Contents

Peter MacCallum Centre CEO’s report 5 1.5 Tumour Angiogenesis program 58 3.2.2 Centre for Cancer Imaging 110 St Andrews Place East 3002 Director’s report 7 1.6 Cancer Therapeutics program 62 3.2.3 Centre for Biostatistics and Clinical Trials 111 Clinical research overview 11 1.6.1 Gene Regulation laboratory 64 Locked Bag 1 A’Beckett Street 3.2.4 Clinical Trials Unit 112 Victoria 8006 About research at Peter Mac 12 1.6.2 Research laboratory 65 3.2.5 Clinical Psychology 113 Telephone (03) 9656 1238 at a glance 14 1.6.3 Molecular Imaging and Targeted Therapeutics laboratory 66 3.2.6 Familial Cancer Care 114 Facsimile (03) 9656 1411 Metrics 15 1.6.4 Translational Research 3.2.7 Infectious Diseases 115 www.petermac.org/Research Research / Cancer Matrix 16 Laboratory 67 3.2.8 kConFab Follow-Up Project 116 For additional copies of this publication Interdisciplinary Matrix 18 1.6.5 Pfizer/Peter Mac Cancer Genomics 3.2.9 Molecular Pathology laboratory 117 or to provide feedback please contact: Recent research highlights with program 68 Peter Mac Communications and Brand impact on cancer care 19 1.6.6 CCV Venture Grant Initiative 69 3.2.10 Nursing and Supportive Care 118 via [email protected] 1.6.7 CRC for Cancer Therapeutics 3.2.11 Nutrition 119 1 Laboratory Research 20 Front cover: Dr Mark Shackleton, Translational Research laboratory 70 3.2.12 onTrac@Peter Mac 120 Pfizer Australia Research Fellow, 1.1 Cancer Immunology program 24 Head, Melanoma Research laboratory 3.2.13 Pain and 121 1.1.1 Death laboratory 26 2 Clinical and Translational and medical oncologist, Melanoma Service. Research 72 3.2.14 Pharmacy 122 Below left: Dr Jamie Lopez, 1.1.2 Cellular Immunity laboratory 27 Cancer Medicine 76 3.2.15 Physical Sciences 123 Cancer Immunology program. 1.1.3 Immune Signalling laboratory 28 Below right: Dr Claire Milton, Cancer Surgery 78 3.2.16 124 1.1.4 Immunotherapy laboratory 29 Cancer Cell Biology program. Radiation and Cancer 3.2.17 Social Work 125 1.1.5 Haematology Immunology Imaging 80 Translational Research laboratory 30 2.1 Medical Oncology and Early Phase 4 Education and Learning 130 1.2 Cancer Genomics program 32 Clinical Trials 82 4.1 Cancer Research Education 1.2.1 Cancer Genetics and 2.2 Breast Service 83 program 133 Genomics laboratory 34 2.3 Gastrointestinal Service 84 4.1.1 Seminar programs 133 1.2.2 Genomics and Genetics laboratory 35 2.4 Gynae-oncology Service 85 4.1.2 Student Training Program 136 1.2.3 Surgical Oncology laboratory 36 2.5 Haematology Service 86 4.1.3 Peter Mac Research Postgraduate Student Society 139 1.2.4 VBCRC Cancer Genetics 2.6 Head and Neck Service 87 4.1.4 Research Awards 140 laboratory 37 2.7 Lung Service 88 4.1.5 Peter Mac Postdoctoral program 142 1.2.5 kConFab 38 2.8 Melanoma and Skin Service 89 4.1.6 Community and School 1.3 Growth Control and 2.9 Paediatrics and Late Effects Service 90 Differentiation program 40 Outreach Activities 143 2.10 Sarcoma Service 91 1.3.1 Growth Control laboratory 42 4.2 Clinical Research Education and 2.11 Uro-oncology Service 92 Training Programs 144 1.3.2 Molecular Oncology laboratory 43

1.3.3 Protein Chemistry laboratory 44 3 Enabling Technologies and 5 Leadership and Governance 146 1.4 Cancer Cell Biology program 46 Interdisciplinary Research 5.1 Research leadership 149 Platforms 96 1.4.1 Cell Cycle and Cancer Genetics 5.2 Cancer Research management 151 laboratory 48 3.1 Enabling Technology Platforms 97 5.3 Governance 152 1.4.2 Cell Cycle Development 3.1.1 Functional Genomics facility 99 5.4 Ethical Conduct of Research 154 laboratory 49 3.1.2 Molecular Genomics facility 100 5.5 Commercialisation 157 1.4.3 Cell Growth and Proliferation 3.1.3 Bioinformatics facility 101 laboratory 50 3.1.4 Flow Cytometry facility 102 1.4.4 Differentiation and Transcription 6 Publications 158 laboratory 51 3.1.5 Microscopy facility 103 1.4.5 Epithelial Stem Cell Biology 3.1.6 Media and Laboratory Services laboratory 52 facility 104 1.4.6 Research laboratory 53 3.1.7 Tissue Bank facility 105 1.4.7 Molecular Radiation Biology 3.2 Interdisciplinary Research laboratory 54 Platforms 107 1.4.8 Tumour Suppression laboratory 55 3.2.1 Centre for Blood Cell Therapies 109 As the largest cancer research site in Australia, CEO’s report Peter MacCallum Cancer Centre is a major contributor to advances in cancer diagnosis and treatment. 2010 was a busy and challenging The co-location of a sophisticated research year for research at Peter Mac. facility and a world-class cancer hospital We continued to win competitive creates a highly synergistic combination. grants; our staff distinguished With researchers and clinicians working themselves in many ways; side-by-side, Peter Mac has made significant we streamlined our research contributions to basic research, translational governance framework and we research and clinical trials. worked hard to strengthen our partnerships with other research organisations and to reach out to the community.

In addition, a lot of passion, energy Our research staff also contributed Highlights during the year included and time were devoted to articulating a strongly to the strategic discussions the opening of the Victorian Centre vision for the research facilities to be sponsored by the Victorian CCC Joint for Functional Genomics in Cancer incorporated into the Comprehensive Venture; a group comprising the four (supported by a $2.5m grant from the Cancer Centre to be built in Parkville. Parkville building partners (as above), Australian Cancer Research Foundation) plus the Walter and Eliza Hall Institute and the establishment of both the As a major focus in 2010, our research of Medical Research, The Royal Women’s Melanoma Research laboratory, as part staff continued collaborating with Hospital and The Royal Children’s of the Cancer Therapeutics program, colleagues from Melbourne Health, Hospital. This group is charged with and the Tumour Angiogenesis program. the Ludwig Institute for Cancer Research enhancing collaboration amongst the Considerable energy was also devoted (Parkville Branch) and The University seven independent members to produce to further strengthening our focus of Melbourne in advising on the research better outcomes for cancer patients on translational research. facilities that will form part of the Victorian treated at the new facility ... and beyond. Comprehensive Cancer Centre (VCCC). A number of Peter Mac researchers We finished the year with the three Professor Joe Trapani took up his and clinician-researchers were bidding consortia having submitted their appointment as Executive Director honoured, or published significant formal responses to the Request for Cancer Research at the beginning of articles, in 2010 — in particular, Tender that had been issued mid-year. January 2010, succeeding Professor Professors Mark Smyth, Joe Sambrook Our research staff worked closely with David Bowtell, who returned to full-time and Joe Trapani; Associate Professors the Department of Health’s Project Team research having completed his second Grant McArthur, Danny Rischin and and with the three consortia in working five year term in December 2009. Scott Williams and Dr Mark Shackleton, through many and varied design options. Professor Trapani was well supported amongst others. Dr Hollie Pegram Whilst very time consuming, this was during a year of strategic, funding, was awarded the 2010 Peter Mac also a very stimulating and rewarding space and other operational challenges Postgraduate Research Medal. process — in which our research staff by Assistant Directors: Associate have a clear interest. Professors Ricky Johnstone and Grant McArthur; Chief Operating Officer: Mary At the time of writing, we await a Harney and the Group Leaders. I am decision on the procurement method. very grateful for all their support, advice Craig Bennett Building work is due to be completed and guidance. Chief Executive Officer in late 2015.

CEO’s report 5 Introducing our new Director Director’s report

‘The next decade holds the promise of many more targeted therapies and the hope that ultimately, cancer therapy will be individualised according to the molecular profile of that patient’s own disease. This will mean people living longer and fuller lives with cancer, a greater hope of total cure and an overall reduction in the impact of many on patients and their carers.’ Professor Joseph A. Trapani MBBS, FRACP, FFSc(RCPA), PhD Professor Joseph A. Trapani Executive Director, Cancer Research

