TNERING WITH QIMR BERGHOFER An industry …...give rise to cancer and those that occur during the formation of a tumour and its subsequent metastasis; and developing and testing novel

PARTNERING

WITH QIMR

BERGHOFER

An industry guide

to commercial

opportunities

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QIMR Berghofer is a fully integrated biomedical research and development centre

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CONTENTSRESEARCH WITH CONSEQUENCES .................................................4

QIMR BERGHOFER HISTORY .............................................................5

QIMR BERGHOFER: YOUR DEVELOPMENT PARTNER ......................6

RESEARCH PROGRAMS ....................................................................9

Cancer Program .........................................................................10

Infectious Diseases .....................................................................32

Mental Health/Complex Disorders ..............................................48

RESEARCH AND TECHNOLOGY PLATFORMS ................................61

TISSUE BANKS .................................................................................63

YOUR PARTNER IN Q-GEN ..............................................................65

QIMR Berghofer is a fully integrated biomedical research and development centre

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RESEARCH WITH CONSEQUENCESQIMR Berghofer is dedicated to discovering and translating research to the clinic locally and internationally.

Some of the Institute’s research with consequence has included:

• establishing a system to test antimalarial drugs in humans infected with malaria parasites and began clinical trials testing effectiveness of drug therapies for malaria;

• carrying out collaborative research activities with institutes in China, India, Hong Kong, Vietnam, UK, USA, European Union and New Zealand;

• attracting researchers from over 20 countries and is actively recruiting worldwide for new talent to occupy the expanded QIMR Berghofer;

• embarking on QSkin, the largest skin cancer research study ever conducted in Australia;

• identifying a new target for treating aggressive brain tumours, which will commence clinical trials shortly;

• participating in a pilot study, releasing Wolbachia infected mosquitoes in Cairns to test the effectiveness against the spread of dengue fever;

• developing a simple blood test to monitor the risk of contracting cytomegalovirus, a virus that often infects the lungs and gastrointestinal tract after transplantation;

• heading up the largest Australian study of asthma genetics, and based on this, launched a two-year trial of the use of a new medication in treating asthma;

• using brain imaging to develop a stress test for dementia, to predict the function of patients for up to two years;

• discovering a way to use insights to the way HIV replicates to beat HIV, with a view to starting animal trials shortly;

• supporting research, particularly in the area of infectious diseases, of relevance to the Aboriginal and Torres Strait Islander communities in its research programs;

• identifying several new genes that increase the risk and hence provide entry points to understanding how pathologies occur in breast, ovarian, prostate and bowel cancer, bowel disease, melanoma, endometriosis, and myopia;

• launching Australia’s first study into lifestyle factors that may improve outcomes for ovarian cancer patients;

• playing a key role in the research behind a new skin cancer drug now on the market;

• confirming new research linking non-melanoma skin cancers to the use of sun beds;

• showing for the first time that heavy alcohol consumption more than doubles the risk of a type of oesophageal cancer;

• developing a new way to monitor the liver health of cystic fibrosis patients;

• launching the QIMR Berghofer Melanoma and Skin Cancer Research Centre; and

• launching the QIMR Berghofer Centre for Immunotherapy and Vaccine Development.

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QIMR BERGHOFER HISTORYQIMR Berghofer was the brainchild of Dr Edward Derrick, an early Director of the Queensland State Health Department Laboratory of Microbiology and Pathology.

Derrick’s work on Q fever, scrub typhus and leptospirosis made him aware of the need for an institute devoted to full-time research into infectious diseases of northern Australia. It was largely through Derrick’s persistence that the Queensland Institute of Medical Research Act was passed by the Queensland Government in 1945.

The Institute has grown steadily to embrace cancer research and clinical sciences with over 600 scientists, students and support staff, now housed in the Bancroft Centre, the Clive Berghofer Cancer Research Centre and the recently opened research facility.

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QIMR BERGHOFER: YOUR DEVELOPMENT PARTNERQIMR Berghofer is one of Australia’s largest and most successful medical research institutes and the highest ranked medical research institute in the Asia-Pacific region according to the Nature Publishing Index.

Our 700 full time researchers, visiting scientists and students are investigating the genetic and environmental causes of nearly 40 diseases as well as developing new diagnostics, better treatments, and prevention strategies such as antibodies and vaccines.

The Institute offers a wealth of partnership, collaborative and commercial opportunities for industry and governments. QIMR Berghofer has the capacity to translate basic research from the discovery phase, through product development, scale-up, manufacture through to Phase I and II clinical trials.

We have strategic alliances with research institutes, hospitals, universities, not-for-profits and commercial partners, including Australian and international biotechnology and pharmaceutical

companies. In particular, QIMR Berghofer is interested in commercial partnerships to further early stage technologies which have the potential to rapidly develop into successful technologies.

Opportunities include:

• Collaborative and contract research

• Development and manufacture of novel therapeutics

• Clinical trials

• Consulting

• Technology licences

• Start-up companies

• Business partnerships

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DISCOVERY

QIMR Berghofer has world class research facilities and laboratories including:

• The Drug Discovery Group

• The Queensland Protein Discovery Centre

• The Centre for Immunotherapy and Vaccine Development

DEVELOPMENT

QIMR Berghofer has the capability and resources to carry out product development, including:

• Research models and cell banks

• State-of-the-art technologies and equipment

• Scientists with commercial experience

MANUFACTURING

Q-Gen is a cGMP facility that offers clean room facilities, state-of-the-art equipment, experienced service and support.

Q-Gen is licensed by the Therapeutic Goods Administration (TGA) for the maintenance and storage of working cell banks, the storage on site of cellular products and the management and release of cellular therapies for humans. The TGA license makes Q-Gen one of a very small number of organisations in Australia able to store human and nonhuman samples under GMP conditions.

Q-Gen is one of the largest GMP facilities in Australia, with 13 ISO Class 7 clean rooms. Each clean room is fully equipped for the manufacture of clinical therapies.

Q-Gen provides QIMR Berghofer with a unique facility to conduct its translational research and processes for clinical therapies and is currently utilised in the manufacture of a number of QIMR Berghofer sponsored developmental immunotherapies and the production of material for malaria trials.

Further information about Q-Gen can be found at the end of this brochure.

CLINICAL TRIALS

Q-Pharm Pty Ltd conducts:

• Phase I and II clinical trials,

• Pharmacokinetic studies,

• Bioequivalence studies, and drug analysis.

In order to facilitate the translation of QIMR Berghofer’s research into clinical practice, Q-Pharm is a related entity with QIMR holding a 24.5% share. Q-Pharm is a specialist contract research organisation that conducts early phase clinical trials of pharmaceutical and biotechnology products spanning the areas of therapeutic, diagnostic and disease prevention agents.

The company offers the best appointed early phase clinical trials facilities in Australasia, including recruitment and outpatient clinics, a specialised 18-bed clinic for the conduct of the most medically demanding trials and an open plan 24 bed facility for larger healthy volunteer trials.

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RESEARCH PROGRAMSQIMR Berghofer is expanding our understanding, diagnosis and treatment of some of the world’s most devastating diseases.

QIMR Berghofer’s research programs range from identifying the environmental risks and genetic basis of cancers as well as new therapeutics; to developing better diagnostics and vaccines for infectious diseases; to trialling biological controls for mosquitoes to reduce the incidence of debilitating diseases such as malaria and dengue fever.

The Institute takes a multi-faceted approach to medical research. We have a strong international reputation for our investigations into disease genetics and epigenetics, immunology, epidemiology, cellular function and infection. Our use of immunotherapy, vaccines, protein and drug discovery to develop new diagnostics and better treatments is widely respected by the medical community and industry.

FACILITIES:

• Genomics research

• Microarray and mass array analysis

• Transgenic and gene knockout mice

• Cancer and infectious disease mouse models

• Confocal and laser dissection microscopy

• FACS and cell sorting facilities

• PC2 animal facilities

Key research areas:

Cancer

Infectious diseases

Mental health and complex disorders

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CANCER PROGRAM

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Coordinator: Professor Georgia Chenevix-Trench

The Cancer Program looks closely at skin cancers, including melanoma; hormone-related cancers, such as those of the breast, prostate, ovary and endometrium; leukaemia and lymphoma, including exploring the complications that can arise after transplantation; brain tumours; and tumours of the gastrointestinal tract. A widely based interest in metastases is found in many of the cancer research groups.

Laboratories within the Cancer Program work on identifying the genetic, epigenetic and environmental risk factors underlying an individual’s cancer risk; studying the molecular changes that occur in precursor lesions that can give rise to cancer and those that occur during the formation of a tumour and its subsequent metastasis; and developing and testing novel therapies for cancer in the laboratory and clinical trials.

By working with clinical oncologists, pathologists and biobanks, members of the Cancer Program are leading or part of large international consortia and making great advances into the understanding of the genes that predispose individuals to many types of cancer.

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Antigen Presentation and ImmunoregulationGroup Leader: Dr Kelli MacDonald

The Antigen Presentation and Immunoregulation Laboratory aims to investigate how donor and host antigen presenting cells (APCs) respond following bone marrow stem cell transplantation (SCT). Basic research in immunology using pre-clinical models follows three streams: APC development, antigen presentation, and APC induced T cell responses and their regulation. Importantly, these studies should lead to the development of new therapeutic protocols that can be translated to clinical practice to improve transplant outcome.

CONDITIONS RESEARCHED

• Graft-versus-host disease

• Leukaemia, lymphomas and myelomas

• Chronic liver disease

CURRENT RESEARCH

• Contribution of donor dendritic cells to immunosuppression which occurs following haematopoeitic stem cell transplantation

• Development of DC immunotherapy protocols for the attenuation of graft versus host disease (GVHD)

• Role of IL-17 and related family members in chronic GVHD

• Role of macrophages in GVHD

• Contribution of regulatory T cells to the development of chronic GVHD

RECENT HIGHLIGHTS:

• Received NHMRC Project grant funding to study the role of MMP-9-expressing macrophages in chronic liver disease

• Identified for the first time a CD8+FoxP3+ regulatory T cell (Treg) population that develops following stem cell transplantation and is highly effective in suppressing graft-versus-host disease. Furthermore, the group has developed strategies to specifically expand this population in vivo,

highlighting the capacity to manipulate this population to control graft-versus-host disease post transplant.

• Demonstrated that immune-suppression in graft-versus-host-disease results from corrupted antigen presentation post transplant.

• Identified non-haematopoietic APC responsible for the induction of graft-versus-host disease post transplant.

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Bone Marrow TransplantationSenior Scientist: Professor Geoff Hill, Department Coordinator: Immunology

The Bone Marrow Transplantation Laboratory uses pre-clinical transplant models to dissect the immunological mechanisms of transplant rejection and aims to improve patient outcome through new therapies to prevent and treat graft-versus-host disease. Research focuses on pathways of alloreactivity leading to graft-versus-host disease and graft-versus-leukaemia (GVL) effects. The ultimate aim is to generate testable therapeutic interventions that attenuate graft-versus-host disease and improve GVL.


• Graft-versus-host disease • Leukaemia, lymphoma and myeloma

CURRENT RESEARCH

• The interleukin-17 family of cytokines as mediators of transplant outcome

• Mechanisms of antigen presentation after transplantation

• Immunological mechanisms of leukaemia and myeloma eradication after transplantation

• Administration of an IL-6R antibody to prevent GVHD in clinical bone marrow transplant (BMT) recipients

• The treatment of steroid refractory acute GVHD with CD52 targeted Ab and TNF antagonists

• The use of type I interferons in preclinical and clinical BMT to improve the eradication of leukaemia.

