prince henry’s institute 2008/09 scientific report phi scientific report 2008/09 | 1 CONTENTS About Us 3 Research Overview 4 Research Highlights 2008/09 6 PHI in the Community 8 Monash Health Translation Precinct 9 Chairman’s Report 10 Director’s Report 11 Institute Governance 12 Research Report - Bone, Joint & Cancer 16 Research Report - Brain and Gender 17 Research Report - Cancer Drug Discovery 18 Research Report - Cardiovascular Endocrinology 19 Research Report - Clinical Andrology 20 Research Report - Embryo Implantation 21 Research Report - Endometrial Remodelling 22 Research Report - Growth Factor Signalling 23 Research Report - Implantation and Placental Development 24 Research Report - Male Fertility Regulation 25 Research Report - Metabolism and Cancer 26 Research Report - Ovarian Biology 27 Research Report - Ovarian Cancer Biomarkers 28 Research Report - Reproductive Development & Cancer 29 Research Report - Reproductive Hormones 30 Research Report - Sex Determination and Gonadal Development 31 Research Report - Steroid Receptor Biology 32 Commercialisation, Scientific Services and Clinical Facilities 33 Awards & Prizes, Service to the Scientific Community 35 Staff List 37 Students 39 Honorary Appointments 42 Committees 43 Publications 46 Invited Presentations 52 Visiting Speakers 54 Grant Funding 56 Community Support 57 Support Us 58 2 | phi scientific report 2008/09 ABOUT US Prince Henry’s Institute is a not-for-profit medical research institute located at Monash Medical Centre Clayton in Victoria, Australia. PHI has over 160 staff and students and our vision is to improve quality of life through the investigation of hormones in the fields of reproductive health, cancer, obesity, bone health and cardiovascular disease. Since its inception in 1960 as the Medical Research Centre at the former Prince Henry’s Hospital, we have made significant contributions to health and medicine. The past five decades have seen major discoveries, impacting the lives of tens of millions of people across the globe. Some highlights include: • New technologies developed by PHI researchers to detect common hormone deficiencies. • We were part of a team of researchers that, after several decades of intensive research, discovered the reproductive hormone inhibin. This hormone was later used by PHI researchers to produce the first blood test for ovarian cancer. • PHI research played a key part in the development of a brand new class of drugs to treat breast cancer - aromatase inhibitors. • PHI studies have proven how the aromatase gene plays an essential role in breast cancer development, sperm formation and the metabolism of body fat. • PHI jointly developed and commercialised a biochemical test for the detection of endometrial cancer. • PHI studies have led to a new hormonal method of contraception for men which has shown this can be an effective approach. We are now leading the Australian arm of a major international late-stage clinical trial of male contraception. Prince Henry’s Institute is: - a partner of the Monash Health Translation Precinct (MHTP) - an affiliated institute of Southern Health - an affiliated institute of Monash University - a member of the Cancer Council Victoria - a member of the Victorian Breast Cancer Research Consortium Inc. - an alliance partner with the Ovarian Cancer Research Foundation - an accredited institute of the National Health and Medical Research Council - supported by the Victorian Government’s Operational Infrastructure Support Program phi scientific report 2008/09 | 3 reseArcH overvIeW PHI specialises in medical research that improves the detection, diagnosis and treatment of serious health conditions that are controlled by hormones. Hormones are made by almost If ovarian cancer is detected and critical need to increase contraceptive every organ of the body and play a treated early survival rates increase options for women. significant role in a person’s health and from less than 30% to 90%. For many women, existing wellbeing. Our primary research areas We are committed to reducing the contraceptives are not acceptable or are: Cancer, Cardiovascular disease, number of women dying from ovarian not available. We are investigating new Reproductive Health and Positive start cancer by conducting research to find ways to prevent pregnancy as well as to life and healthy ageing an early detection test for the disease. block sexually transmitted diseases, including HIV. Endometrial cancer (cancer of the Cancer uterus) We are also studying male hormone contraception, how it affects sperm Breast cancer Endometrial cancer is the most production and action and whether common gynaecological cancer. We there are new opportunities to translate Breast cancer is one of the leading have identified factors that may affect discoveries into