New Director, new directions Among Joe’s research interests are Joe has received many personal In January 2010, I was greatly Immunology and the founding of A recurrent theme in this report is Following an extensive international the cellular and molecular biology awards and prizes including the 2008 honoured to commence a five year Platform Technologies to rival the that the recent massive technological search, Professor Joe Trapani was of cancer cell death induced by the National Health and Medical Research term as the third Executive Director best in the country. Remarkably, an achievements in molecular medicine appointed the Executive Director Cancer immune system, the immunopathology Council Award for Research Excellence of Research at Peter Mac. independent assessment of the impact and genomics find us at the dawn of viral and auto-immune diseases and the 2009 GSK Research Excellence of cancer research publications between of personalised diagnosis and Research at Peter Mac in January 2010, When offered the appointment, and adoptive immunotherapy of cancer. Award, which he shared with long-term 1981 and 2006 (ISI) saw Peter Mac treatment for many cancers. succeeding Professor David Bowtell, my excitement and enthusiasm were Joe first became interested in how the collaborator Mark Smyth. Joe was an ranked third nationally, only narrowly Director for the previous ten years. tempered by the high responsibility There is genuine optimism that within immune system defends us against NHMRC Senior Principal Research behind The Garvan Institute but still Already established as a familiar face that goes with inheriting such a vibrant the foreseeable future, many cancers viruses and while working Fellow from 2003 until 2009, and has some distance behind The Walter and in the wider Melbourne Research and high-achieving division: more than will be managed as chronic diseases, as a post-doctoral fellow at the Sloan- been Chief Investigator on a highly Eliza Hall Institute. This achievement community, Joe began his role as 430 laboratory, translational and clinical rather than fatal conditions. Peter Mac’s Kettering Cancer Institute, New York successful NHMRC Program Grant that was all the more impressive when one Director of Research in his eleventh year researchers collectively ranked amongst unique structure, with a thriving cancer in the late 1980’s. Here, Joe discovered was first awarded in 2003 and only remembers that Peter Mac’s research at Peter Mac. He had previously been the very strongest cancer research laboratory complex embedded within and characterised a number of the recently renewed until 2016. Joe also productivity had only blossomed over Deputy Director Research and co-head institutions in Australia. an iconic specialist cancer hospital, genes and proteins used by killer holds honorary Professorial the final decade of the 25 year of the Cancer Immunology program at presents a generational opportunity lymphocytes to eliminate virus-infected appointments at both UoM and Monash The renaissance of research assessment period. Peter Mac (with Professor Mark Smyth) to propel Peter Mac and the VCCC and cancerous cells. He found that University. Joe’s research interests achievement at Peter Mac clearly since 2000, and Chief Operating Officer The next five years hold the more broadly to a position of one protein (perforin) forms pores in the remain the immunopathology of viral dates to Peter Mac’s move to its East Research Division from 2003 – 2008. promise of further achievement, international leadership. target cell and provides access for other diseases, apoptosis induction by Melbourne campus in 1994, with the Joe is the first Research Director to but on a landscape vastly different proteins (granzymes) to enter and trigger cytotoxic lymphocytes and cancer appointment of Professor Joe Sambrook also be a clinician, having received his to that of recent years, and in the cell death through apoptosis. Joe immunotherapy. He has authored more as the inaugural Director of Research. medical degree at the University face of unprecedented opportunities returned to Melbourne in 1989 with than 230 research papers, reviews and A number of key recruitments, coupled of Melbourne in 1977. He was Registrar and challenges. the support of a Wellcome Trust Senior book chapters on these topics, including with strong philanthropic support and in the Professorial Medical Unit at Research Fellowship and spent the next papers in Nature, Science, Immunity and Joe’s outstanding vision led to significant In 2015/16, the whole of Peter Mac will The Royal Melbourne Hospital in 1981, decade building his research group Nature Medicine. Joe Trapani is also a growth in peer-review grant and move into its new, expanded, purpose- and from 1982 to 1985 completed at The Austin Research Institute, member of the Executive (Board) of the fellowship funding, and the rebirth of built home in Parkville, as part of the his PhD in the Department of Pathology before moving to Peter Mac. With his Cancer Council Victoria and contributes Peter Mac as a significant player on VCCC initiative. The course we set now, at The (UoM) colleagues, Joe also devised novel to many peer-review bodies in academia the Australian cancer research scene. and our capacity to adapt to change will and The Royal Melbourne Hospital. Joe ultimately determine whether Peter Mac ways of harnessing the power of killer and industry. Joe and his wife Dr Vivien Under Professor David Bowtell’s completed his physician training can ascend to the pinnacle lymphocytes and adapting their use Sutton, also a Peter Mac researcher, superb leadership from 2000 – 2009, (FRACP) in Rheumatology in 1985. of laboratory, translational and clinical to vaccines for killing cancer cells. have two teenage children, Sarah the Research Division underwent research achievement in cancer on Joe’s team in the Cancer Cell Death and Nick. a decade of sustained growth, with an international basis, for the benefit laboratory has further identified a rare the establishment of several new and of cancer patients and their carers. group of children with inherited defects sophisticated research programs of perforin function and shown that they such as Cancer Genomics and are abnormally susceptible to leukaemia.

Peter MacCallum Cancer Centre – Research Report 2010 Director’s report 7 Director’s report (cont.)

As the new Director, I face two MAJOR ACHIEVEMENTS IN 2010 form the basis of new therapies with the appointment of Associate was confirmed as interim Director Town Hall, moderated by media major strategic challenges: to Australia Fellowship awarded for melanoma patients. Professors Grant McArthur and Ricky of the OCR during the year. personality Dr Sally Cockburn. Professor maintain and where possible Johnstone as joint Program Heads, David Bowtell and Dr Gillian Mitchell to Professor Mark Smyth Later in 2010, Dr Shackleton was A number of senior Peter Mac clinician augment the momentum of research and the opening of the Melanoma (pictured below) gave fascinating In January 2010, Federal Parliamentary once again honoured with the award researchers were appointed as honorary achievements of the past 15 years, Research laboratory. This brought the and accessible presentations that Secretary for Health, Mark Butler of the Pfizer Senior Research Fellowship, Group Leaders within the Research and to place the Division of number of formal research programs outlined cancer as a ‘disease of the announced that Professor Mark Smyth a five-year $1m award that provides Division during 2010. These included Research laboratory achievements at Peter Mac to six, the others being genes’, and identified genetics as (below) had been awarded a $4m salary and research funding support. Professor Stephen Fox, Director of ever-more into the clinical context, to Cancer Immunology, Cancer Cell the key to future rapid diagnosis Australia Fellowship from the NHMRC. Pathology, Professor Rod Hicks, Director maximise translational opportunities Recruitment of Associate Professors Biology, Cancer Genetics and Predictive and personalised cancer care. The This ‘super’ award provides personal Cancer Imaging, Associate Professor and outcomes for patients. Steven Stacker and Marc Achen and Medicine and Cancer Cell Growth winners of an essay competition for Fellowship support as well as funding Penny Schofield, Senior Research establishment of the new Tumour and Proliferation. The close integration Victorian secondary school students The challenge will be to achieve these for Mark’s research program over Fellow Supportive Care Nursing Angiogenesis program of these programs and the research were presented with cash prizes and aims with minimal space available for the next five years. This extremely Research and Dr Gillian Mitchell, In July 2010, around 20 staff and of their clinical colleagues aims to certificates. further expansion at East Melbourne, prestigious award recognises biomedical Director Familial Cancer Centre. postgraduate students relocated from maximise the translation of research and in the face of significant and researchers of the very highest calibre At the Peter Mac annual general The Ludwig Institute for Cancer Research, into clinical trials, and ultimately Strengthening undergraduate diverse financial risks. Most importantly, in terms of the originality and impact meeting in November, Dr Hollie Pegram, (Parkville Branch) to establish Peter changed practice in cancer care. and postgraduate teaching Government funding agencies must of their research. In Mark’s case, the who performed outstanding PhD studies Mac’s new Tumour Angiogenesis Peter Mac Research Division has find a way to fund the indirect costs Australia Fellowship recognised his Building closer ties with Peter Mac with Associate Professor Mike Kershaw program (p 58), under the leadership of historically enjoyed a strong relationship of research incurred when hospital- superb and sustained work linking the clinicians and clinical researchers and Dr Phil Darcy (Immunotherapy Associate Professors Achen and Stacker with the Department of Pathology at employed researchers win peer-review function of the immune system with An area of particular focus for me has laboratory, pg 29) was presented with (pictured below). Marc and Steven are (UoM), dating back to the 1940s, when grants. Quite remarkably, not a single the genesis and spread of cancer cells. been to maximise links with the clinic, the 2010 postgraduate research medal. highly respected and internationally Sir Peter MacCallum was Head of dollar of indirect cost funding flows to capitalise on Peter Mac’s unique recognised researchers whose research Department. In conjunction with the 2010 also marked the launch of a new to the health care sector at present. governance structure that lends itself covers the range of lab-based cell current Chair of Pathology, Professor quarterly newsletter Forefront that to rapid research translation. I have been To realise our many opportunities, biology through to pre-clinical cancer Paul Waring, senior Peter Mac clinicians outlines recent research achievements greatly encouraged by the positive I propose the following: models and advanced human clinical and clinician/researchers underpin a across Peter Mac. trials. Tumour Angiogenesis is the response of Divisional Directors • As the first clinician to be appointed new, third year undergraduate course in process by which tumours generate the Professor John Zalcberg, Professor Executive Director Cancer Research, Molecular Oncology. Peter Mac Group new blood vessels they need to secure Gillian Duchesne and particularly, newly I firmly believe that Research Division Leader, Associate Professor Rob nutrients and oxygen from the blood appointed Executive Director Cancer must expand and enhance its links Ramsay coordinates this exciting new 12 stream. Marc and Steven are developing Surgery, Professor Alexander Heriot. with clinical colleagues at Peter Mac. lecture series with Professor Waring. new drugs to interfere with this process, In 2010, I initiated a series of three Peter Mac’s research laboratories also • The Research must communicate its to halt local tumour growth and research retreats, the aim of which was supported the projects of 12 BSc achievements and its aspirations more especially its spread through both blood to maximise collaboration and identify honours students enrolled in Pathology effectively to the entire Peter Mac vessels and lymphatic channels. Marc new initiatives that would involve or other UoM departments. community, including the Peter Mac and Steven jointly hold a NHMRC lab-based and clinical researchers At the postgraduate level, Peter Mac Foundation, on whose support we Program Grant, and each is also working in tandem. The three themes Professor Mark Smyth continues to host around 60 higher so strongly rely. supported at a senior level through the were: Genetics and Genomics, Cancer degree students, mostly through PhD NHMRC Fellowship Scheme. Therapeutics (broadly defined) and • Planning for our move to Parkville candidature. The Research Division is Recruitment of Dr Mark Shackleton Tissue Architecture/Inflammation and must involve a genuine desire to a potent focus for attracting clinicians and opening of the Melanoma Metastasis. One or two senior, external maximise collaboration with VCCC Research laboratory wishing to undertake higher degrees, clinician/researchers facilitated each partners. Designing and building with medical oncologists, pathologists Dr Mark Shackleton returned to retreat. Each was strongly attended, with Dr Gillian Mitchell a first class physical facility must be and surgeons all strongly represented. balanced by the desire to maximise Melbourne following a highly successful broad cross-divisional representation. Success in NHMRC project collaborative opportunities, while post-doctoral fellowship at the University I look forward to presenting a number of Communicating our research and fellowship funding maintaining independent governance of Michigan, to establish the Melanoma the initiatives distilled from this excellent aspiration and achievements for all VCCC members. Research laboratory (pg 65) within the process in due course. Raising the profile of research within Of 38 applications for Project Grant new Cancer Therapeutics program. Peter Mac, amongst our colleagues support, 16 (42 per cent) were funded, Consolidating research operational •  Peter Mac’s strong record in post- To support his repatriation, Mark was at other institutions and in the public representing about double the national support at Peter Mac graduate teaching must be extended awarded an Innovation Fellowship from arena is critical for continued success success rate. Of the 22 grants that were A further major initiative has been to encompass more clinician/ the Victorian Endowment for Science in fundraising and for reinforcing Peter not funded, 12 scored in the ‘5’ to establish a formal Office of Cancer researchers taking higher degrees, Knowledge and Innovation (VESKI) Mac’s leadership in cancer treatment category: these are grants that qualify Research (OCR) at Peter Mac. The while our profile in undergraduate to study melanoma and research. Guided tours of the easily on quality but receive no support purpose of an OCR is to provide broad teaching must also be enhanced. progression and explore potential new research laboratories have enabled because of insufficient funds. All in all, operational support for research across therapies. Dr Shackleton is a medical Associate Professors Steven Stacker and Marc Achen many Peter Mac staff to learn of our this meant that 28 of 38 grants (74 per I look forward to reporting on these the whole of Peter Mac, to facilitate grant oncologist who has pioneered novel research capability, or to support cent) scored 5 or above, which is aims and aspirations over the coming submission and financial management, techniques for isolating and growing the Refreshment of research programs the wonderful fundraising efforts absolutely outstanding and a testament several years. research governance and ethics, very cells that underpin the development in the Cancer Research Division of our colleagues in the Peter to the mentoring that all applicants the mentoring of junior researchers of malignant melanoma. These new Along with establishment of the Tumour Mac Foundation. receive from Peter Mac colleagues prior and to foster cross-divisional technologies will underlie our efforts to Angiogenesis program, the Cancer to submission. collaboration. Ms Mary Harney, Chief In October, the second annual Peter Mac identify novel molecular targets that will Therapeutics program was formalised Operating Officer Research Division public lecture was held at the Melbourne Peter MacCallum Cancer Centre – Research Report 2010 Director’s report 9 Director’s report (cont.) Clinical research overview