• The use of suicide gene-transfected effector after clinical haplo-identical BMT

• The use of induced regulatory T cells to treat clinical chronic GVHD

RECENT HIGHLIGHTS:

• Defined the type of cells involved in antigen presentation after bone marrow transplantation.

• Defined IL-6 as a major pathological cytokine during graft-versus-host disease.

• Characterised a new regulatory T cell subset.

• Characterised type I interferon as the major cytokine controlling anti-leukaemia effects after BMT.

• Characterised defects in immune function induced by graft-versus-host disease.

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Cancer Aetiology and PreventionTeam Head: Associate Professor Rachel Neale

The Cancer Aetiology and Prevention team covers three broad research areas: causes and management of pancreatic cancer; role of vitamin D in human health; and causes and management of non-melanoma skin cancer.


• Pancreatic cancer

CURRENT RESEARCH

• D-Health - vitamin D clinical trial • QPCS - Queensland pancreatic cancer study

RECENT HIGHLIGHTS:

• Awarded a grant to conduct trial of vitamin D supplementation in 25,000 Australian adults.

• Published a paper showing that we can predict vitamin D deficiency with reasonable accuracy.

This has led to a new grant application to validate this tool.

• Published for the first time an association between human papilloma viral load and risk of cutaneous squamous cell carcinoma.

Cancer and Population StudiesSenior Scientist: Professor Adele Green AC

The Cancer and Population Studies Group aims to understand the causes of cancer and how to better prevent and manage cancer. The group investigates the roles of environmental and personal factors in the causation of cancer and its precursors, and in cancer prognosis. The group collaborates with clinicians, statisticians and behavioural scientists and also with laboratory scientists to better understand the underlying mechanisms of carcinogenesis. Particular focuses currently are cancers of the skin and of the colon.

The group aims to assess the contributions of personal factors (including psychological and social needs) and environmental factors to quality of life, disease prognosis and survival in patients with early stage, invasive cutaneous melanoma in Queensland, Australia.


• Bowel (colorectal) cancer

• Melanoma


• Skin cancer (basal cell carcinoma and squamous cell carcinoma)

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CURRENT RESEARCH

• Primary Melanoma Project - Quality of Life Study

• Dietary Factors and Actinic Skin Damage

• Association between human papilloma virus and squamous cell carcinoma (SCC) of the skin

• Study of genetic and environmental risk factors for pancreatic cancer

• Exploring the causal pathways to cutaneous melanoma

• 20 year follow-up study of the Nambour Skin Cancer Project

• Working after Cancer Study - Quality of Life Study

RECENT HIGHLIGHTS:

• Showed that people with naevi (moles) on the arms are more likely to develop basal cell carcinomas than those without.

• Contributed insights into the role of nutrients in the causation of basal cell carcinoma and squamous cell carcinoma.

• Validated the use of skin surface microtopography as a measure of skin photoaging in people aged 40 and over, though not past age 70 years.

• Published a chapter on the epidemiology of melanoma in the major US textbook on women’s health.

• Showed that the prevalence of weekend sunburn is still high in Queensland especially in young male adults.

• Published evidence from a randomised trial that sunscreen can slow the prevention of skin photoaging changes.

Cancer ControlGroup Leader: Professor David Whiteman, Department Coordinator: Population Health

The Cancer Control Group has two major areas of research focus: melanoma and skin cancer; and upper gastrointestinal neoplasia. In addition, the Group Leader is also a co-investigator on projects investigating pancreatic, thyroid, cervical and liver cancer.

The group has primary strength in epidemiological approaches to the study of cancer. Historically, the focus has been directed towards cancers of two main organ systems: the skin, and the gastro-intestinal tract.

The group’s largest enterprise currently is the QSkin study, a prospective cohort study of more than 43,000 Queenslanders to be followed up for the next 10 years. In 2012-13, the group completed the first data linkages to external health registers to capture skin cancer events in the QSkin population.


• Melanoma

• Oesophageal cancer and Barrett’s oesophagus


• Skin cancers

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CURRENT RESEARCH

• QSkin - the world’s largest study of melanoma and skin cancer

• PROBE-Net - the Progression of Barrett’s Esophagus Network

• InterSCOPE - the International Collaboration on HPV and Oesophageal Cancer

• BEACON: The Barrett’s Oesophagus and Adenocarcinoma Consortium

RECENT HIGHLIGHTS:

• Awarded $2.5 million for a NHMRC Centre of Research Excellence.

• Completed data linkage for the QSkin study.

• Developed models to describe the incidence of oesophageal adenocarcinoma in the Australian population.

• Published more than 10 publications in the past year.

Cancer Drug Mechanism Team Head: Dr Glen Boyle

The recently formed Cancer Drug Mechanisms Group combines expertise in cancer biology with drug studies.The group’s work on cancer biology currently focuses on understanding the development and progression of cancers of the skin and oral cavity. Specifically, the group is investigating the molecular mechanisms involved in the progression and metastasis of melanoma, head and neck cancer, as well as cutaneous squamous cell carcinoma. These molecular mechanisms also impact on drug resistance of cancers. The identification and understanding of aberrantly regulated pathways in these cancers is crucial prior to the design or identification of suitable agents to treat these diseases.


• Melanoma

• Head and neck cancer

• Oral cancer

• Cutaneous squamous cell carcinoma

CURRENT RESEARCH

• Activities of specific melanoma transcription factors that impact on drug resistance.

• Molecular profiling and biomarker identification in head and neck cancers (including squamous cell carcinoma with perineural invasion).

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Cancer GeneticsGroup Leader: Professor Georgia Chenevix-Trench

The Cancer Genetics Laboratory investigates why some people get cancer, and how these cancers, particularly those of the breast, ovary and stomach, develop from a normal cell. The laboratory also looks at why these cancers are often found together in the same families and share many similar characteristics.


• Breast cancer

• Ovarian cancer

• Gastric cancer

CURRENT RESEARCH

• Understanding germline variation underlying individual differences in risk of breast and ovarian cancer

• Genes involved in response to chemotherapy in patients with ovarian cancer

• Evaluation of the role of the telomerase gene, TERT, in susceptibility to breast and ovarian cancer

• Next generation sequencing approaches to finding novel breast cancer susceptibility genes

• Somatic mutations in basal-like breast tumour, and in brain metastases

• Identification of the gene for gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS syndrome) by exome and genome sequencing

RECENT HIGHLIGHTS:

• Completed the first analyses of the largest cancer genetics experiment ever undertaken.

• Identified 49 genetic polymorphisms associated with risk of breast cancer.

• Identified nine new ovarian cancer risk loci.

• Demonstrated that the polymorphisms at the TERT gene that underlie breast and ovarian cancer risk are usually distinct from those associated with telomere length.

• Demonstrated in mouse models of the efficacy of anti-EGFR directed radioimmunotherapy combined with radio-sensitising chemotherapy and PARP inhibitor for the treatment of triple negative breast cancer.

• Demonstrated the value of restoring DNA from archival formalin fixed paraffin embedded tissues for genomic profiling by SNP-CGH analysis.

• Shown that women from breast cancer families who do not carry mutations in BRCA1 or BRCA2, but instead are in the top quartile of polygenic risk, have a risk of developing contralateral breast cancer that is similar to that of a BRCA2 mutation carrier.

• Developed mouse models of breast-to-brain metastasis and shown that an activating mutation in the EGFR gene can render a tumorigenic breast line capable of colonising the brain.

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Cancer Immunoregulation and ImmunotherapyTeam Head: Dr Michele Teng

The Cancer Immunoregulation and Immunotherapy Group looks at tumour induced immune suppression, Tregs, IL-23 and checkpoint receptors (PD-1/TIM-3/LAG-3).

CURRENT RESEARCH

• Inflammation-induced cancer and cancer immunoediting

• The role of IL-23 family cytokines in tumor immunity

• Tumor-induced immunosuppression

RECENT HIGHLIGHTS:

• Demonstrated that Tim-3 positive Tregs are selectively enriched in tumours but not in the periphery and therefore represent a novel target for depletion.

• Demonstrated that skewing the balance between IL-12/IL-23 can resolve nascent tumour in a de novo mouse model of cancer.

Conjoint GastroenterologyLaboratory Head: Professor Barbara Leggett

The main focus of the Conjoint Gastroenterology Laboratory is in understanding the molecular, histological, clinical and epidemiological features of a particular class of polyps called serrated polyps, as well as the cancers they may develop into. The group is studying a large series of colorectal polyps and cancers using technologies to examine genome-wide changes in DNA methylation, gene expression and copy number variation. The laboratory aims to identify molecular changes associated with high risk of polyp progression, and to identify key pathways altered in colorectal cancer subgroups.


• Colorectal cancer

CURRENT RESEARCH

• The role of the serrated polyp in colorectal cancer

• Existence of the serrated pathway of cancer development by showing it is strongly associated with activating mutations of the ontogeny BRAF

• Discovering further genetic changes underlying different subtypes of colorectal cancer

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RECENT HIGHLIGHTS:

• Completed a proof of principle pilot DNA methylation microarray project that identified cancer subgroups based on BRAF and KRAS mutation status, as well as identifying genes hyper ethylated in these cancer subgroups.

• Described a new type of chromosomal instability associated with BRAF mutation that is defined by regional copy number variation.

• Reviewed over 6,000 bowel polyps to establish the frequency of different polyp types and identified a study population to examine the

molecular features of polyps at different stages of progression.

• Commenced collaboration with QIMR Berghofer’s Cancer and Population Studies Group to examine epidemiological aspects of serrated polyp development.

• Demonstrated that expression of the BRAF V600E mutation in the adult mouse intestine leads to hyperplasia, which likely equates to early serrated polyp development.

Control of Gene ExpressionLaboratory Head: Professor Frank Gannon, CEO and Director

The Control of Gene Expression laboratory has recently started at QIMR Berghofer, focussing on the control of gene expression. The leader of the laboratory, Frank Gannon, has been active in this area of research for many years, but had interrupted his research career when he took a position as Director General of Science Foundation Ireland, the national funding agency in Ireland. He moved to Brisbane as the Director and CEO of QIMR Berghofer in 2011 and now has established a research activity there.

The research of the group is designed to achieve a better understanding of the specifics of the control of gene expression. The most recent research on which the current projects are built was the demonstration of transient cyclical DNA methylation and demethylation (Kangaspeska et al., Nature 452, 2008). This work followed from earlier detailed analysis of the processes by which the estrogen receptor recruited the RNA polymerase and initiated transcription (Métivier et al., Cell 115, 2003; Métivier et al., EMBO reports 7, 2006).

A focus on histone modifications that occur in conjunction with the onset and silencing of transcription has been the focus of the work of Dr Jason Lee who has joined the laboratory. His research activities grow from the histone modification aspects through to the effects of modifying enzymes on other cellular targets and their consequences in cellular physiology.

Whereas the focus of the group radiates from the estrogen receptor, the general questions of epigenetic control of gene expression will be examined in diverse systems. In all cases the aim is to develop insights that can be translated to different disease settings.


• Breast cancer • Endometrial cancer

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CURRENT RESEARCH

• Control of gene expression by ER in breast cancer

• Epigenetic modification of DNA, histones and other proteins

• Impact of hypoxic environment on cancer metastasis

• The role of EphA3 methylation in glioblastoma

Drug DiscoveryGroup Leader: Professor Peter Parsons

The Drug Discovery Group combines expertise in cancer biology with genomics and drug discovery. Cell communication networks in serious cancers reveal responses that provide opportunities for prevention and treatment.