effective contraception causes of cancer related death in the progression of this disease and are methods. Australian women, with one in 12 determining the success of blocking women diagnosed with breast cancer these factors as a form of treatment. Pre-eclampsia before 75. We are also working on an early Pre-eclampsia is a life threatening diagnostic test for those at high risk of We have uncovered how certain condition experienced during developing endometrial cancer. factors drive breast cancer growth, pregnancy, which often causes which is paving the way towards new multi-organ failure in the mother and targeted breast cancer treatments that can result in death for both mother block cancer growth with fewer side- Reproductive health and baby. Onset of pre-eclampsia is effects than current approaches. sudden and as there is no cure the only Fertility treatment is pre-term delivery. PHI researchers are also working to Approximately 15% of Australian identify why cancers such as breast Pre-eclampsia is associated with couples of reproductive age have cancer spread to bone and determine intrauterine growth retardation and problems with fertility. PHI researchers ways to limit this growth. babies of low birth weight, which are working to understand the role of can increase the chance of long- Ovarian cancer hormones in fertility and the changes term health problems such as heart with age. While ovarian cancer isn’t the most disease, hypertension and diabetes in common cancer, it is one of the most We are also working to understand adulthood. frightening – because most women factors regulating sperm production We are endeavouring to develop a who are diagnosed with ovarian cancer and why this fails, causing infertility test to predict high risk pregnancies survive less than five years. and conversely how it can be used for pre-eclampsia, allowing for better for contraception when reversed and Unlike cancers such as breast management of the condition and suppressed. cancer, there are no self-examination reducing life threatening risks to mother techniques or discernible symptoms Contraception and baby. of ovarian cancer and there is no Between 1995 and 2000 more conclusive way to make a diagnosis than 700,000 women, most in without surgery. Sadly the result is the developing world, died due to a very high proportion of late stage causes associated with unintended diagnoses, meaning the cancer is well pregnancies. As a result the World advanced and has often spread to Health Organization has identified a other parts of the body. 4 | phi scientific report 2008/09 Cardiovascular disease Our aim is to identify the genes that cause disorders of sex development Cardiovascular disease (heart, stroke and the mechanisms underlying the and blood vessel disease) is the formation of testes and ovaries in an leading cause of death in Australia, embryo. killing one Australian every ten minutes. In 2006, 46,000 people died as a result Neurological Disorders of cardiovascular disease, representing Chromosomal differences between a staggering 34% of all deaths. men (XY) and women (XX), is a Around 3.67 million Australians are key area of investigation for PHI affected by cardiovascular diseases researchers who are especially with 1.10 million Australians disabled interested in the SRY or ‘male only’ long-term as a result. Sadly, over the gene. past decade, the prevalence of heart, We are unravelling the genetic factors stroke and vascular conditions in that underlie gender differences Australia has increased by 18.2%*. in susceptibility to neurological We are looking at the effects of disorders such as Parkinson’s disease, hormones on the cardiovascular schizophrenia and drug addiction. system in order to develop drugs that Bone health are better targeted to prevent cardiac failure and treating cardiac problems Osteoporosis and other conditions such as hypertension. that affect the skeleton, such as orthopaedic implant failure and cancer- * Statistics sourced from Heart Foundation induced and inflammatory bone loss, are an enormous health cost burden to Australia. Positive start to life and healthy ageing Whilst there are several therapies available to stop the breakdown of Disorders of Sex Development bone, the same is not true for therapies that build new bone. One percent of babies are born with a disorder that affects their sex We are working on new approaches development, meaning their testes or to treatments that build bone and ovaries have not developed correctly, investigating possible treatments for their genitalia may not be distinctly osteoporosis. male or female, the development of their sex anatomy may be incomplete or they may have chromosome abnormalities. . phi scientific report 2008/09 | 5 RESEARCH HIGHLIGHTS 2008/09 2008 2009 Older men testosterone boost