INDIVIDUAL RESEARCH AWARDS cutting edge resource was centred advanced malignant melanoma. • Dr Mark Shackleton and Associate on a $2.5m grant from the Australian This ground breaking work offers Through dedication to reducing the burden Professor Penny Schofield (pictured Cancer Research Foundation (ACRF), new hope for countless sufferers below) received awards for Research together with grants from the Victorian of this devastating disease. A further of cancer in Australia for over 60 years, Excellence from the NHMRC (‘Top ten Government and the Peter Mac paper describing results of the clinical projects’). Foundation. The VCFG in Cancer is trials was published in the prestigious Peter Mac has earned an international a national resource in cancer genomics clinical journal, The New England and houses various research platforms Journal of Medicine. reputation for excellence and innovation including robotically-controlled RNA • Peter Mac was announced as part of a knockdown technologies and next in cancer research, treatment and patient care. breakthrough international project that generation DNA sequencing to has uncovered a genetic mutation rapidly decipher cancer genomes. connecting to • Dr Scott Williams was awarded a endometriosis. Peter Mac Program highly prestigious research grant Head in Genetics and Principal from the Prostate Cancer Foundation, Investigator in the Australian Ovarian USA. Scott, who has established Cancer study, Professor David Bowtell As Australia’s only public hospital It is difficult to select research study collaborations with a number described the findings as a potent solely dedicated to cancer, Peter highlights of the year due to the of Research laboratories, also example of the power of the new DNA Mac is in a unique position to drive plethora of successes. However received a five year clinician sequencing technologies to find developments in cancer research, collaborative translational research researcher Fellowship from the critical genes that control ovarian underpinned by a vibrant clinical research leading to the identification of a novel Professor Gillian Duchesne Victorian Cancer Agency. cancer growth. program integrated with a sophisticated molecular target for non-small cell lung Executive Director, Radiation laboratory cancer research facility. cancer, and the clinical demonstration Oncology and Cancer Imaging • Professor Joe Sambrook, inaugural • Members of the laboratory of of the therapeutic benefit of an inhibitor The geographical and functional Director of Research at Peter Mac Professor Joe Trapani (Cancer Cell of mutated BRAF gene in malignant intertwining of the basic science and was presented with a life-time Death laboratory, pg 26) were featured melanoma, must be considered to be clinical research programs, supported achievement award by Monash as principal authors in a publication a couple of the highlights of 2010. University, in recognition of his in Nature that described the crystal by clinician scientists working across stellar research career and countless and electron microscope structure both areas and close interaction between As we plan towards the development Associate Professor Alexander Heriot contributions to research leadership of perforin, a key protein involved in the scientists and clinicians, provides the of the new Peter Mac at Parkville, Dr Mark Shackleton and Associate Professor Executive Director, Cancer Surgery Penny Schofileld and peer-reviews. the elimination of virus-infected and ideal synergistic environment to facilitate we have opportunities to plan for the cancerous cells by the immune system. translational research. This is pivotal continued growth and development • Associate Professor Grant McArthur • Mr Tony Lupton, Cabinet Secretary of in the development of new therapeutic of our clinical research — research was a major contributor to a paper • Dr Andreas Moeller was awarded the Parliament of Victoria opened the approaches and individualisation of that is pivotal to the development of published in Nature that described a prestigious Early Career Fellowship ACRF Victorian Centre for Functional cancer care. new directions in treatment. clinical efficacy of a BRAF inhibitor from the National Genomics in Cancer. Support for this that is revolutionising care in Foundation. Clinical research is embedded within the We take this opportunity to thank all Professor John Zalcberg OAM 11 tumour streams that deliver clinical our researchers for their contributions to Executive Director, Cancer Medicine care. The streams are underpinned clinical research and congratulate them by specialist laboratories and enabling on their leadership and achievements 2010 has been a challenging but highly invigorating and successful year for Peter Mac researchers. technology and interdisciplinary research in 2010. platforms, all with research programs I am greatly indebted to the Board and Senior Management of Peter Mac for their continual support of research, that function both independent of and and to the Peter Mac Foundation whose tireless efforts continue to provide the philanthropic support that underpins integrated with the tumour streams. The our every effort and achievement. four divisions, Cancer Medicine, Cancer Professor Sanchia Aranda Finally, I thank our generous donors, our funding agencies and particularly our dedicated researchers and postgraduate Surgery, Radiation Oncology and Cancer Executive Director, Cancer Nursing students whose stellar achievements promise so much in alleviating cancer suffering. Research, complete the matrix.

Professor Joseph A Trapani MBBS, FRACP, FFSc (RCPA), PhD Executive Director Cancer Research

Peter MacCallum Cancer Centre – Research Report 2010 Clinical research overview 11 About research at Peter Mac About research at Peter Mac

Peter Mac strives to lead the charge in discovering Peter Mac’s research goal is to alleviate the impact of more about cancer, ultimately leading to a goal cancer on the community through innovative research where more cures are possible. and through collaboration and contribution to national and international cancer research programs.

Our Key Research Strategic DirectionS PETER MAC RESEARCH MODEL Research and innovation to cure or control cancer The model below is representative of both the structure of research at Peter Mac and of the structure of this report. Key core components within this research strategic direction include: Our laboratory, clinical and translational research is Peter Mac plays an extremely important role in the Our Vision supported by an extensive base of enabling technologies • A pre-Parkville Strategy, with a focus on growth and community as the only public hospital in Australia solely and interdisciplinary research platforms that underpin development of collaborative relationships and platform dedicated to cancer. Even more unique is the integration The best in cancer care — our nationally and internationally recognised research. of an extremely strong research program that is technologies pre-2015. accelerating discovery, With this breadth of expertise and resources available, internationally renowned. • Developing Peter Mac as a leading centre for innovative we aim to drive the translation of our laboratory and translating to cures. research and treatment, including further developing Peter Mac delivers care through a multidisciplinary model clinical research into best clinical practice and better personalised medicine approaches (e.g. genomics), across 11 tumour streams. The provision of care is closely patient outcomes. and responding to innovative opportunities to develop all integrated with the largest cancer research team in Australia. Our Mission laboratory, translational and clinical research programs. Peter Mac’s key research strengths include that: As Australia’s only public hospital solely dedicated to cancer, • Further develop the laboratory /clinical interface, including as a national leader in multidisciplinary cancer care, and a • It is one of the few hospitals in the world with the benefit resources to enable Peter Mac to lead in the development national and international leader in laboratory, clinical and of having its own integrated cancer research programs of translational research programs across all clinical translational research, Peter Mac: and laboratories, providing the opportunity to lead the way services, and a structure to support further development of in translational research in cancer. • Is dedicated to providing care across all clinical services to tumour stream-based research. improve the outcomes for individual cancer patients, and • Its research program continually drives improvements • Continuing to develop and enhance Peter Mac’s clinical reduce the impact of cancer on our community. in all aspects of treatment and clinical care. research capacity and profile. • It provides a multidisciplinary tumour stream-based • Through its dedicated focus to cancer and the critical mass and holistic model of care — experts from all fields come of its services, provides specialist treatment in rare together to provide the best treatment possible at all stages and complex cancers to ensure that all Victorian patients, of a patient’s illness, across the full spectrum of cancers. regardless of where they live, will have access to the expert care they require. • It has a pre-eminent academic program, with internationally renowned researchers and clinical researchers. • Ensures that discoveries progress to increasing the cancer knowledge base that then translates to the development of • It has specialised equipment and technology, the best cancer treatments. BETTER PATIENT enabling highly complex research and treatments. OUTCOMES • Provides the best in educational opportunities resulting in the Peter MacCallum Cancer Centre 2010–2015 Strategic Plan training of the best cancer clinicians for today and the future. LABORATORY RESEARCH Our Values CLINICAL RESEARCH We strive for Excellence ensuring that clinical practice is evidence based, patient centred and is provided by qualified and experienced staff that are accountable and appropriately credentialled. We strive to ensure that Innovation is fostered by supporting research and a learning culture. INTERDISCIPLINARY RESEARCH PLATFORMS Adhering to the strongest ethical standards to ensure a culture of openness, mutual respect and trust, ENABLING Compassion is at our core. TECHNOLOGY PLATFORMS