• Head and neck cancers

• Melanoma

• Oral cancer

• Cutaneous squamous cell carcinoma

CURRENT RESEARCH

• Development of the novel anticancer drug EBC-46

• Identifying plant compounds with potential for addressing health problems other than cancer

• Activities of specific melanoma transcription factors

• Molecular profiling and biomarker identification in head and neck cancers (including squamous cell carcinoma with perineural invasion)

RECENT HIGHLIGHTS:

• Confirmed that the efficacy of EBC-46 is due to haemorrhagic necrosis.

• Discovered EBC-46-like molecules in other plant species.

• Noted first indications that the efficacy of EBC-46 in vivo can be inhibited by pharmacological agents.

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Functional Cancer GenomicsTeam Head: Dr Stacey Edwards

The Functional Cancer Genomics team is focused on post-GWAS (genome-wide association studies) functional characterisation of breast and ovarian cancer genetics.

More than 60 different breast cancer risk loci and nine ovarian cancer loci have now been discovered via GWAS, but until recently it has not been possible to identify the variants that are directly responsible for the increased risk. Importantly, the majority of variants lie within non-coding regions of the genome and appear to act as enhancers of genes through long-range interactions mediated by the formation of chromatin loops. Over the last year, the team have developed a successful strategy for analysing these regulatory regions to narrow down the candidate causative variants at each area and describe their likely actions in breast cancer.


• Breast cancer • Ovarian cancer

CURRENT RESEARCH

• Functional evaluation of novel long-range DNA sequence elements that regulate the major breast cancer genes, BRCA1 and BRCA2.

• Understanding how germline DNA variation contributes to the risk of developing breast and ovarian cancer.

• Genome-wide chromatin approaches to identify novel target genes and the relevant changes in their regulation that confer an increased risk of cancer.

RECENT HIGHLIGHTS:

• Published paper in the American Journal of Human Genetics; Functional Variants at the 11q13 Breast Cancer Risk Loci Regulate Cyclin D1 Expression through Long-Range Enhancers.

• Published in Nature Genetics; Multiple independent variants at the TERT locus are

associated with telomere length and risks of breast and ovarian cancer.

• Authored paper in Nature Genetics; DNaseI-hypersensitive exons co-localize with promoters and distal regulatory elements.

• Published senior author review in Genes, Chromosomes and Cancer.

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Functional GeneticsTeam Head: Dr Juliet French

The Function Genetics Group is focused on the post-GWAS functional characterisation of breast and ovarian cancer loci. In collaboration with geneticists at Cambridge and QIMR Berghofer the Group is fine-mapping breast cancer loci to pinpoint the likely causal variants. The majority of variants fall in non-coding regions of the genome suggesting the regulatory elements and non-coding RNAs are likely mechanisms of the associated risk.


• Breast cancer • Ovarian cancer

CURRENT RESEARCH

• Understanding how genetic variants cause an increase in risk of breast and ovarian cancer.

• Understanding how the breast cancer susceptibility gene, BRCA1 is regulated

• Exploring the function of breast cancer-associated variants in long non-coding RNAs

RECENT HIGHLIGHTS:

• Authored a paper in Nature Genetics describing the fine-mapping of the TERT locus for breast cancer risk and functional follow-up.

• Published in American Journal of Human Genetics describing the fine-mapping of the genetic association at 11q13 and functional follow-up.

Genomic BiologyTeam Head: Dr Nicole Cloonan

Choice of chemotherapy has relied on data from populations rather than individuals, but the recently available cancer genomic data shows that every cancer is different. To personalise therapy, doctors need to move away from treating cancers based on where they develop in the body, and instead move towards treating what has gone wrong in the cells of the individual patient.

Our current research focus is determining the relationship between miRNAs and drug sensitivity, with the short term aim of using these as markers in personalised therapy, and the long term aim of using these as adjunct chemosensitisers.

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• Breast cancer

• Endometriosis

• Lung cancer

• Melanoma

• Ovarian cancer


• Schizophrenia

CURRENT RESEARCH

• Decoding susceptibility to breast cancer

• The role of BRCA non-coding mutations in breast cancer susceptibility

• Decoding miRNA regulated genetic circuits

RECENT HIGHLIGHTS:

• Identified the relationship between miRNAs and EGRF inhibitor sensitivity.

• Identified novel biology behind miR-139’s link to metastasis and migration function.

Gynaecological CancersGroup Leader: Associate Professor Penny Webb

The Gynaecological Cancers Group investigates all aspects of cancer, particularly gynaecological cancer, from aetiology to diagnosis, patterns of care, quality of life and survival. A particular focus is on the role of environmental (non-genetic) factors and the interaction between genetic and environmental factors in the causation of gynaecological cancer. More recently, this has extended to assessing how gynaecological cancers are managed in Australia and investigating the role of lifestyle in determining quality of life and survival after a diagnosis of cancer. Much of this work is conducted within three national population-based studies: the Australian Ovarian Cancer Study (AOCS), the Ovarian Cancer Patterns of Care Study (POCS) and the Australian National Endometrial Cancer Study (ANECS).


• Endometrial cancer • Ovarian cancer

CURRENT RESEARCH

• Improving Outcomes for Women with Endometrial Cancer: Follow-up, Survival and Quality of Life

• Patterns of Care Study for Ovarian Cancer

• Molecular epidemiology of endometrial cancer: the Australian National Endometrial Cancer Study

• Molecular epidemiology of ovarian cancer: The Australian Ovarian Cancer Study (AOCS)

• Comparison of quality of life and standard end-points of chemotherapy in advanced ovarian cancer

• Quality of life and psychosocial predictors of outcome in a population based study of ovarian cancer

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RECENT HIGHLIGHTS:

• Conducted an international pooled analysis showing that obesity is associated with increased risks of non-serous ovarian cancer, but does not appear to increase risk of the most common and most aggressive high-grade serous subtype.

• Observed that aspirin use may be associated with a reduced risk of endometrial cancer, particularly among obese women.

• Observed that only about one third of women with ovarian cancer complete the recommended six cycles of combination chemotherapy.

• Published a paper suggesting that although obese women are at greatly increased risk of

endometrial cancer, if they lose weight their risk is reduced again.

• Contributed to international pooled analyses showing that tubal sterilization reduces risk of ovarian cancer but smoking increases risk of the mucinous subtype.

• Showed women with ovarian cancer report needing ongoing assistance to deal with psychological and physical needs over the first two years after first-line treatment. Risk factors for unmet needs included older age, advanced disease, anxiety, depression, insomnia and lower social support.

Immunology in Cancer and InfectionSenior Scientist: Professor Mark Smyth

The Immunology in Cancer and Infection Group study the immune reaction to cancer in mouse models and cancer patients (most notably in multiple myeloma).

CURRENT RESEARCH

• Inflammation-induced cancer and cancer immunoediting

• The role of IL-23 family cytokines in tumor immunity

• T and NKT cells in infection and cancer

• NK cell recognition of cancer and metastases

• Tumor-induced immunosuppression

• Immunogenic cell death

• Combination immunotherapies for solid and haematological malignancies

RECENT HIGHLIGHTS:

• Showed that CD73-deficient mice are resistant to carcinogenesis.

• Identified that radiotherapy combines with antibody-based immunotherapy in mouse models of breast cancer.

• Demonstrated that NK cells contribute to the pre-metastatic niche.

• Showed that IL-12 and IL-23 have opposing roles in immune-mediated tumour dormancy.

• Demonstrated that NLRP3 promotes skin cancer in mice.

• Showed that non classical MHC H2-M3 recognizes Ly-49A.

• Showed that host immunity contributes to anti-melanoma activity of Braf inhibitors.

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Leukaemia Foundation of Queensland LaboratoryGroup Leader: Professor Andrew Boyd

The Leukaemia Foundation Group are investigating tumour-associated genes in cancer, in particular Eph, ephrin and Nfib in leukaemia, sarcomas and brain tumours. The group’s research includes basic cancer biology and development of targeted therapies.


• Leukaemia

• Spinal cord injuries

• Brain tumours (glioma, blastoma)

• Prostate cancer


CURRENT RESEARCH

• Investigating the role of Eph and ephrin membrane proteins in cancer

• Exploring the use of EphA4 inhibitors in spinal cord injury

• Exploring the protein Fat1 as a candidate target for new therapeutics

RECENT HIGHLIGHTS:

• Discovered the role of EphA3 in glioma. • Identified EphA4 as a target in motor nerve injury and disease.

Molecular Cancer EpidemiologyGroup Leader: Associate Professor Amanda Spurdle

The Molecular Cancer Epidemiology Laboratory studies breast, ovarian, endometrial, colon and prostate cancer, with a focus on identifying molecular signatures of normal and tumour tissue that can point to the genetic and environmental causes of these cancers. The laboratory covers a range of projects with the themes of cancer epidemiology and molecular pathology.


• Breast cancer

• Ovarian cancer

• Endometrial cancer


• Prostate cancer

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CURRENT RESEARCH

• The Australian National Endometrial Cancer Study (ANECS)

• Clinical classification of Mismatch Repair gene variants

• Clinical classification of BRCA1 and BRCA2 gene variants

• Breast and ovarian cancer predisposition and prognosis and modifier genes

• Prostate cancer predisposition and prognosis genes

• Breast and ovarian cancer predisposition and prognosis and modifier genes

RECENT HIGHLIGHTS:• Demonstrated that a BRCA1 variant with

intermediate functional activity are associated with moderate risk of cancer.

• Published a statistical model for classification of variants in MMR genes.

• Demonstrated inadequacy of collection of family history data in the clinical setting, and poor referral of patients for genetic testing.

• Applied five tier quantitative and qualitative classification system to an international database of MMR gene variants.

• Investigated endometrial tumour features as positive and negative predictors of germline MMR gene mutation status.

OncogenomicsSenior Scientist: Professor Nick Hayward

The Oncogenomics Laboratory researches the genetics and genomics of melanoma, mouse models of multiple endocrine neoplasia type 1 and the molecular genetics of Barrett’s oesophagus and oesophageal cancer.

The laboratory is interested in investigating the process of cancer development at the level of individual cancer predisposition genes, and by looking at the whole genome scale. Better understanding the genetic events that cause cancer is hoped to lead to better ways of diagnosing or treating cancers in the future.


• Melanoma

• Oesophageal cancer and Barrett’s oesophagus

• Multiple endocrine neoplasia type 1

CURRENT RESEARCH

• Studying melanoma susceptibility genes

• Studying the molecular genetics of MEN 1 (multiple endocrine neoplasia type 1)

• Identifying environmental and genetic risk factors for oesophageal cancer and Barrett’s oesophagus

• Cellular and molecular changes that occur in the progression of normal oesophageal epithelium, through Barrett’s oesophagus, to oesophageal cancer

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RECENT HIGHLIGHTS:

• Helped identify a variant in the FTO gene associated with melanoma risk in the general population.

• Helped identify a recurrent activating ‘drug targetable’ mutation in RAC1 that occurs in 5% of sun exposed melanomas.

• Completed the largest and most comprehensive genetic analysis of melanomas of unknown

primary, revealing insights into the origin of this rare subset of tumours.

• Completed the first population-based study of germline BAP1 mutations in uveal melanoma cases.