Breast cancer, hormones and Sticky proteins required for A clinical study led by researchers at obesity link pregnancy Prince Henry’s Institute provided strong A new molecular link was discovered Research, which may explain why evidence that a testosterone boost that helps account for the increased some women have fertility problems, could have the benefits for some older incidence of breast cancer in obese revealed how two proteins are needed men. older women. for the embryo to successfully attach to the inside of the uterus. Allan CA, Strauss BJ, Burger HG, Forbes EA Brown KA, McInnes KJ, Hunger NI, Oakhill JS, & McLachlan RI. (2008). Testosterone therapy Steinberg GR & Simpson ER. (2009). Subcellular Marwood M, Visser K, Salamonsen LA & prevents gain in visceral adipose tissue and loss of localization of cyclic AMP-responsive element Dimitriadis E. (2009). Interleukin-11 and leukemia skeletal muscle in nonobese aging men. Journal binding protein-regulated transcription coactivator inhibitory factor regulate the adhesion of of Clinical and Endocrinology and Metabolism 93, 2 provides a link between obesity and breast endometrial epithelial cells: implications in fertility 139-146. cancer in postmenopausal women. Cancer regulation. Endocrinology 150, 2915-2923. Research 69, 5392-5399. 3D view of sperm development Sex reversal gene Study links enzyme to family breast pathway A gene has been identified that is cancer PHI research has provided a 3D important for male sex determination A study showed that some women, view of how genes and hormones and the finding may help explain known to be at high family risk of interact in diverse ways during sperm unexplained cases of Disorders of Sex breast cancer, have higher levels production. This understanding may Development. than other women of a key enzyme, also lead to novel approaches to male Bagheri-Fam S, Sim H, Bernard P, Jayakody aromotase, in their breast tissues. contraception. I, Taketo MM, Scherer G & Harley VR. (2008). Chand AL, Simpson ER & Clyne CD. (2009). Loss of Fgfr2 leads to partial XY sex reversal. o’Donnell L, Pratis K, Wagenfeld A, Gottwald U, Aromatase expression is increased in BRCA1 Developmental Biology 314, 71-83 Muller J, Leder G, McLachlan RI & Stanton PG. mutation carriers. BMC Cancer 9, 148. (2009). Transcriptional profiling of the hormone- responsive stages of spermatogenesis reveals Hormone changes in menopausal cell-, stage-, and hormone-specific events. Gene link gender identity transition Endocrinology 150, 5074-5084. The largest ever genetic study of A series of studies have shown how male to female transsexuals found hormones produced by the ovary are a significant genetic link between involved with the decline in eggs during Bone loss mechanisms gender identity and a gene involved in late reproductive life. A study found that an experimental testosterone action. drug with potential as a diabetes Robertson DM, Hale GE, Fraser IS, Hughes CL Hare L, Bernard P, Sanchez FJ, Baird PN, Vilain treatment causes rapid loss of bone. & Burger HG. (2008). A proposed classification E, Kennedy T & Harley VR. (2009). Androgen system for menstrual cycles in the menopause Quinn JM, Tam S, Sims NA, Saleh H, McGregor receptor repeat length polymorphism associated transition based on changes in serum hormone NE, Poulton IJ, et al. Germline deletion of with male-to-female transsexualism. Biological profiles. Menopause 15, 1139-1144 AMP-activated protein kinase {beta} subunits Psychiatry 65, 93-96. reduces bone mass without altering osteoclast differentiation or function. FASEB J. 2009 Sep 2. Development of the ovary Endometrial repair and activin A study has shown that transforming In a study that may lead to new growth factor-beta inhibits follicle treatments of abnormal uterine development by increasing the rate of bleeding problems it was shown that follicle death. endometrial repair is controlled by the Rosairo D, Kuyznierewicz I, Findlay J & Drummond action of activin. A. (2008). Transforming growth factor-beta: its role in ovarian follicle development. Reproduction 136, Kaitu’u-Lino TJ, Phillips DJ, Morison NB & Salamonsen LA. (2009). A new role for activin in 799-809. endometrial repair after menses. Endocrinology 150, 1904-1911. 