Peter MacCallum Cancer Centre – Research Report 2010 About research at Peter Mac 13 Cancer research at a glance Metrics

Powerful trends in genetics, Laboratory Cancer Research Clinical and Translational Publications Research molecular therapeutics, imaging, and Cancer Research is home to over 420 In 2010, the cancer research of Peter Mac was published in a range of international peer reviewed journals, including: personalised medicine will shape the laboratory-based scientists and support Our clinical and translational research future of cancer service delivery. As staff including over 100 postgraduate, is embedded within the 11 tumour Publication Impact Factor 2009 2010 a specialist cancer centre and with a honours and advanced medical science streams that deliver clinical care, and is New England Journal of Medicine 52.59 1 4 strong disease focus in our research, underpinned by interdisciplinary research students. Cell 29.89 2 1 Peter Mac is exceptionally well placed platforms all with research programs Our laboratory-based translational to translate research findings into clinical that function both independent of, and Science 29.75 - 1 research programs are conducted practice and to help devise the most integrated with, the tumour streams. Nature 28.75 1 4 beneficial and cost-effective new across 27 laboratories, organised Nature Reviews Cancer 29.54 - 2 approaches to cancer management. into collaborative research programs: Over 200 clinician researchers across Peter Mac are involved in clinical trials Lancet 28.64 2 2 • Cancer Cell Biology Our cancer research program is and clinical research. These include (Associate Professor Rob Ramsay) Nature Reviews Immunology 28.30 1 - underpinned at all levels by a belief medical, radiation and surgical Nature Medicine 26.38 1 - in the importance of developing a deep • Cancer Genetics and Genomics oncologists, and staff from allied health, understanding of the processes that (Professor David Bowtell) nursing and supportive care, physical Nature Immunology 26 - 1 control cancer cells, and employing sciences, imaging and radiation therapy, Nature Genetics 25.56 3 2 this knowledge in the clinic to develop • Cancer Immunology Research statisticians and research nurses. Cancer Cell 23.86 1 2 rational, evidence based protocols that (Professors Joseph Trapani and improve cancer outcomes. Mark Smyth) Over 200 clinical trials were active Immunity 19.27 3 - at Peter Mac through both the • Cancer Therapeutics, incorporating Journal of Clinical Oncology 17.79 14 16 Patient care at Peter Mac is modelled Clinical Trials Unit (CTU) and through Molecular Imaging and Translational around tumour-specific clinical services, trials coordinated by the Centre for Nature Cell Biology 17.62 1 - Medicine (Associate Professors Ricky provided by multidisciplinary teams Bioinformatics and Clinical Trials (BaCT). Journal of Clinical Investigation 16.92 2 - Johnstone and Grant McArthur) of surgeons, radiation oncologists, Journal of the National Cancer Institute 15.68 2 2 medical oncologists, specialist nurses, • Growth Control and Differentiation Fellowships and awards in 2010 Lancet Oncology 12.25 2 6 allied health and other support staff. (Associate Professors Ross Hannan • 15 senior fellowships Gastroenterology 11.67 2 1 Our clinical services are underpinned and Rick Pearson) (NHMRC and others) by a strong research program that • Tumour Angiogenesis American Journal of Human Genetics 11.09 1 - extends from basic laboratory research • 13 NHMRC career development (Associate Professors Marc Achen and Blood 10.90 9 5 through to translational research and postdoctoral awards Steven Stacker). Gut 10.02 1 - programs and clinical trials of new • 8 clinical research fellowship cancer treatments. In addition, we Our laboratory programs are supported awards (CCV, VCA) Total (JIF>10) 49 49 support a growing program of research by nine core technology platforms, • 13 new scholarships awarded in supportive care and palliative care. from advanced microscopy facilities Grants through to sophisticated functional to postgraduate students in 2010. Our laboratory, clinical and translational and molecular genomic facilities. With a budget of over $40m annually, the excellence of our research is reflected in our success in obtaining competitive funding to research is supported by an extensive support our research endeavours. We continue to achieve more than double the national average for success in grants from the base of enabling technologies and (NHMRC), and are proud of the success of our researchers in obtaining competitive funding from national and international interdisciplinary research platforms organisations. that underpin our nationally and internationally recognised research.

Research Output Our scientific excellence, underpinned by grant successes, is evident in the strong impact of our research publications.

Publications types and quantities

Publication type 2010 Original research articles 291 Reviews 63 Editorials and comments, letters, author replies 59 Book chapters 12 Total 425

Peter MacCallum Cancer Centre – Research Report 2010 Research/Cancer Matrix

LABORATORY PLATFORM TECHNOLOGY CANCER TYPES

Transgenic Microscopy Next Gen Flow VCFG Bioinformatics Tissue Bank Micro- All Breast Gastro- Gynae- Haematology Head & Neck Lung Melanoma Neuro- Sarcoma Uro- Models Sequencing Cytometry array Cancers intestinal oncology & Skin Oncology Oncology

1.1 Cancer Immunology Progarm 1.1.1 Cancer Cell Death •••••••• ••• • • 1.1.2 Cellular Immunity •• • ••• ••• • •• •• 1.1.3 Immune Signalling •••• ••• • • 1.1.4 Immunotherapy •• • •• •• • •• • 1.1.5 Haematology Immunology Translational Research •• • • • 1.2 Cancer Genetics Program 1.2.1 Cancer Genetics and Genomic •••••••• •••• 1.2.2 Sarcoma Genetics and Genomics •••••••• • 1.2.3 Surgical Oncology •••••••• ••• 1.2.4 VBRC ••••••• • • 1.2.5 kConFab • • • ••• •• 1.3 Growth Control and Differentiation Program 1.3.1 Growth Control • ••••• • •• •• • • 1.3.2 Molecular Oncology •••••••• •••• •••• 1.3.3 Protein Chemistry •••••••• • •• • 1.4 Cancer Cell Biology Program 1.4.1 Cell Cycle and Cancer Genetics •••••••• •• • • 1.4.2 Cell Cycle and Development ••••• • •••• • • 1.4.3 Cell Growth and Proliferation •• •••• • • •• 1.4.4 Differentiation and Transcription •••• •• •• 1.4.5 Epithelial Stem Cell Biology •• • ••• • • •• 1.4.6 Metastisis Research •• ••••• •• 1.4.7 Molecular Radiation Biology •• • •• •• • 1.4.8 Tumour Suppresion •• ••••• ••• • • 1.5 Tumour Angiogenesis Program 1.5.1 Tumour Angiogenesis •• •••• • 1.6 Cancer Therapeutics Program 1.6.1 Gene Regulation •••••• ••• • •• • 1.6.2 Melanoma Research •• • • • 1.6.3 Molecular Imaging and Targeting Therapeutics •• • • • 1.6.4 Translational Research •• • •• • ••• 1.6.5 Pfizer/Peter Mac Cancer Genomics program ••• • • • 1.6.6 CCV Venture ••• • 1.6.7 CRC for Cancer Therapeutics •• • •••

Peter MacCallum Cancer Centre – Research Report 2010 Research / Cancer matrix 17 Interdisciplinary Matrix Recent research highlights with impact on cancer care

CANCER TYPES INTERDISCIPLINARY • Establishment of the use of PET as a global standard technique for the staging and RESEARCH All Breast Gastro- Gynae- Haema- Head & Lung Melanoma Neuro- Paeds/ Sarcoma Uro- PLATFORMS Cancers intestinal oncology tology Neck & Skin Oncology Late Oncology response to treatment in lung and Effects 3.2.1 Centre for Blood • Efficacy of tirapazamine in hypoxic tumours such as head and neck Cell Therapies •

3.2.2 Centre for • RANKL as a novel therapeutic for large cell cancer in bone Cancer Imaging •••••••••••• 3.2.3 Centre for • BRAF inhibitors in melanoma: world first clinical trials Biostatistics and •• •• Clinical Trials • The establishment of as a global standard of care for dermatofibrosarcoma protuberans

3.2.4 Clinical Trials Unit • •• •• • • New methods of diagnosing cancers of unknown primary (CUP) 3.2.5 Clinical • Establishment of HDACi as a standard of care in cutaneous T cell lymphoma Psychology •• • 3.2.6 Familial Cancer • Identification of PI-3 kinase as an important in several Centre •••• cancers including colon and ovarian 3.2.2 Infectious • • Diseases • Identification of molecular markers that distinguish various types 3.2.3 kConFab Follow-Up • • of stomach and ovarian cancer 3.2.4 Molecular Pathology ••• ••• • • Identification of cell size regulation as important in cancer causation laboratory • Realisation that the immune system is an important regulator 3.2.5 Nursing and • • • • Supportive Care of cancer development, particularly leukaemia/lymphoma 3.3.1 Nutrition • • ••• • • New methodologies for diagnosis of hemophagocytic lymphohistiocytosis 3.3.2 onTrac@ PeterMac • • • • Demonstration that stromal cells in ovarian cancer are not genetically mutated 3.3.3 Pain and • Accurate definition of stem cells in skin Palliative Care • 3.4.1 Pharmacy • • Leading practice in the application of brachytherapy in prostate cancer

3.4.2 Physical • Leading practice in eliminating movement as a confounder •• • •• • Sciences in delivery of radiotherapy 3.4.3 Radiation •••• •• •• • Therapy • The development of the world’s first radio-protector molecules 3.4.4 Social Work • • • • World’s best practice in management of the psycho-social aspects of adolescent cancer (onTrac@Petermac) • p16 as a prognostic marker in head and neck cancer • ALK inhibitor in lung cancer: world first clinical trials • Use of radiotherapy in lymph node metastases from melanoma • The discovery of new breast cancer genes that will explain the cause of these cancers • Development of highly efficient and clinically relevant models of human melanoma progression • Translation of research patients into effective targeted therapies for breast, ovarian and prostate cancers

Peter MacCallum Cancer Centre – Research Report 2010 Research awards and highlights 19 Laboratory Research 1 Laboratory Research 1

While completing his PhD degree at Andy works at the interface of the Mater Hospital through the University laboratory and clinical research. With of Queensland, Andy Hsu was part of his colleagues from the Haematology a bone marrow transplantation laboratory Immunology Translational Research — from then on, he knew the value and laboratory and across clinical areas, importance of translational research. Andy exemplifies the multidisciplinary approach to combating cancer, ‘Since then I have been very proactive supported by the advanced platform and passionate about my research technologies available at Peter Mac. in cancer immunology; as a leader in this field, Peter Mac was the ideal ‘The dedication of my colleagues location for me.’ across Peter Mac inspires my translational research directions.’