• Helped show that a germline BAP1 splice mutation in a family with uveal and cutaneous melanoma also confers predisposition to paraganglioma.

Radiation Biology and OncologyGroup Leader: Professor Martin Lavin

The Radiation Biology and Oncology Group is focuses on:

• Investigating the molecular basis of autosomal recessive ataxias including ataxia-telangiectasia (A-T) and ataxia oculomotor apraxia type 2 (AOA2);

• Early detection of prostate cancer; and

• Venomics-developing a serum tube for analyte determination.


• Ataxia-telangiectasia

• Ataxia with oculomotor apraxia type 1 or 2

• Blood cancers (leukaemia, lymphoma)

• Prostate cancer

CURRENT RESEARCH

The major area of research interest is centred on the genetics and biology of the human genetic disorder ataxia-telangiectasia (A-T). Research areas include:

• Characterise rat models of ataxia-telangiectasia (A-T)

• Investigate neurodegeneration in the rat models

• Generate induced pluripotent stem cells (iPSC) from all patients attending the A-T clinic in Brisbane

• Generate olfactory neuronal progenitor cells from these A-T patients in collaboration with Professor Alan Mackay-Sim, Griffith University

• Investigate the role of ATM in DNA damage response and in oxidative stress

• Complete the characterisation of the Setx-/- mouse model and the role of senataxin in meiosis

• Investigate the role of senataxin in the cerebellum

• Further characterise the role of SMG-1 protein in inflammation and tumour development.

• Develop biomarkers for diagnosis and prognosis in prostate cancer

• Complete work on the development of the Q-Sera tube

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RECENT HIGHLIGHTS:

• Generated the first stem cells from patients with A-T.

• Produced two rat models for A-T.

• Generated first mouse model for ataxia oculomotor apraxia type 2.

• Identified new autophosphorylation sites during ATM activation.

• Demonstrated that ATM-dependent Rad50 phosphorylation is important in DNA repair and cell cycle control.

• Demonstrated a novel role for SMG-1 protein in stress granule formation.

• Cloned and characterised genes from a snake venom gland.

Signal TransductionGroup Leader: Professor Kum Kum Khanna

The Signal Transduction Group’s major focus of research is on signalling pathways that maintain genome stability during normal cell division cycle and in the face of DNA damage. The group seek to exploit dysregulation of these pathways in breast cancer to develop new targeted therapeutic approaches.


• Breast cancer

CURRENT RESEARCH

• To understand the role of Cep55 in cancer initiation and progression using overexpression mouse models

• To elucidate the pathophysiological role SSB1 and SSB2 using knockout mouse models

• To functionally characterise SSB1 and SSB2 interacting proteins

• To understand the role of Centrobin in the regulation of microtubule dynamics

• To perform pathway profiling in breast cancer for development of targeted therapies

• Development of novel combination treatments against cancer in animal models including specific pathway inhibitors and targeted drug delivery

• Understanding the cellular and molecular factors which determine the extent of tumour response to therapy including proliferation, apoptosis, DNA-repair, and cell cycle.

RECENT HIGHLIGHTS:

• Developed a novel combination therapy that prevents breast cancer recurrence in preclinical models.

• Provided a mechanistic explanation as to how KAP1 phosphorylation might regulate heterochromatin repair.

• Generated a mouse model of SSB1 and uncovered its essential developmental role in the regulation of skeletogenesis.

• Contributed significantly to the development of a therapeutic approach against glioblastoma; radioimmunotherapy using anti-EphA3 antibody.

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Tumour Micro-environmentTeam Head: Dr Andreas Moller

The Tumour Microenvironment Team investigates how epithelial cancer cells interact with surrounding non-tumour stromal cells to enable tumour progression and metastatic spread to distant tissues.

Work in the laboratory focuses on how low oxygen (hypoxic) environments and other stress conditions experienced by tumours change the interaction and communication between the tumour cells and fibroblasts, immune and endothelial cells, with a focus on three main processes crucial to tumour progression. Firstly, the group is interested how tumour cells initiate new blood vessel formation (neo-angiogenesis) under hypoxia and ways to prevent or alter these processes. Secondly, the laboratory investigates the mechanisms that control epithelial to mesenchymal transition (EMT), an essential process for tumour cells to invade the stroma, enter the vascular system and metastasise to distant tissues.

The third research topic of the laboratory centres around investigating how a hypoxic tumour can alter the tissue of distant organs by modifying cell differentiation and behaviours to generate permissive environments (pre-metastatic niches) at these sites. These pre-metastatic niches promote metastatic growth of subsequently arriving tumour cells, and the aim is to translate findings into prognostic, diagnostic and curative treatment options for cancer patients.


• Breast cancer • Lung cancer

CURRENT RESEARCH

• How do cancer-derived factors initiate and maintain the pre-metastatic niche at distant sites?

• Can tumour-derived factors, which initiate the pre-metastatic niche, be predictive or diagnostic markers in breast or lung cancer?

• What is the role of Siah ubiquitin ligases (hypoxia-induced signalling mediators) in endothelial cell function and blood vessel formation (neo-angiogenesis).

RECENT HIGHLIGHTS:

• Investigated pre-metastatic niche induced by tumour cell hypoxia.

• Found neo-angiogenesis is controlled by Siah ubiquitin ligases.

• Determined the underlying mechanisms of pre-metastatic niche formation.

• Determined that the hypoxic response pathway in breast cancer cells mediates pre-metastatic niche formation in distant tissues.

• Identified that the hypoxia-regulator Siah controls neo-angiogenesis in breast cancer.

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Translational Leukaemia ResearchTeam Head: Dr Steven Lane

The Translational Leukaemia Research Team is researching myeloid blood cancers such as acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS) and the myeloproliferative neoplasms (MPN). These are very aggressive and rapidly fatal blood cancers that are among the most common types of cancer affecting Australians. The laboratory’s efforts are concentrated on understanding how leukaemia stem cells in AML and MPN are able to regenerate leukaemia (or cause relapse in patients), even after cytotoxic chemotherapy. To achieve this, research has focused on generating robust models of leukaemia and dissecting the pathways of self-renewal in leukaemia stem cells and normal blood stem cells.


• Blood cancers, including:

• Acute myeloid leukaemia

• Myeloproliferative neoplasm (polycythemia vera, myelofibrosis, essential thrombocythemia)

• Myelodysplastic syndrome

CURRENT RESEARCH

Myeloproliferative neoplasms (MPN)

• Targeting disease-initiating stem cell populations through targeted inhibitors of Jak2 signalling or

through inhibition of self-renewal pathways within stem cell populations

Acute myeloid leukaemia

• Examining the effect of inhibitors used alone, or in combination with chemotherapy on the preferential dependency of AML stem cells (compared to normal bone marrow) on

pathways regulating DNA damage response and chromosomal stability

• Identifying novel LSC-specific targets that may be of broader interest

Normal blood development

• Novel pathways that regulate blood stem cell development

• Cytokine mobilisation of stem cells for use in transplantation medicine

RECENT HIGHLIGHTS:

• Identified novel pathways of stem cell mobilisation.

• Identified genetic susceptibilities of leukaemia stem cells.

• Targeted disease-initiating stem cell populations through targeted inhibitors of Jak2 signalling or through inhibition of self-renewal pathways within stem cell populations.

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INFECTIOUS DISEASES

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Coordinator: Professor James Mccarthy

QIMR Berghofer’s Infectious Diseases Program studies how a range of important pathogenic organisms cause illness, investigates improved diagnosis and treatment techniques and develops vaccines to prevent infections. The Program focuses its work on conditions that have major impacts in the developing world and tropical regions.

The Program researches HIV, cytomegalovirus (CMV), Epstein-Barr virus (EBV), mosquito-borne viruses; bacteria such as streptococci; and parasites such as malaria, intestinal protozoa, worms and scabies.

Working closely with clinicians, other research institutes, and pharmaceutical companies, the Infectious Disease Program aims to use strong collaborations to improve the health of many.

QIMR Berghofer is a founding member of the Queensland Tropical Health Alliance (QTHA), which is designed to enhance collaborations and networking in tropical health issues, and the Australian Infectious Diseases Research Centre (AID), which supports research into diseases such as malaria, dengue fever and schistosomiasis. QIMR Berghofer’s collaboration with James Cook University, Griffith University, QUT, and The University of Queensland through the QTHA and again with the University of Queensland though AID brings strength and focus for plans to address serious tropical and infectious disease issues through Queensland, across Australia, and in the Asia-Pacific region.

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Bacterial PathogenesisGroup Leader: Professor Sri Sriprakash

The Bacterial Pathogenesis Laboratory undertakes research into the two human pathogens Streptococcus pyogenes and Streptococcus dysgalactiae subsp equisimilis. S. pyogenes is a leading cause of bacterial related death in humans. Streptococcus dysgalactiae subsp equisimilis is a related species whose contribution to disease is only now being understood. These two bacterial species cause a number of diseases that target different organs in the body. The laboratory’s research is aimed at understanding the pathogenic processes associated with infection by these organisms, and developing novel strategies to prevent streptococcal disease.

The group also has a research interest in bacterial colonisation of medical devices. The insertion of a catheter into a vein provides a portal by which bacteria can cross the skin and enter normally sterile body sites, thereby causing disease. The group in interested in characterising the pathogenic and non-pathogenic species that colonise these devices, identifying the sources of bacterial contamination, and ultimately developing novel technologies or practices that reduce device colonisation.


• Streptococcal disease (rheumatic fever, rheumatic heart diseases, invasive diseases, glomerulonephritis)

• Scabies

CURRENT RESEARCH

Bacterial Pathogenesis

• Molecular epidemiology and population genetics of streptococci

• Pathogenesis of streptococcal infections

• Development of novel group A streptococcal vaccines

• Characterisation of bacterial colonisation of medical devices

Scabies

• Genes for SMIPP-Ss amplified in the scabies mite genome to overcome host defence strategies

• The mechanism which protects the scabies mite from complement-mediated gut damage

• Inhibition of host defences in mite burrows utilised by bacterial pathogens such as GAS

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RECENT HIGHLIGHTS:

• Found the population endemic for Streptococcus pyogenes and S. dysgalactiae subsp equisimilis colonisation exhibit increased recovery of novel recombinants with possible increased pathogenic potential.

• Designed and demonstrated the efficacy against S. pyogenes infection of recombinant vaccine candidate representing variants from

the conserved regions of the M protein. By this design, the group have eliminated the need for using extraneous sequences for maintaining the conformation of the vaccine candidate.

• Showed that past infection with SIC-positive group A streptococcus is a risk factor for chronic kidney disease and that SIC seropositivity is predictive of poor prognosis of CKD patients.

BioinformaticsTeam Head: Dr Lutz Krause

The Bioinformatics Team develops and applies bioinformatics methods in the context of biomedical research. It specialises in biomarker discovery, infectious diseases and genetics and epigenetics of complex disorders.

The Team’s research focus is on investigating the role of the human microbiota in health and disease, revealing the role of epigenetics in depression and the discovery of biomarkers for progression, personalised treatment and prognosis of oesophageal adenocarcinoma.