6 | phi scientific report 2008/09 Proteomics and establishing Immune cells and hypertension pregnancy This research has demonstrated Proteomics technology has been an important, unexpected role for used to identify novel proteins key to the mineralocorticoid receptor in establishing pregnancy. The study macrophage function and of the showed how the enzyme PC6 is macrophage in determining the regulated in the uterus. inflammation in cardiac fibrosis and high blood pressure. Kilpatrick LM, Stephens AN, Hardman BM, Salamonsen LA, Li Y, Stanton PG, et al. rickard AJ, Morgan J, Tesch G, Funder JW, Proteomic identification of caldesmon as a Fuller PJ & Young MJ. (2009). Deletion of physiological substrate of proprotein convertase mineralocorticoid receptors from macrophages 6 in human uterine decidual cells essential for protects against deoxycorticosterone/salt-induced pregnancy establishment. J Proteome Res. 2009 cardiac fibrosis and increased blood pressure. Nov;8(11):4983-92. Hypertension 54, 537-543. Identification of a protein which inhibits the spread of cancer A study showed how the molecule betaglycan may affect cell behaviours including the ability of ovarian cancer cells to metastasise. Bilandzic M, Chu S, Farnworth P, Harrison CA, Nicholls P, Wang Y, escalona rM, Fuller PJ, Findlay JK, Stenvers KL. 2009. Loss of betaglycan contributes to the malignant properties of human granulosa tumor cells. Mol Endocrinol. 23(4): 539- 548. Ageing and female hormones A detailed study has helped unpick the complex relationships between several female hormones involved in the menstrual cycle and how these alter in later life. Robertson DM, Hale GE, Jolley D, Fraser IS, Hughes CL & Burger HG. (2009). Interrelationships between ovarian and pituitary hormones in ovulatory menstrual cycles across reproductive age. Journal of Clinical Endocrinology & Metabolism 94, 138-144. phi scientific report 2008/09 | 7 PHI IN THE COMMUNITY Medical research should never simply begin and end in the laboratory. Central to research are the benefits it provides to the broader community. PHI embraces the multiple opportunities to engage with the wider community, to share how our discoveries are bringing science to life. The support and generosity of the community also further enhances our capacity to undertake research and for that we are very thankful. Raising awareness and public PHI on the Internet through the CSIRO’s Scientists in support for ovarian cancer Schools scheme. They have developed In 2009 the Institute developed and ongoing partnerships with teachers In partnership with the Ovarian Cancer launched a brand new “community and these special relationships Research Foundation, our researchers friendly” web site. New social broaden school students’ experiences have provided scientific expertise at media initiatives such as Twitter and in their science studies. dozens of major community, education, Facebook also broadened the online fundraising campaigns such as opportunities to promote the Institute’s Other researchers have gone on the the NAB Silver Ribbon Appeal and latest discoveries. road with the Australian Society for other social events such as L’Oréal Medical Research (ASMR) to visit Melbourne International Fashion Week. schools through country Victoria. The Community support of clinical ASMR is the peak body for Australian research Media engagement medical researchers and in 2009 PHI researcher Dr Sarah Meachem was Hundreds of non-scientists play an PHI research discoveries are promoted ASMR President. Sarah led dozens essential role in the Institute’s research through local, state, national and of further related events and activities by supporting our research in a very international media. which raised community awareness special fashion. These are research of Victorian medical research and Major coverage in 2009 included our participants in clinical studies and trials innovation. research trial of male contraception, who are generous enough to give us endometriosis research and the some of their time. discovery of a molecular link between Hundreds of Victorian women have breast cancer and obesity, which was actively supported our sample featured nationally on ABC TV news. collection for ovarian cancer research. Also, during 2009, participant Reliable health information for recruitment commenced for the Victorians Melbourne arm of a major international study of a new male contraceptive Institute researchers provide scientific method. The male contraception study expertise and editorial content for is supported by the World Health multiple community health factsheets Organization. which are available through the Victorian Government’s website Better Health Channel. Researchers in the community Many PHI researchers are active in school education initiatives which promote careers in medical research and innovation. Some researchers have been matched with local schools 8 | phi scientific report 2008/09 MONASH HEALTH TRANSLATION PRECINCT The Institute is proud to be associated with Southern Health, Monash University and Monash Institute of Medical Research in the Monash Health Translation Precinct (MHTP). The Precinct has been awarded $71M by the Commonwealth Government towards the development of a new translation research facility. MHTP vision • To optimise productive interactions MHTP research themes are specifically