Peter MacCallum Cancer Centre – Research Report 2010 1 Laboratory Research

Working at the interface between basic biology and clinical cancer care, our scientists are committed to reducing the impact of cancer on people.

With 27 integrated research laboratories Cancer Immunology program Tumour Angiogenesis program embedded in a world-class cancer Cancer Cell Death laboratory Tumour Angiogenesis laboratories hospital and researchers and clinicians Cellular Immunity laboratory working side-by-side, we have Immune Signalling laboratory Cancer Therapeutics program established an outstanding reputation Immunotherapy laboratory Gene Regulation laboratory for excellence in cancer research. Haematology Immunology Melanoma Research laboratory A focus on translating our laboratory Translational Research laboratory Molecular Imaging and Targeting Therapeutics laboratory research into clinical practice underpins Cancer Genetics program Translational Research laboratory our strategic research directions. Cancer Genetics and Genomics Pfizer/Peter Mac Cancer Working in an integrated environment laboratory Genomics program delivers unique opportunities for medical Sarcoma Genetics and Genomics CCV Venture Grant Initiative advances to be developed and tested, laboratory CRC for Cancer Therapeutics and for clinically oriented questions Surgical Oncology laboratory to guide research agendas. This has a VBCRC Cancer Genetics laboratory profound effect on the understanding kConFab of cancer biology, leading to more Growth Control and Differentiation effective and individualised patient program care, in effect, research from ‘bench Growth Control laboratory to bedside’ and back again. Molecular Oncology laboratory Protein Chemistry laboratory Cancer Cell Biology program Cell Cycle and Cancer Genetics laboratory Cell Cycle and Development laboratory Cell Growth and Proliferation laboratory Differentiation and Transcription laboratory Epithelial Stem Cell Biology laboratory Metastasis Research laboratory Molecular Radiation Biology laboratory Tumour Suppression laboratory

Peter MacCallum Cancer Centre – Research Report 2010 Laboratory Research 23 1.1 Cancer Immunology program 1.1 Cancer Immunology program

Harnessing the power of the immune system to fight cancer

The Cancer Immunology program Complementing these approaches Cancer Cell Death laboratory performs internationally recognised is the development of genetically Prof. Joseph Trapani work on cancer immune surveillance enhanced T cells for adoptive Cellular Immunity laboratory and chemo/immuno-therapy, defining immunotherapy, whose potency Prof. Mark Smyth key cells and molecules that constitute and specificity have rapidly moved an effective response to tumour. this strategy into phase I clinical trials. Immune Signalling laboratory Dr Sarah Russell Immunotherapy is of increasing interest The Immune Signalling laboratory as an approach to arrest cancer at a (led by Dr Sarah Russell) is part of the Immunotherapy laboratory much earlier stage. Strategies range Cell Polarity program, and is making Assoc. Prof. Michael Kershaw from vaccines that mobilise the immune important discoveries about the polarity and Dr Phil Darcy system de novo (active immunotherapy), of immune cells and the structural Haematology Immunology to administering preformed biologicals network that controls immune cell Translational Research laboratory such as monoclonal antibodies (mAbs), synapse, migration, division and Assoc. Prof. David Ritchie cytokines, or exogenously activated effector function. and Dr Paul Neeson immune cells (adoptive immunotherapy). The Gene Regulation laboratory For immunology research conducted The program has recently strengthened (led by Assoc. Prof. Ricky Johnstone) within associated programs: its focus on haematological cancers, in the Cancer Therapeutics program is greatly strengthening links with Peter closely linked with the Cancer - Gene Regulation laboratory Mac’s Division of Cancer Medicine. Immunology program, collaborating in a Assoc. Professor Ricky Johnstone program of chemo-immunotherapy in Current and future efforts are directed (See Cancer Therapeutics program, breast cancer. at understanding the fine balance pg 62) between the developing tumour - Haematology Service (pg 86) microenvironment and the immune system, the key molecules that link innate and adaptive immunity and promote lasting memory to tumour antigens, and the molecular pathways that underpin the signalling of anti- tumour interferons.

Peter Mac Fellow Dr Jane Oliaro is With her colleagues in the Immune a postdoctoral scientist in the Cancer Signalling laboratory, Jane hopes Immunology program. Using the latest to further understanding of immune confocal, electron and time-lapse cell development and determine microscopes, Jane’s research involves the processes that are disturbed imaging immune cells: understanding in cancers such as leukaemia. how we can activate a type of immune ‘By using the microscopy facilities cell, called a T cell, to mount an at Peter Mac I can image, in real time, immune response to clear infected cells communicating with each other, and cancerous cells. growing and killing cancer cells, and monitoring the movement of molecules within individual cells.’

Cancer Immunology program 25 1.1.1 Cancer Cell Death laboratory 1.1.2 Cellular Immunity laboratory

RESEARCH FOCUS murine perforin, together with a cryo- KEY 2010 RESEARCH ACHIEVEMENT proof-of-concept studies investigating • Investigation of molecular mechanisms electron microscopy reconstruction CD73 as a novel therapy in primary the therapeutic potential and mechanism behind cytotoxic lymphocyte-induced of the entire perforin pore. Not only did cancer growth and metastasis of action of monoclonal antibody apoptosis of cancer cells. these studies support our earlier work, (mAb)-based therapy against CD73. but they also allowed the elucidation It is becoming increasingly apparent We found that anti-CD73 mAb therapy • Understanding the structure, of the mechanism of perforin pore that one of the difficulties of inducing could significantly delay primary mechanism and genetics of a key formation, which remained one of clinically relevant mammary tumour growth in immune regulator of cytotoxic lymphocyte the most puzzling secrets of cytotoxic is the tight regulation associated with competent mice. Furthermore, we activity, perforin. lymphocyte biology for well over immune responses. observed that anti-CD73 mAb therapy • Development of cytotoxic lymphocyte two decades. One of the most important regulatory significantly reduced the number of suppressors based on targeted lung metastases. The anticancer activity Perforin turns out to be a thin ‘key- processes that restricts immune inhibition of perforin function by of anti-CD73 mAb therapy against shaped’ molecule, comprising an activation is the accumulation of novel compounds. primary tumours was essentially amino-terminal membrane attack extracellular adenosine in tissue. dependent on the induction of adaptive complex perforin-like (MACPF)/ It has been observed that extracellular anti-tumour immune responses. Research Leader: Prof. Joe Trapani, Executive KEY 2010 RESEARCH ACHIEVEMENT cholesterol dependent cytolysin (CDC) Research leader: Prof. Mark Smyth, NHMRC adenosine is a potent immunosuppressor Director Cancer Research Knockdown of CD73 in 4T1.2 tumour domain followed by an epidermal growth Senior Principal Research Fellow that accumulates during tumour growth. The crystal structure of perforin cells confirmed the immunosuppressive factor domain that, together with the One of the sources of extracellular monomer and the three-dimensional effect of CD73. However, anti-metastatic We investigate immune mechanisms extreme carboxy-terminal sequence, adenosine is through the activity of reconstruction of the entire The Cellular Immunity laboratory activity was observed in both immune of defence against viral pathogens forms a central shelf-like structure. CD73, an ecto-enzyme that catalyses perforin pore undertakes basic and pre-clinical competent and immunodeficient mice. and cancerous (transformed) cells. A C-terminal C2 domain mediates initial, the dephosphorylation of adenosine research in cancer immunology, Using selective adenosine Understanding these processes Natural killer cells and cytotoxic Ca-dependent membrane binding. monophasphates into adenosine. CD73 with a view to combining new antagonists, we demonstrated that will help to better understand T lymphocytes accomplish the critically Most unexpectedly, however, electron is normally expressed on endothelial cancer immunotherapies with activation of A2B adenosine receptors molecular mechanisms that govern important function of killing virus- microscopy reveals that the orientation cells and subsets of leukocytes, and is current first line cancer therapies. promoted 4T1.2 tumour cells chemotaxis. the immune system; identify genetic infected and neoplastic cells. They do of the perforin MACPF domain in the induced in response to cellular stress predisposition to haematological this by releasing the pore-forming pore is inside-out relative to the subunit such as hypoxia. Importantly, CD73 In conclusion, our study identified protein perforin and granzyme proteases is overexpressed in various cancer ; design novel therapeutic arrangement in ancestral homologous RESEARCH FOCUS tumour-derived CD73 as a novel approaches to prevent life-threatening from cytoplasmic granules into the cleft bacterial CDC. These data reveal cell types, including breast cancer. mechanism of tumour immune escape complications of bone marrow stem formed between the abutting killer remarkable flexibility in the mechanism • Basic studies of the role of immunity We hypothesised that blocking the and tumour metastasis, and established cell transplantation. and target cell membranes. Perforin, of action of the conserved MACPF/CDC in the tumour microenvironment. activity of CD73 would decrease the the proof-of-concept for therapeutically a 67-kilodalton multidomain protein, fold and provide new insights into how • Immunosuppressive pathways level of extracellular adenosine in the targeting CD73. oligomerises to form pores that deliver related immune defense molecules that prevent tumour regression. tumour microenviroment, break immune tolerance to the tumour and promote Reference: Stagg J, Divisekera U, McLaughlin N, the pro-apoptopic granzymes into the such as complement proteins assemble • The biology of natural killer (NK) immune-mediated tumour cell destruction. et al. Anti-CD73 antibody therapy inhibits breast cytosol of the target cell. The importance into pores. cells and NKT cells. tumour growth and metastasis. Proc. Natl. Acad. of perforin is highlighted by the fatal Sci. USA 107:1547–1552, 2010. These studies now provide a valid • Translational studies designing To investigate CD73 as a potential target consequences of congenital perforin framework for the rational design and testing new combination for anticancer strategies, we performed deficiency: autosomal recessive of modulators of perforin function, immunotherapies pre-clinically immunoregulatory disorder, familial which may potentially be used to and clinically in cancer patients. haemophagocytic lymphohistiocytosis alleviate undesirable outcomes (type 2 FHL). In the past, we of cytotoxic lymphocyte activity in characterised many of those mutations autoimmune diseases, such as Type I and also defined some of the key Diabetes and cerebral malaria. aspects of perforin mechanism of action. In collaboration with colleagues at Reference: Law RH, Lukoyanova N, Voskoboinik I, et al. The structural basis for membrane binding Monash University and Birkbeck College and pore formation by lymphocyte perforin. Nature. (London) we have now resolved the 468: 447– 451, 2010. X-ray crystal structure of monomeric