• Cancers

• Cystic fibrosis liver disease

• Depression

• Diabetes

• Endometriosis

• Inflammatory bowel diseases

• Metabolic disorders

• Obesity

• Oesophageal cancer

• Psychiatric disorders

• Schistosomiasis

• Streptococcal-related infections

CURRENT RESEARCH

• Comparative genomics of human parasites, identification of vaccine and drug targets

• Discovery of biomarkers for prognosis, progression and personalised treatment in cancer

• Epigenetics in complex disorders

• Role of the human microbiota and viruses in health and disease

• Genome-wide association studies of genetic disorders

• Development of methods for integrating, mining and visualising heterogeneous datasets, including genomic variations, gene expression and epigenetic modifications

• Development of data-mining methods, machine learning techniques and algorithms for the analysis of microbial and viral metagenomes, epigenetic samples, whole genome association studies, next-generation sequence data

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RECENT HIGHLIGHTS:

• Identified potential biomarkers for prognosis and personalised treatment in oesophageal adenocarcinoma.

• Published a genome-wide epigenetic association study in the context of major depressive disorder.

• Started de novo sequencing of Schistosoma bovis genome.

• Established several bioinformatics pipelines for analysing next-generation sequencing data, which are widely used for calling SNPs and analysing RNAseq, MeDIP-seq and Chip-seq data.

• Identified mutations and rearrangements important for cancer initiation and progression using whole-genome and exome sequencing of oesophageal adenocarcinoma samples in collaboration with Princess Alexandra Hospital and the Institute for Molecular Bioscience.

• Conducted a genome-wide epigenetic association study in oesophageal adenocarcinoma and Barrett’s oesophagus.

• Investigated the role of human microbiota in various diseases and disorders including cystic fibrosis, diabetes and parasite-bacteria co-infections.

Biomarkers and Biology of Infection Related CancersTeam Head: Dr Jason Mulvenna

RECENT HIGHLIGHTS:

• Characterised structure of TSP-2, a vaccine antigen for schistosomiasis.

• Characterised proteomics of Necator americanus for hookworm genome project.

• Discovered potential miRNA markers for nasopharyngeal carcinoma.

Cellular ImmunologyGroup Leader: Associate Professor Scott Burrows

The Cellular Immunology Group focuses on the T cell immune response to viral infection, particularly Epstein-Barr virus which causes glandular fever and is associated with various malignancies and autoimmunity. The molecular interactions that control the specificity of T cells recognition of virus-infected cells are complex and could hold the key to preventing Epstein-Barr virus associated diseases.


• Glandular fever

• Hodgkin’s lymphoma

• Burkitt’s lymphoma

• Nasopharyngeal carcinoma (nose and throat cancer)

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CURRENT RESEARCH

• Sequencing EBV genes from individuals in different countries with different EBV-related diseases helps to identify important EBV strains

• Helping to understand how our immune system detects viruses in our body at the highest possible resolution

RECENT HIGHLIGHTS:

• Showed that the dominant T cells of the immune system remain stable throughout life.

• Showed that individual T cells of the immune system are programmed to recognise peptides of a particular size.

• Showed that very minor genetic differences between people can have a major influence on their immune response to pathogens.

Clinical Tropical MedicineSenior Scientist: Professor James McCarthy

The Clinical Tropical Medicine Laboratory investigates how parasites such as the malaria parasite, hookworm, threadworm and scabies cause disease and how they become resistant to drugs used to treat them. The group also identifies new drugs and drug targets, and develops novel diagnostic techniques.

The focus of this laboratory is to apply modern techniques in microbiology, molecular biology and immunology to study clinical problems associated with infectious diseases in tropical environments.

A particular interest in this laboratory is the study of drug resistance in a range of parasites, and the development of novel diagnostic techniques.

CONDITIONS RESEARCHED• Malaria

• Scabies

• Intestinal worms, including hookworm and strongyloides

CURRENT RESEARCH • Using experimental human malaria infection to

improve the understanding of the pathogenesis of malaria and to develop new diagnostics, drugs and vaccines.

• Improving the diagnosis and treatment of scabies and intestinal helminth infections.

• Clinical trials of new drugs and vaccines for infectious diseases.

RECENT HIGHLIGHTS:• Defined the effectiveness of the experimental

antimalarial OZ439.

• Developed tests to measure the prevalence and intensity of parasite infections in East Timor.

• Developed a system to undertake experimental blood stage Plasmodium vivax malaria infections.

• Begun a Phase I study of a new vaccine for group A streptococcus.

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HIV Molecular VirologyGroup Leader: Associate Professor David Harrich

The HIV Molecular Virology Group investigates fundamental mechanisms of virus replication with an overall goal to identify key virus and host interactions required to support optimal virus replication. A main research direction is analysis of a HIV-1 specific process called reverse transcription by which the viral RNA genome is converted into DNA that can be inserted into human chromosomes, a permanent and irreversible event. Using biochemical assays developed at QIMR Berghofer, the Molecular Virology Group identified human proteins subverted by HIV to complete reverse transcription.


• HIV/AIDS

• Respiratory syncytial virus (RSV)

• Hendra virus

CURRENT RESEARCH

• Analysis of HIV host dependency factors required for early steps of HIV replication

• Regulation of HIV replication by RNA and ribonucleoprotein complexes

• Development of potent antiviral proteins based on the viral Tat protein

• Analysis of cellular proteins regulating HIV Rev protein function and trafficking in the cell

• Investigation of how cellular proteins facilitate replication of RSV and Hendra virus.

RECENT HIGHLIGHTS:

• Showed a novel protein inhibitor of HIV called Nullbasic provided excellent protection from infection in human cells in vitro.

• Identified two cellular proteins that enable early steps of HIV-1 infection.

• Discovered two unidentified host proteins controlling the function of an important HIV-1 regulatory protein called Rev.

• Challenged the role of a host protein called PRMT6 as an HIV-1 restriction factors. A role for PRTM6 in regulating a critical HIV-1 protein called Tat, other than on increased protein stability, remains unclear.

Human ImmunityTeam Head: Dr John Miles

The Human Immunity Laboratory studies the immune processes which determine the host’s response to infectious disease, cancer and innocuous agents. The team’s research focuses on T cells and their ligands, exploring receptor genetics, biology, engagement and molecular structure across a number of human disease systems. The team used information from these basic studies to modify T cell interactions and T cell repertoires for use in rational vaccine design and therapeutic interventions.

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• Epstein-Barr virus (EBV)

• Nasopharyngeal carcinoma (NPC) (nose and throat cancer)

• Glandular fever

• Burkitt’s lymphoma

• Hodgkin lymphoma

• Human cytomegalovirus (HCMV)

CURRENT RESEARCH

• Determining the biological relevance of T cell receptor diversity in disease pathogenesis

• Determining fundamental rules of engagement between T cell receptors and their ligands

• Determining the immunological consequences of genetic diversity on pathogen defence

• Engineering affinity-enhanced T cell receptors and ligands for new cancer therapeutics

RECENT HIGHLIGHTS:

• Deconstructed the proliferating neonate T cell repertoire.

• Led the first study to deep sequence the human alpha/beta T cell repertoire over decades of life.

• Described the antigen recognition compartmentalisation of the human T cell repertoire.

• Authored two reviews on manipulating the immune system for therapeutic purposes.

• Involved in studies revealing the basic mechanisms behind human T cell function.

Immunology and InfectionGroup Leader: Dr Christian Engwerda

The Immunology and Infection Laboratory continues to try and understand why some immune responses safely control parasite growth and protect against re-infection, whereas others cause disease during malaria and leishmaniasis. The research has moved from a primary focus on studying immune regulation during parasite infections in pre-clinical models of disease to validating our findings from these models using samples from patients and volunteers deliberately infected with the parasites that the laboratory works on.


• Malaria • Visceral leishmaniasis (VL)

CURRENT RESEARCH

• Understanding how T cells behave during malaria and leishmania.

• Identifying how T cells are regulated during malaria and leishmania.

• Investigating novel immune pathways activated during malaria and leishmania.

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RECENT HIGHLIGHTS:

• Identified Blimp-1 as an important T cell transcription factor for inducing immunoregulatory IL-10 during malaria and leishmania.

• Showed that CTLA-4 blocks anti-malaria immune responses.

• Discovered that a specialised T cell population produces IL-17 very early during leishmania

infection and suppresses the ability of monocytes to kill parasites.

• Identified new and critical roles for monocytes in visceral leishmaniasis.

• Discovered that type I interferons suppress anti-parasitic T cell responses in a pre-clinical model of visceral leishmaniasis, as well as in clinical samples from leishmania patients.

Inflammation BiologyGroup Leader: Professor Andreas Suhrbier

The Inflammation Biology Laboratory is developing and exploiting knowledge about interactions between viruses and the immune system to develop new anti-cancer, antiviral and anti-inflammation strategies.


• HIV

• Inflammatory diseases

• Mosquito-borne viruses (Ross River, chikungunya)


• Skin cancers (including squamous cell carcinoma and actinic keratosis)

CURRENT RESEARCH

• Investigating the role of SerpinB2 (Plasminogen Activator Inhibitor Type-2) during inflammation and its potential role in regulating the adaptive immune responses

• Investigating chikungunya virus and Ross River virus disease – utilising mouse models to understand how these virus causes arthritis. Evidence suggests that the disease is caused by the persistent productive infection of

macrophages in the joints and the release of pro-inflammatory mediators

• Investigating the mechanisms of action of Cpn10, a proprietary drug being developed by Invion limited as an immunomodulator for inflammatory conditions such as rheumatoid arthritis and lupus

• Investigation the mechanisms of action of topical ingenol mebutate / Picato a recently approved drug for treatment of actinic keratoses (sun spots)

• Pancreatic cancer and Sin1

RECENT HIGHLIGHTS:

• Illustrated the utility of ingenol mebutate for field-directed therapy of actinic keratoses to prevent future development of skin cancers.

• Uncovered the similarity in the inflammatory disease seen in chikungunya virus and rheumatoid arthritis, which suggests drugs being

developed for rheumatoid arthritis may find utility in the treatment of alphaviral diseases such as Ross River virus and chikungunya disease.

• Showed that deficiency in interferon responses in alphaviral infections is sufficient for haemorrhagic fever and shock.

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Malaria ImmunologyTeam Head: Dr Ashraful Haque

The Malaria Immunology Team use state of the art in vivo techniques to assess the immune response to Plasmodium infection. The Team’s aim is to modulate the immune system to improve control of parasites.


• Malaria

CURRENT RESEARCH

• Defining the role of type I interferon-associated immune responses during Plasmodium infection.

• Discovering novel host genes that contribute to pathogenesis during severe Plasmodium infection.

RECENT HIGHLIGHTS:

• Demonstrated that CD8- dendritic cells are suppressed via type I interferon signalling during experimental malaria.

• Used mathematical and in vivo modelling techniques to determine that parasite

sequestration in peripheral tissues drives large increases in parasite biomass during severe malaria.

• Demonstrated the role of IRF7 in suppressing T cell immunity to Plasmodium.

Molecular ImmunologyTeam Head: Dr Michelle Wykes

The Molecular Immunology Team focuses on three areas:

• Identifying the role of PD-1 in malaria;

• Exploring their role of synthetically generated immunological proteins as novel therapies for malaria; and

• Investigating the kinetics of red cell clearance during malaria.


• Malaria

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CURRENT RESEARCH

The major area of research interest is centred on understanding immunology of malaria and using this knowledge to address fundamental questions in immunology. Research areas include:

• Identification of host molecular pathways or immunological signals that contribute to protection against malaria

• Using experimental rodent malaria infection to understand the pathogenesis of malaria

• Identifying the role of dendritic cells in the life cycle of the malaria parasite, Plasmodium spp.

