or anti TIM 3 plus anti PD 1 will enhance anti tumour immunity, by specifically targeting intratumoural Treg and Teff respectively, leading to control of tumour growth and an increased survival. Aim 2b: Compare local (i.t.) vs. systemic (i.p.) targeted dual ICPB to enhance anti tumour immunity Hyp: Local delivery of dual ICPB antibodies at a much lower dose will enhance anti tumour immunity to a similar level as effective systemic full dose delivery. Research Group Project suitable for Asst Prof Scott Fisher Ph: scott.fisher@uwa.edu.au Tumour Immunology Group Investigating the effect of chemotherapy on tumour associated B lymphocytes Dr Alison McDonnell, Dr Alistair Cook Hons Tumour infiltrating B cells have been associated with a favourable prognosis in patients with many types of cancer including non small cell lung cancer (NSCLC), however their role in malignant mesothelioma (MM) has not been fully elucidated. Since most patients diagnosed with MM present with advanced disease and receive only palliative chemotherapy, access to tumour tissue by surgery or biopsy is rarely feasible in clinical practice. Pleural effusion (PE) associated with thoracic malignancies contains cancer cells and lymphocytes and is routinely drained for palliation, thus providing a potential window into the tumour microenvironment. Therefore we will examine the B cell compartment of pleural fluid in patients with MM and NSCLC and compare this with matched peripheral blood samples and investigate the effect of chemotherapy on these cells. 12.

15 Research Projects Respiratory Medicine AIM: Comprehensively investigate and compare the B cell compartment of pleural fluid and peripheral blood samples in patients with MM and NSCLC. Characterise and compare B cell subsets by flow cytometry in pleural fluid and blood. Examine and compare tumour specific antibodies in pleural fluid and blood. Characterise and compare the B cell compartment of serial pleural fluid and blood samples in the context of standard care chemotherapy Research Group Project suitable for Dr Alison McDonnell Ph: alison.mcdonnell@uwa.edu.au Tumour Immunology Group A systems biology approach to improve cancer immunotherapy Assistant Professor Joost Lesterhuis and Professor Richard Lake Hons. PhD This concerns ongoing projects with possibilities for honours and PhD students Project description: With many treatments for cancer, there is a difference in outcome between patients: some display a clear response and the cancer completely regresses, while other patients do not respond at all, the cancer keeps growing. This black and white phenomenon is particularly seen after immunotherapy with immune checkpoint blocking antibodies. In this project, we characterise the events that occur in a cancer that is cured by immunotherapy, while it regresses. We subsequently aim to reinforce those processes in order to increase the efficacy of treatment. To do this, we use animal models in which some tumour bearing mice respond to immunotherapy while some do not. Gene expression data from these tumours are obtained using RNAseq, and computational techniques developed in network science are used to pinpoint the key molecules that govern the treatment response. We subsequently identify already existing drugs that modify these molecules in the desired manner, using online databases of drug treated cells, and the identified drugs are tested for their capacity to increase the response rate to immunotherapy in mouse models. The identified key molecules will be validated on tumour tissues from melanoma patients and correlated with response to immunotherapy. A clinical trial investigating combination treatment of immune checkpoint blockade and one of the identified synergistic drugs in advanced melanoma patients has been planned. Overall, we aim to discover drugs that will enhance the efficacy of current immune therapies for cancer and we aim to understand how successful immunotherapy exerts its effect. Our results may change the way we discover new drugs. This project is at the intersection between cutting edge cancer biology, immunology, and computational biology and extends from basic science to animal models and translation into the clinic. It involves collaborations with clinicians at the department of Oncology (Prof. A. Nowak and Prof. M. Millward) and computational biologists at Telethon Kids Institute (Dr. A. Bosco). Please note that several potential projects exist within this broad programme of research and we welcome all enquires Asst/ Prof Joost Lesterhuis Ph: willem.lesterhuis@uwa.edu.au 13.

16 Research Projects Other Groups Offering Research Projects Other Groups Offering Research Projects Hepatology Kidney Disease Clinical Education and staff development Professor Leon Adams Professor Neil Boudville Adjunct Associate Professor Aron Chakera Winthrop Professor Fiona Lake Projects exploring nutritional, genetic and microbiome associations with liver injury in NAFLD are available. Current projects include: 1) Clinical trials: Exercise in NAFLD cirrhosis Nutritional therapy in NAFLD 2) The gut microbiome and metabolome and liver injury in NAFLD. 3) Nutritional intervention, bile acids and FXR activation in NAFLD. 4) Non invasive assessment of liver fibrosis 5) Metabolic factors and liver transplant outcomes 6) Genetic associations with liver fibrosis in chronic liver disease. Current research focuses on Living Kidney Donor outcomes; peritoneal dialysis outcomes; chronic kidney disease; hypertension 14. Ongoing projects include Prospective study on the Long term outcomes of living kidney donors; CKD FIX study (allopurinol and its effect on progression of CKD); IMPROVE study (fosrenol and its effect on vascular function); and PDOPPS study (Peritoneal dialysis outcomes and practice patterns). Current research focuses improving outcomes for patients with kidney disease and ranges from clinical trials to laboratory work. Main clinical interests of the group include peritoneal dialysis and peritonitis, autoimmune diseases and transplantation. Laboratory based studies are examining interactions between the immune system and microorganisms in patients, particularly those on immunosuppression. people/laboratoryheads/chakera profile/ A range of possible projects are available looking at the impact of staff and learner development. In addition, staff have extensive skills in educational research and are happy to be involved in supervising educational research projects in candidates own areas.

17 Research Projects Other Groups Offering Research Projects Oncology Professor Anna Nowak Current research Mesothelioma: Radiological Imaging of Response PET imaging; FDG and novel agents. Clinical trials of novel agents and immunotherapy (Phase I, II). Quality of Life research. Animal models of chemo immunotherapy and small animal PET imaging High Grade Glioma: AGOG collaboration principal investigator Exercise in glioma psycho oncology studies. Pluripotency transcription factors in glioma 15.