Figure 1: A cryo-electron microscopy reconstruction of a perforin pore (from Law, Lukoyanova, Voskoboinik I, et al. The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature. 468: 447– 451, 2010).

Figure 1: In our study, we identified CD73 expression on tumour cells as an important mechanism of tumour immune evasion. The image represents CD73 expression (in green) detected by immunofluorescence microscopy on MDA-MB-231 human breast cancer cells.

Peter MacCallum Cancer Centre – Research Report 2010 Cancer Immunology program 27 1.1.3 Immune Signalling laboratory 1.1.4 Immunotherapy laboratory

RESEARCH FOCUS These studies rely on time lapse RESEARCH FOCUS Using gene-modified T cells we • Map lineage pedigrees of developing microscopy to ‘watch’ the behaviour • Anti-cancer gene design. have shown in the past that this form of cells over time, and similar studies of therapy can cause regression of hematopoietic cells to elucidate • Testing of various gene-modified have not previously been possible in some cancers in mice. However, our how fates such as death, proliferation immune system cells to eradicate blood cells due to technical difficulties previous therapies were performed and differentiation affect immune cancer in pre-clinical animal models. cell development and are altered related to the dynamic behaviour of in immunodeficient mice that lack • Development of novel combination in . blood cells. We have recently made expression of tumour antigens on some key technical breakthroughs that therapies against cancer. normal tissues of the body. This is • Determine how asymmetric cell division now enable us to perform such lineage • Translation of basic research not the case in patients, with tumour determines the fate of blood cells. tracing. These breakthroughs come discoveries into clinical practice. antigens being expressed on some • Determine whether alterations from our interactions with physicists • Molecular construction of genes normal tissues including vital organs. in asymmetric cell division lead and engineers in our sister laboratory for enabling T cells to recognise Therefore, it has been difficult to to or alter leukemia. (also run by Dr Sarah Russell) at and respond against cancer cells. gauge the safety of the adoptive T cell • Determine how asymmetric Swinburne University. Firstly, we approach in mice up to now. • Use of Toll-like receptor division of blood cells is regulated, manufacture ‘cell paddocks’ which Research leader: Dr Sarah Russell, Research leaders: Dr Phillip Darcy, NHMRC CDA and immune antibodies Recently, we have used transgenic mice ARC Future Fellow and develop means to disrupt or contain the blood cells in the field of Research Fellow and Assoc. Prof. Michael Kershaw, NHMRC Senior Research Fellow for cancer therapy in mice. that express a human tumour antigen, promote asymmetric cell division. view — these paddocks allow long term called Her-2, on some of their normal imaging of hematopoietic stem cells, Health depends upon each cell in tissues including breast and brain. developing and mature immune cells, The Immunotherapy laboratory KEY 2010 RESEARCH ACHIEVEMENT We have generated mouse cancers our body conforming appropriately to KEY 2010 RESEARCH ACHIEVEMENT and leukemic cells. Secondly, we have its prescribed fate — dying, proliferating focuses on pre-clinical development Genetically modifying white blood expressing human Her-2 and used From chaos to order: new approaches developed systems for fluorescent or altering its characteristics to remain of novel immune therapies for cancer cells to destroy cancer these in mice along with adoptive to quantifying the behaviour tagging of the cells, and of proteins in an appropriate ratio to all other cells. with the aim of translating the most transfer of gene-modified T cells, of rapidly moving blood cells within the cells, which enable us to effective treatments into the clinic. Adoptive immunotherapy is a very to see if we can cause regression Cancer occurs when cells ignore monitor cellular and molecular promising approach to cancer therapy. The most effective way to study of established cancer safely without the signals that usually control fate, behaviours. Thirdly, we have developed This form of therapy involves taking a cell fate decisions and their influence causing damage to normal breast and to combat cancer we need to custom software which not only sample of blood from patients, activating on development and cancer is by and brain. understand exactly how these signals automatically tracks and quantifies these T cells from this blood in the laboratory a technique called lineage tracing, work. We have recently found that behaviours, but can assemble and growing them to large numbers Using this approach in this new strain in which the daughters, granddaughters asymmetric cell division, in which the the data in the form of pedigree trees. before injecting them back into the of mouse, we have demonstrated that and subsequent generations of a cell two daughters of a dividing cell inherit patient. This form of therapy has been established cancer metastases in the are tracked, processes such as cell Together these tools provide an different properties from their parent used very effectively in clinical trials lungs of mice can be eradicated using division, death and differentiation are extremely powerful new way of studying cell, controls the fate of blood cells. to induce tumour regression in patients T cells. This effect was achieved in the monitored for each cell, and lineage how fate decisions are managed in with melanoma and those with some absence of damage to normal tissues. pedigrees assemble. The power of this blood cells, and we hope that our lymphomas. To make this form of approach is perhaps best illustrated by findings with this approach will provide Reference: Wang LX, Westwood JA, Moeller M, therapy suitable for other types of cancer, et al. Tumour ablation by gene-modified T cells lineage tracing in the model organism, a new platform of knowledge form like breast cancer, we have genetically in the absence of autoimmunity. Cancer Res. c. elegans, which led to an explosion which to determine how cancers arise, 70:9591–8, 2010. modified T cells to express a receptor of knowledge, much of which has and how they can be treated. on their surface that enables recognition impact in the clinic. and response against tumour cells.

Figure 1: Tracking divisions during T cell Figure 1: Adoptive transfer of gene-modified development. We have established new T cells into tumour-bearing mice does not software methods with which to track migrating cause damage to normal breast and brain tissue. cells and quantify aspects of their behaviour, Top: Microscopic views of breast tissue from fluorescence, orientation and morphology. In this mice that received gene-modified T cells for instance, we identify cells at the time of division, cancer treatment. Bottom: Brain tissues appear and automatically create a montage of time normal with no evidence of destruction by T cells. lapse images of the cells (left panels) in which the orientation is fixed in silico against an axis that we define. From these images, numerous attributes can be quantified and plotted over time, such as the summed fluorescence along the axis of division as shown in the right panels. In this instance, Kim Pham and Raz Shimoni have analysed the polarity of a fate determinant called Numb in dividing thymocytes.

Peter MacCallum Cancer Centre – Research Report 2010 Cancer Immunology program 29 1.1.5 Haematology Immunology Cancer Immunology program – personnel Translational Research Laboratory