• Development of novel efficacious long term treatments for malaria.

RECENT HIGHLIGHTS:

• European Journal of Immunology commissioned a commentary on the group’s publication showing why antibody-based malaria vaccines may not work.

Molecular ParasitologySenior Scientist: Professor Don McManus

The Molecular Parasitology Laboratory researches the biology, pathogenesis and epidemiology of parasitic worms that cause major clinical disease (schistosomiasis, echinococcosis (hydatid disease), soil transmitted helminthiases), with the aim of developing new public health interventions, including vaccines, and diagnostic procedures that will lead to their elimination through integrated control.


• Schistosomiasis (Bilharzia) • Hydatid disease

CURRENT RESEARCH

• Extensive human schistosome field studies in Hunan Province (Dongting Lake region), Jiangxi Province (Poyang Lake) and other provinces in China.

• Characterising nuclear and mitochondrial genomes and investigating molecular variation both in the genomes and in key molecules that may be the targets of new anti-schistosome and anti-Echinococcus vaccines.

• Dissecting the molecular and immunological mechanisms involved in human disease caused by schistosomes and Echinococcus.

• Identifying novel drugs and vaccine targets for schistosomiasi.

• Development of new diagnosis methods for hydatid diseas.

• Development of a vaccine against Echinococcus for use in dog hosts.

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RECENT HIGHLIGHTS:

• Determined the diagnostic value of non-invasive biomarkers for stage-specific diagnosis of hepatic fibrosis in patients with advanced schistosomiasis japonica.

• Identified signalling pathways as putative targets for control interventions against schistosomiasis.

• Completed a five year longitudinal study of schistosomiasis transmission in an endemic area in Schuan Province, China.

• Undertook an extensive proteomic characterisation of Echinococcus granulosus hydatid cyst fluid from sheep, cattle and humans.

• Defined a role for peroxisome proliferator-activated receptors in the immunopathology of schistosomiasis.

• Showed the value of schistosomiasis research in the Dongting Lake region and its impact on local and national control strategies in China.

• Defined the risk factors for helminth infections in a rural and a peri-urban setting of the Dongting Lake area, China.

• Completed a five-year longitudinal assessment of the downstream impact on schistosomiasis

transmission in China following closure of the Three Gorges Dam.

• Demonstrated that the insulin receptor is an effective transmission blocking veterinary vaccine target for zoonotic Schistosoma japonicum.

• Completed a cluster-randomised trial demonstrating that a video-based health education package prevents soil-transmitted helminth infections in Chinese schoolchildren.

• Published a major article in the New England Journal of Medicine describing the highly successful outcome of a health education package to prevent worm infections in Chinese schoolchildren.

• Published a major review article in the New England Journal of Medicine on chronic enteropathogens in returning travellers.

• Published a major review on the structure and function of invertebrate Kunitz serine protease inhibitors.

• Completed a draft genomic sequence for Echinococcus granulosus in collaboration with Chinese colleagues.

Molecular VaccinologyGroup Leader: Professor Denise Doolan, Department Coordinator: Biology

The Molecular Vaccinology Laboratory’s research is focused on rational vaccine design, primarily for malaria, and encompasses core themes of:

• Basic research on immune mechanisms and adjuvant activity;

• Antigen and epitope discovery from genomic sequence data using protein microarrays and

epitope prediction algorithms with biologically relevant laboratory and field specimens; and

• Pre-clinical research and development of antigen and epitope based molecular vaccine technologies.


• Malaria

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CURRENT RESEARCH

• Identifying and characterising target antigens and epitopes for vaccine development

• Understanding mechanisms of protective immunity and regulation of immunity

• Identifying novel adjuvants which enhance vaccine-induced immunity, especially cell mediated immune responses

• Evaluating novel vaccine delivery systems

RECENT HIGHLIGHTS:

• Identified four new malaria antigens as targets of infection-blocking protective immunity against malaria, and showed that antigen combinations are more effective than individual antigens.

• Established that antigens that are highly reactive for T cells are not dominant for antibodies and are highly conserved; these data overturn conventional dogma and suggest that new strategies are required for T cell based vaccine development.

• Produced protein microarrays for Plasmodium vivax to identify excellent candidates for a malaria vaccine or diagnostic test.

• Identified an adjuvant that activates dermal dendritic cells, a specialised cell type shown to

be important for cross-presenting antigens and activating CD8+ T cells.

• Developed a high throughput adjuvant screening assay to identify novel adjuvants to enhance cell mediated immunity.

• Showed that a natural product derived from rainforests can protect against malaria, in a mouse model.

• Evaluated a novel platform technology capable of presenting multiple epitopes from a complex pathogen in an authentic manner that maintains the native antigenic structure.

• Evaluated the vaccine potential of a novel bacterial platform shown to be effective for drug delivery.

Mosquito ControlGroup Leader: Greg Devine

Research in the Mosquito Control Laboratory focuses on the biology and control of mosquito-borne viruses such as dengue, Ross River virus and Barmah Forest virus. This laboratory is designated by the World Health Organization (WHO) as an official global Collaborating Centre for Environmental Management for Vector Control.

The laboratory specialises in designing new mosquito surveillance and control strategies and has strong collaborative linkages with dengue prevention research groups in Vietnam and Australia. Mosquito Control researchers also work directly with State and local government in Queensland on mosquito control and all mosquito-transmitted arboviruses.

HIGHLIGHTS:

• Wrote and edited a book on a world-first eradication of the Australian southern saltmarsh mosquito from New Zealand.

• Completed of a 5,000 household survey of Brisbane to determine presence of exotic mosquitoes.

• Identified several proteins which can be used to determine mosquito age.

• Conducted the first Wolbachia release for dengue control in Vietnam.

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Protein Discovery CentreGroup Leader: Professor Jeff Gorman

The QIMR Berghofer Protein Discovery Centre is a state-of-the-art facility recognised as a world leader in the mass spectrometry and proteomics field and is one of the most advanced and best equipped of its kind in Australia. The centre collaborates broadly on both national and international projects.

The centre aims to discover the identities of proteins involved in or affected by physiological and disease processes and the ways in which these proteins function and interact and to develop techniques to observe stimulated cells and the reaction within cell proteins.

CURRENT RESEARCH

• Viruses that cause serious respiratory diseases of children

• Signal-activated transcription factors involved in cancer progression

• Virally infected cells versus non-infected cells – aimed at vaccine development

• Hypoxia inducible factor which controls the response to hypoxia – to determine if a particular enzyme affects other proteins

• Dioxin receptor – a xenobiotic regulator response involved in cancer

• Cancer stem cell phenotype analysis – developing markers for cancer stem cells

• Oxidative stress – in relation to virus infection and mosquito age grading

RECENT HIGHLIGHTS:

• Characterised the proteomic component of A549 cells regulated by RSV infection and deduced associated pathways.

• Developed a methodology for identifying specific proteoforms from ambiguous protein group database entries.

• Developed and deployed high-performance proteomic approaches for analysing catalytic properties and substrates of Kallikrein proteases that putatively contribute to prostate cancer progression.

• Produced recombinant RSV-NS1 protein using cell free and bacterial expression systems for structural biology and protein-protein interaction studies.

• Advanced the knowledge of protein expression in the matrix of developing cartilage chondrocytes.

• Produced proteomic data to revolutionalise annotation of the fungal pathogens of wheat.

• Developed and validated methods for production of versatile probes of the calcitonin receptor.

• Characterised asparagine hydroxylation sites on the TRPV3 protein.

• Developed advanced proteomic methodologies to facilitate Rio Tinto Ride to Conquer Cancer projects involving ephrin signalling and cancer vaccines.

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Tumour ImmunologyGroup Leader: Professor Rajiv Khanna

The major goal of the Tumour Immunology Laboratory is to obtain a deeper understanding of the mechanisms by which an immune response to tumours may be generated, augmented and exploited for the treatment of these cancers.


• Epstein-Barr virus (EBV)

• Nasopharyngeal carcinoma (NPC) (nose and throat cancer)

• Hodgkin’s lymphoma

• Human cytomegalovirus (HCMV)

CURRENT RESEARCH

• Design of recombinant therapeutic vaccines to EBV-associated nasopharyngeal carcinoma and Hodgkin’s lymphoma

• Developing a prophylactic vaccine for human cytomegalovirus

• Targeting ubiquitously expressed EBV cancer-associated antigen EBNA1 for immunotherapy

RECENT HIGHLIGHTS:

• Completed Phase I clinical trial on adoptive immunotherapy for stage IV nasopharyngeal carcinoma (in collaboration with University of Hong Kong).

• Developed novel T cell based therapy for the treatment of brain cancer, glioblastoma.

• Completed pre-clinical studies on the prophylactic vaccine for human cytomegalovirus to prevent birth defects.

• Completed clinical testing of a new diagnostic test to predict cytomegalovirus-associated complications in transplant patients.

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MENTAL HEALTH/COMPLEX DISORDERS

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Coordinator: Professor Michael Breakspear

QIMR Berghofer’s Mental Health/Complex Disorders Program combines a number of disciplines to study the genetic and multi-factorial environmental influences in a range of diseases from schizophrenia and depression to haemochromatosis and migraine. These conditions hold an enormous burden of illness and unmet research need.

QIMR Berghofer utilises imaging and gene sequencing technologies to provide unprecedented insight into the biology of cells, animals and humans and the genetic basis for a number of conditions.

Using brain imaging, computational modelling and epidemiological studies, the Mental Health/Complex Disorders Program works to bring public awareness and better understanding to mental illness and complex disorders, while working to improve outcomes and recovery for those suffering with these diseases.

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Asthma GeneticsTeam Head: Dr Manuel Ferreira

The Asthma Genetics Team aims to identify genetic variants that influence the risk of developing asthma, understand how genetic variants influence the risk of asthma and establish clinical trials to test new treatments for asthma.


• Asthma

CURRENT RESEARCH

• Analysis of whole-genome sequence data to identify rare variants influencing the risk of asthma

• Characterisation of the asthma transcriptome

• Clinical trial of tocilizumab for asthma treatment

• Developing a new delivery method for tocilizumab, so that it can be delivered directly to the lungs

RECENT HIGHLIGHTS:

• Identified 10 loci influencing allergic sensitisation.

• Identified two new loci for asthma.

• Identified an additional regulatory variant in the IL6R gene that associates with asthma risk.

Genetic EpidemiologySenior Scientist: Professor Nick Martin

The Genetic Epidemiology Laboratory investigates the pattern of disease in families to assess the relative importance of genes and environment in a variety of important health problems and to locate the genes responsible using genome-wide association analysis.


• Melanoma

• Alcohol and nicotine dependence

• Mole development

• Iron absorption

• Endometriosis

• Super-fertility and twinning

• Migraine

• Anxiety, depression and fatigue

• Osteoarthritis

• Asthma

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CURRENT RESEARCH

• Genetics of asthma

• Genetics of alcohol and nicotine dependence

• A twin study of mole development in adolescence

• A twin study of mental abilities and cognitive performance

• A twin study of blood cell numbers

• Biology and molecular genetics of dizygotic twinning

• The role of ADH and ALDH polymorphisms in alcohol sensitivity in humans

• The role of HFE polymorphisms in iron metabolism in Australian twins

• Genetic influences on endometriosis

• Asthma and allergy in Australian twins and their families

• Osteoarthritis in ageing twins

• Psychosocial factors in cancer proneness in ageing twins

• Genetic factors in anxiety, depression and fatigue

• Genetic analysis of migraine and comorbid psychiatric disorders using twin families

RECENT HIGHLIGHTS:

• Played a leading role in the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium and identified the first confirmed locus for a brain imaging phenotype, for hippocampal volume on chromosome 12.