between MHTP partners and external aligned to national health priorities: Monash Health Translation Precinct stakeholders (MHTP) will be a world leader in • cancer delivering the best healthcare by • To increase efficiency in the utilisation • cardiovascular translating innovative scientific of shared resources and cutting edge discoveries into best clinical practice platform technologies • endocrinology and metabolism in a dynamic and collaborative environment. • Inflammatory and infectious diseases MHTP key facts • Men’s health MHTP purpose We are: • Mental health and neurosciences Monash Health Translation Precinct • Prince Henry’s Institute – world is dedicated to translating medical • Paediatrics leaders in the field of endocrinology, research to improve healthcare; uses the study of hormones • Women’s health clinical insights to focus the agenda of basic research; is committed to • southern Health – victoria’s largest For further information about Monash innovative research development and public health service providing uniquely Health Translation Precinct visit enhances research collaboration. integrated care across the entire www.mhtp.org.au lifespan MHTP aims • Monash Institute of Medical Research – leaders in stem cell, • To develop the Precinct’s capacity for infection, immunity and cancer world-leading innovative translational research research • Monash University – Australia’s • To identify new opportunities for the largest university with an international translation of research into advances in reputation for innovative health healthcare research • To improve the health and wellbeing The Precinct is located in Melbourne’s of the population South Eastern corridor within the grounds of Southern Health’s 640 bed • To encourage collaboration and tertiary teaching and research hospital, partnerships between clinicians and Monash Medical Centre, and in close researchers proximity to some of Australia’s leading research organisations and companies, including the Australian Synchrotron, Monash on-campus Centres, CSIRO and emerging biotechnology entities. phi scientific report 2008/09 | 9 CHAIRMAN’S REPORT The Institute’s report this year is the first under its new structure. In 2009 PHI became a corporate entity limited by guarantee, having previously operated under the Prince Henry’s Institute of Medical Research Act. This change, recommended by the The coming year marks the 50th Victorian Government and endorsed by anniversary of Prince Henry’s Institute Parliament in 2008, allows the Institute and it is with great pride we look back to operate under a structure that better over achievements of the past five supports the Institute’s operations decades and see the contributions PHI and governance as a modern medical has made to the world of medicine. research institute. Highlighted throughout this report Changes to the Board have also are some recent scientific discoveries occurred and I would like to made by our researchers such acknowledge the contribution of former as discovering a molecular link Board members Mr Richard Amos, Mrs that contributes to the increased Margaret Lothian, Ms Carmel Mortell, incidence of breast cancer in obese Mr Trevor Montgomery, Professor older women; demonstration of Nicos Nicola, Mr John Robinson and the importance of immune cells in Mr Bob Stensholt. hypertension; identifying a protein which inhibits the spread of cancer I would particularly like to thank and finding that an experimental drug Trevor Montgomery for his more than with potential as a diabetes treatment 15 years of service during which he results in rapid bone loss. made significant and long lasting contributions. Mr John Robinson, It is discoveries such as these and should also be recognised for his their wide-reaching impact that are leadership as the past Chairman of at the heart of PHI and why the work the Board taking the Institute safely conducted here is so important. The through its transition to a corporate new members of the Board are greatly entity. impressed by the calibre of the PHI research team and the importance of The Institute has been fortunate to the work conducted at the Institute. secure new Board members - Ms I hope readers of this report will gain Jennifer Joiner, Professor Steve insight into these discoveries as well Wesselingh and Mr John Weste, who the ones we are hoping to make in the all bring with them a range of skills and future. expertise that will guide PHI through the coming years. The job of a Board is always easier Bob Edgar when it has confidence in the Chairman organisation’s operational leadership. Institute Director Professor Matthew Gillespie has now been with the Institute for two years and on behalf of the Board I would like to acknowledge his leadership and direction. 10 | phi scientific report 2008/09