KEY 2010 RESEARCH ACHIEVEMENT bortezomib-Mapa (or LTB-Mapa), Cancer Cell Death Postgraduate Students Haematology Immunology laboratory Translational Research Myeloma immunogenic death induced apoptosis of myeloma cells. Chris Chan laboratory We demonstrated (by live video Head Melvyn Chow This is an ongoing project examining microscopy and flow cytometry) that Shin Foong Ngiow Heads whether a rational combination of novel Prof. Joseph A. Trapani LTB-Mapa-treated myeloma cells form Dr Paul Neeson therapies can induce both myeloma Peter Mac Fellow Genotypers apoptotic bodies which are rapidly Assoc. Prof. David Ritchie cell death and simultaneously promote endocytosed by autologous immature Dr Ilia Voskoboinik Debbie Allen an endogenous immune response DCs (iDCs). Interestingly, these myeloma Janelle Sharkey Clinical Collaborators Senior Research Officer to myeloma. cell apoptotic bodies inhibit iDC Dr Simon Harrison Immune Signalling Dr Vivien Sutton Dr Stefan Peinert Evidence to date indicates that tumour maturation, either constitutive iDC laboratory cells can display signature molecules on maturation or that induced by the TLR4 Research Officers Prof. Miles Prince Head apoptotic bodies or release them from ligand lipopolysaccharide (LPS). Dr Daniella Brasachio Postdoctoral Fellows Dr Sarah Russell necrotic cells; these molecules incite Subsequent studies examined the Dr Amelia Brennan Dr Joanne Davis dendritic cell (DC) maturation. DC potential for induction of myeloma- Dr Magdalena Hagn Peter Mac Research Fellow Dr Andy Hsu maturation, following endocytosis of specific T cell responses to LTB-Mapa Dr Jamie Lopez Dr Jane Oliaro Research leaders: Dr Paul Neeson Clinical Fellow and Assoc. Prof. David Ritchie tumour cell apoptotic bodies, leads induced myeloma cell apoptosis. Thus, Research Assistants Postdoctoral Scientists to display of tumour-derived peptides there was no increase in myeloma- Dr Michael Dickinson Kylie Browne Dr Edwin Hawkins to antigen-specific T cell and induction specific T cells when autologous DCs Research Assistants The Haematology Immunology of the endogenous response. However, Annette Ciccone Dr Betty Kouskousis pulsed with LTB-Mapa killed myeloma Karen Chen Translational Research Laboratory data to date also indicate many drugs Susie Roczo Dr Kerrie-Ann McMahon cells were used to prime T cells. Kevin Thia Tsin Tai (HITRL) investigates the efficacy used for conventional therapy of This is likely due to suppression Dr Stephen Ting of novel immunotherapeutics against Sandra Vershoor Kellie Tainton myeloma are toxic to the immune of iDC maturation by myeloma-derived Senior Research Assistant human blood cancers. We focus system (e.g. ), making Technician cytokines (e.g. VEGF, IL-6 and IL-10), a Postgraduate Students Mandy Ludford-Menting on induction of human immune the induction of a myeloma-specific topic for ongoing investigation. Desiree Anthony Josh Noske responses to provide ongoing immune response impossible. Research Assistants Nonetheless, there was a significant Jenny Chia Visiting Scholar control over blood cancers. increase in induction of myeloma- Olivia Susanto Olivia Cakebread We are using combination therapy Dr Patries Herst with a dose of the proteasome inhibitor specific T cells when the DC endocytosis Michael Harvey Advanced Medical Science Kelly Ramsbottom (bortezomib), that does not inhibit of myeloma apoptotic bodies occurred (AMS) Student Postgraduate Students RESEARCH FOCUS in the presence of LTB-Mapa. Vanessa van Ham dendritic cell (or other immune system Wei Zhen Yeh (2009–10) Dr Michael Dickinson • Translational research adapting novel cells) function, with a TRAIL-R1 agonistic Subsequent studies are now examining Sam Williams Saar Gill therapeutics to the human system antibody (Mapatumumab). This novel the mechanism whereby this could occur. Executive Assistant Postgraduate Students to Professor Joseph Trapani Advanced Medical Science and moving it into phase 1 clinical combination therapy, termed low dose Anupama Pasam (AMS) Student Diana Motion trials. Kim Pham Reece Cordy (2009–10) • Testing patient responses to novel Cellular Immunity Faruk Sacirbegovic Joanna Loh (2010–11) therapeutics and adjusting therapy laboratory Raz Shimoni Mohammed Yassin Cancer Immunology to gain maximum benefit with Head minimum . Program Prof. Mark Smyth Honours Student Administrative Assistant • Investigation of novel immunotherapy Ivan Fung Research Officers for human multiple myeloma, leukemia Belinda Kelly Dr Daniel Andrews Immunotherapy and lymphoma. Laboratory Manager Dr Nikola Baschuk laboratory • Investigation of human immune system Jason Brady Dr Nicole Haynes Heads responses to multiple myeloma in Dr Stephen Mattarollo Dr Phillip Darcy response to novel immunotherapy. Dr Christophe Paget Assoc. Prof. Michael Kershaw • Modelling of the effect of novel Dr John Stagg vaccines to multiple myeloma in a Dr Trina Stewart Postdoctoral Scientists humanised mouse model. Dr Michele Woei Ling Teng Dr Christel Devaud Dr Linda Howland Research Assistants • Investigation of graft-versus-host Dr Liza John disease in allogeneic bone marrow Claire Cotterell transplantation. Upulie Divisekera Research Assistant Helene Duret Jennifer Westwood • Close collaboration with the Fransisca Go Cancer Immunology program. Postgraduate Students Ming Li Connie Duong Figure 1: Combination LTB-Mapa therapy induces myeloma immunogenic death. (A) Immature monocyte- Nicole McLaughlin derived dendritic cells (CD11c, green) rapidly phagocytose apoptotic U266 cells (pre-treated with 1nM Bianca von Scheidt Leanne Wang bortezomib and 0.12mg Mapa). pHrodo-labelled U266 cells fluoresce bright red when they pass into endosomes of pH≤5. (B) U266 myeloma-pulsed iDCs induce increased numbers of myeloma-specific Sally Watt CD8+ T cells and NK cells compared to controls (i) when combination LTB-Mapa was present at the priming phase of the CTL culture (ii).

Peter MacCallum Cancer Centre – Research Report 2010 Cancer Immunology program 31 1.2 Cancer Genomics program 1.2 Cancer Genomics program

As an academic clinician, Alex heads Peter Mac’s Gastroenterology Service. Using sophisticated highthroughput genomic As a researcher, Alex and his team in the Cancer Genetics and technologies to improve our understanding of cancer Genomics laboratory investigate upper gastrointestinal cancer — The Cancer Genomics program seeks The program includes internationally Cancer Genetics particularly Barrett’s Oesophagus, to use sophisticated high throughput recognised, large-scale national and Genomics laboratory oesophageal adenocarcinoma, genomic technologies to improve molecular and epidemiological studies Prof. David Bowtell gastric intestinal metaplasia and our understanding of the biology into breast, ovarian and sarcoma cancer, gastric cancer — through research Sarcoma Genomics of cancer and to advance the clinical notably in the research conducted encompassing a number of disciplines and Genetics laboratory management of cancer patients, through by the Australian Ovarian Cancer and collaboration with partners Assoc. Prof. David Thomas the development of individualised Study, kConFab familial breast cancer in Japan, Singapore, South Korea approaches to treatment. consortium and the International Surgical Oncology laboratory and the UK. Sarcoma Kindred Study, and in key Research in the program focuses Assoc. Prof. Wayne Phillips Alex is committed to translational collaborations with national and primarily on breast, upper gastrointestinal, research that aims to realise clinical international researchers. VBCRC Cancer Genetics laboratory prostate, ovarian, and sarcoma cancer benefits for patients at-risk-of or Prof. Ian Campbell types, and involves some of the largest diagnosed with gastrointestinal cancer. familial and population-based cancer kConFab ‘As a clinician, compassion and caring cohorts in the world. Ms Heather Thorne for patients are guiding principles; as a These studies address questions scientist, knowledge and scholarship of general importance to solid are my goals. Together, these cancers such as genome-wide principles guide me at Peter Mac.’ genetic and epigenetic changes during tumourigenesis; as well as more specific questions including inherited susceptibility to cancer, prediction of response to therapy, gene status linked to treatment and survival, the use of molecular profiling for accurate cancer diagnosis, and screening surveillance to improve detection and clinical management.

Cancer Genomics program 33 1.2.1 Cancer Genetics and Genomics laboratory 1.2.2 Sarcoma Genomics and Genetics laboratory

KEY 2010 RESEARCH ACHIEVEMENT Our studies with CCNE1 are typical RESEARCH FOCUS at WEHI. Neochromosomes are Amplification of cyclin E1 drives of much of the current work in our • Germline and somatic genetics supernumerary or marker chromosomes treatment failure in women with laboratory where we aim to develop of , focusing on observed in more than 80% of well- serous ovarian cancer useful diagnostic and therapeutic osteosarcoma and liposarcoma. differentiated liposarcomas, however approaches, but also seek to their structure and oncogenic properties Surgery followed by a combination understand the molecular wiring • Animal models of osteosarcoma are not fully understood. We used of and taxol form the and biological processes that drive and liposarcoma. next-generation sequencing of mainstay of treatment for women with the growth of tumour cells. • Translational and clinical research neochromosomes and their derived ovarian cancer. About 70 per cent of in sarcoma. transcriptome to comprehensively map those with the most common histotype, Reference: Etemadmoghadam D, George J, molecular variations associated with Cowin P, et al. Amplicon-dependent CCNE1 • Research into adolescent high grade serous cancers, have a expression is critical for clonogenic survival after well-differentiated liposarcoma. durable response to . treatment and is correlated with 20q11 and young adult cancers. However, the tumours of a significant gain in ovarian cancer. PLoS One 5, e15498, 2010. We have a long-standing interest in fraction of women are resistant to the molecule Wnt inhibitory factor-1 primary treatment, with a rapid return to KEY 2010 RESEARCH (WIF1) as a tumour suppressor in Research Leader: Prof. David Bowtell Research Leader: Assoc. Prof. David Thomas, osteosarcoma. In studies performed growth soon after the end of VCA Clinical Researcher Fellow ACHIEVEMENTS chemotherapy. Previously we by Dr Maya Kansara, ecombinant WIF1 The highlight of the year was the final protein suppresses tumour growth in Our laboratory focuses on the demonstrated that amplification of the publication of the results of a phase 2 The Sarcoma Genomics and a mouse model of osteosarcoma. molecular characterisation of ovarian 19q12 chromosomal locus is the most study using denosumab in patients with Genetics laboratory undertakes We are investigating the mechanism and gastric cancer, cancers of unknown important chromosomal copy number unresectable giant cell tumour of bone translational research into the inherited by which this occurs to determine the primary, and on understanding the role change associated with primary (Lancet Oncology). This study established and somatic genetic causes of sarcoma. clinical potential of this molecule. of the Siah E3 ligases in angiogenesis treatment failure. In our latest work, we a new paradigm for treatment for such Our research program is founded and cancer progression. have shown that CCNE1, which encodes patients, and has generated considerable To investigate the role of the on the Australasian Sarcoma Study CyclinE1, is a driver oncogene within the interest from the clinical community immune system in the development Group (ASSG), a national cooperative 19q12 locus. Knockdown of CCNE1 caring for patients with sarcomas. The of osteosarcoma we are undertaking research group which acts as a conduit RESEARCH FOCUS results in cell cycle arrest and overall response rate on this study was a systematic screen using a radiation for early phase clinical research arising attenuation of clonogenic survival an astonishing 86 per cent, with clinical model (45Ca) of osteosarcoma and • Genomic characterisation of from basic discoveries. We have a specifically in cells with amplification benefit commonly reported. The eventual knockout-mice deficient in immune human ovarian and gastric cancer. broad interest in cancers that affect of 19q12, demonstrating an oncogene role of denosumab in sarcomas remains cells or cytokines to investigate the role adolescents and young adults. • Coordination of the Australian addiction of these tumour cells. CyclinE1 an active subject for research. of these molecules in osteosarcoma Ovarian Cancer Study cohort. interacts with cell cycle kinases, including development and progression. These Cdx2, providing a therapeutic approach The International Sarcoma Kindred studies are giving insights into potential • Development of a molecular diagnostic to inactivating the protein complex Study, led by Dr Mandy Ballinger, has immunomodulatory targets for the for cancers of unknown primary. using small molecule inhibitors of kinase begun to generate research outcomes. treatment of osteosarcoma. • Biochemical and functional function. Approximately 20 per cent of Over 300 families have now been Recent work in the laboratory includes characterisation of Siah E3 ligases high grade serous cancers have enrolled onto this study across five development of a syngeneic mouse in cancer models. amplification of the 19q12 locus. national centres, with recruitment well exceeding projected rates. International model of osteosarcoma using cell • Development of novel small molecules CCNE1 gain is present in cells prior involvement has extended to India, lines derived from our radiaocarcinogen to chemotherapy, so it must provide Figure 1: Model outlining the stages of the targeted to the Siah proteins. initiation and progression of high-grade serious France, Italy, USA and the UK. Initial data model. The tumours that arise from a selective advantage to their growth, ovarian cancer. Our recent genomic studies in suggest a strong heritable component these cell lines are currently being independent of treatment. To better ovarian cancer have led us to a model of the characterised. This mouse model molecular evolution of high grade serous cancers, to sarcoma, and an unexpectedly high understand how CCNE1 amplification initiated by p53 loss and BRCA loss, deficiency incidence of what appear to be de will form an invaluable tool for interacts with other mutations, we in homologous recombination repair (HRR), novo mutations in the tumour suppressor, investigation of potential therapeutics mapped chromosomal aberrations that chromosomal instability and widespread copy in osteosarcoma as well as number (CN) change (Bowtell, 2010, Nature TP53. We have also begun to undertake correlated with 19q12 gain. Amplification Reviews Cancer 10, 803-08). Figure 1: Positron emission tomographic images deep sequencing of unexplained understanding the development of 20q11, involving the cell cycle protein demonstrating metabolic response to denosumab high risk families, in order to identify and progression of this disease. TPX2, was highly correlated with CCNE1 treatment of a patient with recurrent i schial Giant Cell Tumour of bone. the causal mutation. gain, suggesting that genes in the 20q11 Reference: Thomas DM, Henshaw R, Skubitz K, We have almost completed a definitive et al. Denosumab in subjects with giant cell tumour locus form part of a mutational network of bone: results from a phase 2 study. Lancet that controls the growth of this poor study of the molecular structure of a key Oncology, 11:275-80, 2010. prognosis tumour. molecular feature of liposarcomas — neochromosomes. These studies have been led by Mr Dale Garsed in collaboration with Dr Tony Papenfuss