• Conducted the first full genome sequencing project for a complex trait, which resulted in finding a causal variant for melanoma in MITF.

• Discovered a new locus for melanoma on chromosome one.

• Contributed to genome-wide association scan (GWAS) meta-analysis, which found 65 new loci for platelets with strong therapeutic potential.

• Contributed to GWAS meta-analysis, which discovered six new loci for male pattern baldness with overlap with prostate cancer and other diseases.

• Contributed data that uncovering three new loci for eczema.

• Contributed to discovery of a new susceptibility locus near ODZ4 for bipolar disorder.

• Contributed to GWAS showing a tentative association with depression on chromosome three.

• Contributed to study finding new variants for menopause and triple-negative breast cancer.

Hepatic FibrosisGroup Leader: Professor Grant Ramm, Department Coordinator: Cell and Molegular Biology

The Hepatic Fibrosis Laboratory investigates the cellular and molecular mechanisms of scar tissue formation in the liver. This leads to fibrosis and cirrhosis in adult liver diseases, such as haemochromatosis and in children, in diseases such as cystic fibrosis and biliary atresia.

The group is funded by the NHMRC to further investigate the role of hepatic stellate cells in human chronic liver disease and the mechanisms associated with both their transformation into collagen-producing myofibroblastic cells, as well as their role in wound healing in the regenerating liver following liver insult.

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• Cystic fibrosis liver scarring

• Biliary atresia

• Haemochromatosis

• Hepatitis C virus

• Liver cancer

• Non-alcoholic fatty liver disease

CURRENT RESEARCH

• Role of hepatic stellate cells in fibrogenesis associated with haemochromatosis

• Cellular and molecular mechanisms associated with liver injury, wound healing, fibrogenesis and tissue regeneration in chronic liver disease.

• Biomarker development for detecting, monitoring progression and predicting clinical outcome of chronic liver disease in children and adults

RECENT HIGHLIGHTS:

• Demonstrated a role for diabetes as a risk factor for severe hepatic fibrosis in patients with haemochromatosis.

Inflammatory Bowel Diseases GroupGroup Leader: Dr Graham Radford-Smith

Inflammatory bowel diseases (IBD) are a group of diseases that affect the colon and small intestine, including Crohn’s disease and ulcerative colitis. They affect up to one in every 200 Australians.

IBD is a medical condition that affects the gastrointestinal system, or gut. People with this illness often have ongoing symptoms of tummy pain, diarrhoea, the passing of blood, and weight loss. They can also suffer from other conditions that affect the skin, eyes and joints. Patients need medication for long periods of time and many have bowel surgery. IBD affects both males and females, including children.


• Inflammatory bowel diseases

• Crohn’s disease

• Ulcerative colitis

CURRENT RESEARCH

• Identification of genes associated with Crohn’s disease and ulcerative colitis

• The role of paneth cells in ileal Crohn’s Disease

• Determination of disease-specific gene expression signatures

• Incidence and prevalence of inflammatory bowel disease in South-East Queensland

• A research project looking into the causes of inflammatory bowel disease

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RECENT HIGHLIGHTS:

• Awarded grant for an ulcerative colitis GWAS.

• Carried out an immunochip study in collaboration with the International IBD Genetics Consortium, leading to a Nature publication.

• Consolidated a major collaboration with Amgen (translational IBD research program).

• Analysed GWAS and immunochip data to identify molecular signatures for IBD sub-phenotypes, including acute severe colitis (and its response to different therapies) and colorectal cancer complicating colitis.

• Carried out parallel studies in colorectal cancer cases complicating ulcerative colitis using exome sequencing, to identify novel SNPs in this sub-group.

• Executed a GWAS in patients with refractory ulcerative colitis.

• Completion of the first phase of the Crohn’s disease PBS study – this has investigated factors that significantly influence maintenance of response to anti-TNF therapy across Australia and New Zealand.

Iron MetabolismGroup Leader: Professor Greg Anderson, Deputy Director

The Iron Metabolism Laboratory focuses on understanding the homeostasis of the essential trace element iron in the body and the natural history of disorders of iron metabolism, such as the iron loading disease haemochromatosis. The laboratory’s work takes a broad approach from basic molecular mechanisms to clinical applications.


• Iron overload conditions (such as haemochromatosis)

• Iron nutrition and supplementation during pregnancy

• Iron homeostasis in neonates

• Iron loading anaemias (including thalassaemia and haemolytic anaemias)

• Cystic fibrosis

CURRENT RESEARCH

• Mechanisms of intestinal iron absorption

• The role of iron oxidases in iron homeostasis

• Regulation of iron absorption and body iron recycling

• Population and clinical studies of haemochromatosis

• Iron homeostasis in the perinatal period (in pregnancy and newborns)

• The relationship between iron and Pseudomonas infections in cystic fibrosis

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RECENT HIGHLIGHTS:

• Showed a critical role for hephaestin and related oxidases in iron absorption.

• Assessed the combined effects of multiple hepatic toxins (iron, alcohol, fat) on liver disease progression.

• Identified factors responsible for regulating iron homeostasis in thalassaemia and other haemolytic anaemias.

• Defined the effects of transfusion therapy on iron and haematological parameters in patients with beta thalassaemia.

• Identifed mutations in iron-related genes in the Chinese population.

• Assessed the efficacy of nanoparticulate oral iron supplements in rodent models.

Lung Inflammation and InfectionTeam Head: Dr David Reid

The Lung Inflammation and Infection Team have focused on the role of iron in promoting bacterial infection in the cystic fibrosis lung and whether this in turn is related to dysregulation of cell iron homeostasis in cystic fibrosis. The team have spent the last year breeding the necessary mouse models and conducting preliminary analyses of iron phenotype, while collecting samples from human subjects to conduct an epidemiological study of gene mutations related to iron homeosatsis in CF patients. The team now has the required flow cell bacterial biofilm models to allow testing of new therapeutic compounds.


• Bronchiectasis

• Cystic fibrosis

• Infectious diseases of the lung

CURRENT RESEARCH

• Combine studies in humans, mice and transfected cell lines to demonstrate that abnormal iron homeostasis in CF promotes bacterial infection with the pathogen Pseudomonas aeruginosa and leads to worse disease outcomes.

• Confirm the efficacy of interventions that target bacterial iron homeostasis - particularly against biofilm dwelling bacteria. These experiments at present are targeting P. aeruginosa, but will expand to antibiotic multi-resistant pathogens such as MRSA and seek industry support as well as generate an IP position.

• Study the microbiome of the normal human lung and how this is affected by cigarrette smoking and therapeutic interventions such as inhaled

corticosteroids. The team has spent 15 years contributing to a very large biobank of human lung tissues and have now completed analysis of the lung microbiome in smokers with and without COPD and will publish findings in 2013.

• Expand our biometal research into other chronic respiratory diseases using a combination of human and mouse studies with the goal of investigating the role of metals, especially iron in the development of COPD and lung malignancies; lung cancer and mesothelioma.

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RECENT HIGHLIGHTS:

• Developed a cystic fibrosis mouse model on a new genetic background. This will allow novel approaches to elucidation of the underlying mechanisms of disease pathogenesis in this lethal genetic disease.

• Developed therapeutic approaches targeting bacterial iron homeostasis, which appear very active against bacterial biofilms.

• Developed methods to examine neutrophil function in the lung and demonstration that the oxidative burst potential of airway neutrophils from CF patients is affected by airway environmental conditions.

• Commenced a new collaboration with a bacteriophage company based in US.

Membrane TransportGroup Leader: Associate Professor Nathan Subramaniam

The major focus of the Membrane Transport Group is aimed at understanding how iron levels in the body are regulated, the genes involved, their mechanism of action, and the role iron plays in various disorders including liver disease and cancer.


• Haemochromatosis (including juvenile haemochromatosis)

• Anaemia

• Atypical iron disorders

• Cancer-related proteins

CURRENT RESEARCH

• Hereditary haemochromatosis caused by HFE and non-HFE mutations

• Juvenile haemochromatosis

• Molecular, cellular and functional characterisation of Transferrin Receptor 2

• Ferroportin disease or Type 4 haemochromatosis clinical applications and population studies

RECENT HIGHLIGHTS:

• Showed that the presence of excess iron in combination with a high calorie diet significantly potentiates the progression of non-alcoholic fatty liver disease, a relatively benign condition, to non-alcoholic steatohepatitis with fibrosis, a disorder with significant associated morbidity and mortality.

• Demonstrated in mouse models of haemochromatosis that, contrary to anecdotal belief, iron accumulation in the liver does not reflect iron loading of other organs, and is therefore not a suitable surrogate for assessment of disease potential in other organs in cases of iron overload.

• Identified novel mutations in patients with atypical iron overload through novel screening strategies.

• Developed and established novel and cost-effective next-generation sequencing tools for the rapid screening of genes involved in iron metabolism.

• Demonstrated that in mouse studies treatment with an antioxidant and a common spice can reduce liver injury associated with excess iron and a high calorie diet.

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Molecular EpidemiologyGroup Leader: Professor Grant Montgomery, Department Coordinator: Genetics and Computational Biology

The Molecular Epidemiology Laboratory seeks to identify genes and gene pathways contributing to risk for common human diseases. The laboratory is a world leader in the genetics of endometriosis and works on melanoma, inflammatory bowel disease and a range of other diseases including asthma, migraine, depression, and alcohol, nicotine and drug dependence. The group maintains a large biobank supporting projects in the laboratory and major collaborations with QIMR Berghofer’s Statistical Genetics, Genetic Epidemiology, Oncogenomics, Asthma Genetics and Neurogenetics Laboratories.


• Endometriosis

• Melanoma

• Alcohol, nicotine and drug dependence

• Migraine

• Depression

• Inflammatory bowel disease

• Twins and twinning

CURRENT RESEARCH

• Endometriosis

• Dizygotic twins

• Genetic Epidemiology studies

RECENT HIGHLIGHTS:

• Led significant advances in understanding genes and pathways contributing to risk for endometriosis by finding additional genomic regions associated with risk, demonstrating that the genetic factors underlying disease are similar in European and Japanese populations, and obtaining new funding to identify the specific genes and pathways underlying increased disease risk.

• Completed PhaseI genotyping for a genome-wide association study (GWAS) in carefully selected refractory and non-refractory cases to identify specific genes that either alone or together with key clinical variables will predict the risk of developing medically refractory ulcerative colitis.

• Discovered new genomic regions associated with increased melanoma risk including discovery of novel rare variants that predisposes to familial and sporadic melanoma.

• Contributed to an international consortium analysing the complex regulation of gene expression and the role of genetic varaints affecting complex disease.

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NeurogeneticsGroup Leader: Dr Dale Nyholt

The Neurogenetics Group’s focus is on the genetic analysis of migraine, endometriosis and traits comorbid with migraine including depression and epilepsy. The primary goal of this research is to identify genetic risk factors that lead to new knowledge of the underlying biological pathways contributing to disease pathophysiology.


• Depression

• Endometriosis

• Migraine

CURRENT RESEARCH

• Molecular genetic study of migraine

• Investigating link between endometriosis and migraines

• Investigating links between migraine and depression, anxiety, stroke, irritable bowel syndrome, epilepsy and hypertension

• Identifying novel schizophrenia risk genes (1p31.1 and 1q23-25)

• Genome-wide association linking male pattern-baldness and prostate cancer

RECENT HIGHLIGHTS:

• Reported six novel risk loci for androgenetic alopecia and their association with Parkinson’s disease and decreased fertility.

• Discovered four novel risk genes for migraine without aura.

• Identified five new loci in a large endometriosis meta-analysis.

• Reported five novel risk loci for migraine.

Neuroimaging GeneticsGroup Leader: Dr Margie Wright

The Neuroimaging Genetics Group focuses on elucidating the neurobiological and genetic causes of major mental illnesses through the integration of structural and functional neuroimaging, measures of cognition and health and well being, and behavioural and molecular genetic approaches. The primary goal of this research is the identification of the genes and pathways that influence the structure and function of the human brain, and provide a window into the biological mechanisms leading to mental illness.


• Depression

• Anxiety

• Dementia

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CURRENT RESEARCH

• Genetics of brain structure and function: The QTIM (Queensland Twin IMaging) study

• Neurodevelopment during adolescence: a longitudinal twin imaging study

• The Older Australian Twins Study (OATS) of healthy brain ageing and age-related neurocognitive disorders.

• Identifying genes for cognition.

• ENIGMA – Enhancing NeuroImaging Genetics through Meta-Analysis

RECENT HIGHLIGHTS:

• Showed for the first time developmental changes in structural connectivity and network efficiency.

• Provided evidence for a role of genetic factors in several key brain metrics.

• Identified associations between specific genes and measures of brain structure and connectivity.

• Conducted the first GWAS meta-analysis of childhood intelligence.

• Identified genetic variants associated with bipolar disorder.

• Identified seven loci affecting mean telomere length. The findings support a causal role of telomere-length variation in some age-related diseases.

• Carried out GWAS met-analysis to identify genetic variants associated with personality traits. Variation in personality is predictive of many outcomes in life, including mental health.

Quantitative GeneticsTeam Head: Dr Sarah Medland

The Quantitative Genetics Team has focused on elucidating the biological pathways influencing common psychiatric conditions including attention deficit hyperactivity disorder and substance use disorders.


• Attention disorders • Substance abuse

CURRENT RESEARCH

• Imaging and genetics

• Child and adolescent mental health issues

• Biometrics

RECENT HIGHLIGHTS:

• Published work on the genetics of educational attainment.

• Launched a new study on severe morning sickness.

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Statistical GeneticsTeam Head: Associate Professor Stuart MacGregor

The Statistical Genetics Team studies the role that genetic variation plays in determining risk of disease and its risk factors. The laboratory develops and applies statistical genetic methods to gene mapping studies across a wide range of traits and diseases.

One major focus is understanding genetic and epigenetic variation in various cancers including melanoma, ovarian cancer, and oesophageal cancer. Ultimately this work will lead to better understanding of why particular individuals are affected by cancer or why they respond poorly to cancer treatment.

Another major interest is ophthalmological genetics, with work ongoing to identify the specific genes involved in both eye disease and in underlying quantitative risk factors.


• Breast cancer

• Eye disease (myopia and glaucoma)

• Endometriosis

• Melanoma

• Oesophageal cancer

• Ovarian cancer

CURRENT RESEARCH

• Statistical and computational methods in genetics

• Gene mapping studies in melanoma

• Epigenetic studies in ovarian and breast cancer

• Response to chemotherapy in ovarian cancer

• Genetic factors underlying esophageal cancer and its risk factors

• Twin studies examining ophthalmogical traits

• Gene mapping studies on eye disease

RECENT HIGHLIGHTS:

• Identified a genetic variant in the obesity gene FTO that confers risk of melanoma.

• Identified 16 new genetic variants influencing corneal thickness, several of which confer high risk for the eye disease keratoconus.

• Identified 24 new genetic variants conferring risk of myopia.

• Found common genetic variants which predispose Barrett’s oesophagus.

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System NeuroscienceGroup Leader: Professor Michael Breakspear

Systems Neuroscience is an approach to brain sciences that seeks the fundamental principles of brain organisation, dynamics and function across a hierarchy of spatial and temporal scales. It is a rapidly growing field that differs considerably from the traditional reductionist paradigm in neuroscience that seeks purely sufficient causes for local phenomena. In contrast, systems neuroscience seeks unifying explanations for emergent phenomena.


• Schizophrenia

• Depression

• Bipolar disorder

• Dementia

• Epilepsy

CURRENT RESEARCH

• Quantitative assessment of affect in major depression

• Psychosis and errors in perception during natural vision.

• Cortical rhythms: The role of dynamics and noise

• Brain network mechanisms of resilience to acquired cognitive impairment

• Fundamental mechanisms of perception and motor control

RECENT HIGHLIGHTS:

• Detected a biomarker for risk of bipolar disorder.

• Developed a new diagnostic test for cerebral palsy.

• Created an imaging test for major depression.

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RESEARCH AND TECHNOLOGY PLATFORMSOur disease models and technologies are used globally

Oncology • Compound screening for anti-tumour activity against a panel of human cancer cell lines (cell growth and reporter gene assays)

• Mechanism of action of candidate anti-cancer drugs

• Mechanisms of gene regulation by agents, including use of microarray technology

• Monoclonal antibodies for research and diagnosis

• Xenograft models

• Models investigating human cancer susceptibility

• EBV models

Cell and tissue biology

• Confocal, electron, and laser dissection microscopy

• Signal transduction assays

• Histology and histopathology

• Cell sorting

• Fluorescence microscopy

Epidemiology • QIMR Berghofer has access to extensive resources to facilitate nationwide studies on important diseases. We combine classical epidemiological methodology with genetic analysis of blood and tissue samples.

Genomics • Mass array SNP typing facility

• Genome scans

• Zebra fish facility with many cutting edge methods for gene detection and analysis

• Gene expression profiling of cancer cell lines and tumours

• cDNA library construction

• Information database on 30,000 twins and relatives

• DNA database of 5000 twins

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Infectious disease

• Models for investigating the efficacy of vaccines or candidate drugs against infectious disease, including malaria, leishmania, Group A streptococcus, schistosomiasis and hook worms

• Viral protection assays

• Models for the effects of compounds on viruses including alphaviruses, poxvirus (vaccinia) and herpes virus (cytomegalovirus)

• Models for evaluating drug resistance

Immunology • Graft versus Host Disease transplantation models

• Models for evaluating anti-viral activity

• Effect of novel compounds, drugs, vaccines, immune-suppressants and immune-stimulators on cytotoxic T lymphocytes

• In vitro and in vivo assays of activation of macrophages, NK cells, T cells, B cells, Dendritic cells

• FACS analysis

• Multi-analyte system – multiplex for antibody and cytokine assays

Transgenic/knockout mice

• Generation of knockout and transgenic mice

• Mouse embryo freezing

• Production of gene knockouts in specific tissues in mice

• Live animal imaging – detection of reporter gene expression

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TISSUE BANKSQIMR Berghofer has developed cancer tissue banks for vital research

Tissue type BackgroundSamples available

References

Ovarian cancer (1)

Blood, tissue and urine samples and matching clinical data have been collected from more than 1500 women with ovarian cancer. Blood samples were also collected from 1000 cancer-free control women across Australia. Epidemiological data is available.

Blood, urine and tumour tissue

Australian Ovarian Cancer Study

Ovarian cancer (2)

Blood samples have been collected from 200 women with ovarian cancer, 250 with benign ovarian tumours

Blood and tumour tissue

Breast cancer A cohort study of multiple case breast cancer families from whom extensive genetic, clinical and epidemiological data is available as well as biological specimens. Collection is complete on more than 900 families.

Blood and tissue samples

Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer

Colon cancer This bank contains over 800 fresh frozen primary colorectal cancers. Collection started in 1992 and is ongoing. There are matched normal mucosa and blood samples. Most samples have had DNA extracted and paraffin fixed blocks and RNA is available from selected samples.

Tissue from primary tumours

Walter Paulsen Tumour Bank

Melanoma and skin cancer

Newly-diagnosed patients with melanoma have been identified from the Queensland Cancer Registry. Information is collected on age, ethnicity, medical history and family history of melanoma and skin cancer. A brief sun exposure history has been recorded, including details of residential ambient solar exposure, as well as occupational and recreational sun exposure for each decade of life.

Paraffin sections of tumour tissue

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Tissue type BackgroundSamples available

References

Oesophageal cancer

These samples are part of a national population-based study of oesophageal cancer. Blood and questionnaire data is available for 1000 patients and 1500 cancer-free controls. Paraffin tissue blocks are available for 800 patients.

Blood, tumour tissue and paraffin blocks of tumour tissue

Australian Cancer Study

Barrett’s oesophagus and reflux conditions

Blood samples are available from 380 patients with Barrett’s oesophagus, 250 with gastro-oesophageal reflux disease and 700 controls

Blood samples Study of Digestive Health

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YOUR PARTNER IN- Clinical trial quality support- Good manufacturing practice (GMP): Clean room hire;

GMP cell storage; Quality control testing

The QIMR Berghofer Medical Research Institute (QIMR Berghofer) has been at the forefront of medical research for the past 65 years.

Initially established to meet the needs of translational research within QIMR Berghofer, Q-Gen has since gone on to have a strong track record of clinical trials.

Q-Gen is licensed by the TGA (Licence No. MI-11112004- LI-000153-1) for the maintenance and storage of working cell banks, the storage on site of cellular products. This licence makes Q-Gen one of a very small number of organisations in Australia able to store human samples under GMP conditions.

The Q-Gen Facility Our GMP infrastructure, including our TGA licensed quality system, is designed to meet your clinical research or start-up needs.

• ~1000m2 of dedicated floor space

• Clean rooms to meet ISO Class 7 and PC2

• Up to 13 rooms available, from 20m2 - 35m2

• Dedicated air handling units

• Swipe card access control on all rooms

THE Q-GEN SERVICE

We can offer a range of services backed by our licensed quality system, risk based management framework and project management policies. A dedicated project manager is assigned to every project to oversee all critical aspects of your process.

• Research through to GMP storage of human and non-human cells and cellular products

• Storage temperature range of -190°C through to ambient

• Quality control testing – sterility, Mycoplasma, flow cytometry cell viability and identification

• Records management

• Stock control

• Documentation development

• Leading clinical research, project management and quality management advice

THE Q-GEN EQUIPMENT

Critical equipment is continuously connected to an independent back-up power generator, with 24 hour monitoring of the equipment parameters through our building management system. All equipment is on a scheduled maintenance and validation program to ensure high performance standards are always met.

• Biological safety cabinets

• Incubators

• Centrifuges

• Liquid and vapour phase liquid nitrogen vessels

• -80°C to -20°C freezers

• Stability fridges

• Access to a wide range of general and specialised research equipment

Please direct enquires to: Darron Laing Q-Gen Facility Manager T +61 7 3845 3851 E [email protected] 300 Herston Road, Herston, Qld 4006

300 Herston Road

Herston QLD 4006 Australia

Locked Bag 2000

RBH QLD 4029 Australia

T +61 7 3362 0222

1800 993 000

F +61 7 3362 0102

E [email protected]

Better health through medical research | www.qimrberghofer.edu.au

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TNERING WITH QIMR BERGHOFER An industry …...give rise to cancer and those that occur during the formation of a tumour and its subsequent metastasis; and developing and testing novel