Peter MacCallum Cancer Centre – Research Report 2010 Cancer Genomics program 35 1.2.3 Surgical Oncology laboratory 1.2.4 VBCRC Cancer Genetics laboratory

RESEARCH FOCUS we have demonstrated enhanced RESEARCH FOCUS • PI3-kinase signalling pathway. proliferation of epithelial cells lining the • Identification of genes involved mammary ducts and increased ductal in breast cancer predisposition • Links between Barrett’s branching during mammary gland through next generation sequencing. Oesophagus and the onset of development. These mice do eventually oesophageal adenocarcinoma. get mammary cancers but not for over • Genome-wide genome copy 12 months. This long latency period number analysis of breast ductal KEY 2010 RESEARCH ACHIEVEMENT suggests that PIK3CA mutation alone in situ identify markers The role of PIK3CA mutations is not sufficient to induce tumourigenesis of disease progression. in tumour development and that a ‘second hit’ (an additional • Next generation sequencing and Mutations in the PI3K gene, PIK3CA, mutation) in another gene is likely to function screens to identify driver are found at high frequency in many be required for tumour development. genes of ovarian tumourigenesis. human cancers, particularly colorectal Our studies are now focussing on • Integrated genomic analysis to identify and breast tumours. PIK3CA mutations identifying these secondary events genes involved in breast and ovarian Research Leader: Assoc. Prof. Wayne Phillips are common in many human tumours that cooperate with PIK3CA mutations Research leader: Prof. Ian Campbell, NHMRC . including breast cancer. to induce progression to cancer in Senior Principal Research Fellow the mammary gland. We are also The Surgical Oncology laboratory uses Our laboratory has developed a novel extending our studies to other cancer molecular and cellular approaches mouse model in which we can target The major focus of the Victorian KEY 2010 RESEARCH ACHIEVEMENT This unique cohort will recruit 100,000 expression of the common PIK3CA types by using this model to target the Breast Cancer Research Consortium to understand the development H1047R Victorian women and support a range H1047R PIK3CA mutation to other tissues. The building of a major cohort and progression of gastrointestinal mutation PIK3CA to specific tissues. (VBCRC) Cancer Genetics laboratory of research into breast cancer and In addition, our model will be a valuable to investigate issues in breast cancers and to identify new treatments. The mutant protein is expressed only is the identification of genes involved other important women’s health issues. tool for the pre-clinical testing of new cancer epidemiology and biology at normal levels and only in cells that in the predisposition, initiation Eventually it is anticipated that anti-cancer therapies that target the normally express PIK3CA, thus and progression of breast and The VBCRC Cancer Genetics laboratory Lifepool will expand to include PI3K pathway. replicating the physiological scenario ovarian cancer. uses an integrative genomics approach recruitment through BreastScreen to investigate genes involved in breast of a spontaneous mutation occurring Reference: Loi SB, Haibe-Kains F, Lallemand V, services in other states. This long-term in the endogenous PIK3CA gene. et al. PIK3CA mutations associated with gene and ovarian cancer, whereby data from cohort study will integrate clinical By targeting the PIK3CAH1047R mutation signature of low mTORC1 signalling and better several genome-wide array-based follow-up, epidemiological information outcomes in estrogen receptor positive breast to the mammary gland of the mouse cancer. PNAS, 107: 10208-13, 2010. platforms are combined to more rapidly and molecular profiling of breast define the critical cancer-causing genes. tumours detected through BreastScreen. A key focus of the laboratory is familial breast cancer, where the majority of Lifepool will perform nested case-control familial risk is yet to be attributed to studies on patients diagnosed with genetic variants. We are continuing breast cancer to better understand how to apply next generation sequencing factors such as mammographic density, to identify these genes. The ability to genetics and gene expression is identify disease-causing mutations associated with breast cancer risk and in high-risk breast cancer families has behaviour. By combining the information broad implications for those affected, provided by such a large group of in terms of risk assessment and women, Lifepool will support a range management, as well as treatment. of studies on prevention, screening and treatments aimed at reducing the A major new initiative during 2010 has impact of breast cancer. Lifepool has been the establishment of Lifepool been made possible through a $5m cohort. Headed by Ian Campbell, grant from the National Breast Cancer Lifepool is a collaboration between Peter Foundation Collaborative Grant scheme Mac, BreastScreen Victoria, University of for Breast Cancer Research, and in Melbourne School of Population Health partnership with Cancer Australia. and The Royal Melbourne Hospital. Figure 1: Whole mounts of the developing mammary gland from (A) wild type and (B) PIK3CA mutant mice at 12 weeks of age showing the increased ductal branching induced by expression of the PIK3CAH1047R mutation.

Peter MacCallum Cancer Centre – Research Report 2010 Cancer Genomics program 37 1.2.5 kConFab Cancer Genomics program – personnel

RESEARCH FOCUS Cancer Clinics with a unique opportunity Cancer Genetics Postgraduate Students VBCRC Cancer Genetics and Genomics laboratory laboratory • Germline screening for the known to meet and optimise clinical practice, Dr Rachel Conyers genes such as BRCA1, BRCA2, enabling the identification of individuals Head Dale Garsed Head ATM, CHEK2, PALB2 implicated in and families who carry pathogenic Prof. David Bowtell Sophie Young Prof. Ian Campbell breast, ovarian and prostate cancer the causation of breast and ovarian VCA Translational predisposing mutations (genetic faults) Peter Mac Research Fellow Research Fellows cancer, and a gene discovery search Research in Sarcoma Project for new cancer susceptibility genes. and rapidly translating research findings Dr Andreas Möller Lisa Devereux made by kConFab into clinical practice. Project Officer Dr Kylie Gorringe Research Fellows • Development of predictive risk models Anna Tarasova Dr Sally Hunter In recent times kConFab played an to determine which mutation carriers Dr Michael Anglesio Dr Ella Thompson increasing role in clinical trial activity. Dr Rita Busuttil International Sarcoma are at risk of developing breast or Kindred Study ovarian cancer and at what age. Examples of this activity include the Dr Prue Cowin Research Assistants IMPACT study, which is determining the Dr Dariush Etemadmoghadam Project Manager Samantha Boyle • Use of fresh normal and tumour utility of prostate cancer screening and Colin House Mandy Ballinger tissue collections for the isolation and new biomarker discovery amongst men David Choong Research Associate Research Administrator Research Manager: Heather Thorne identification of stem cells that may from mutation positive families, assisting Postgraduate Students be involved in cancer development. Dr Alex Boussioutas Faina Zlatsin with a carboplatin chemotherapy trial Jennifer Bearfoot for BRCA1 and BRCA2 mutation carriers, The Kathleen Cuningham Foundation • Delivery of clinically significant Senior Research Officers Research Assistant Sally Davis and more recently PARP inhibitor studies. Consortium for Research into Familial research mutation test results back Sian Fereday Jess McDonald Clint Johnson to the clinic and family. Joyce Lin Breast Cancer (kConFab) brings Researchers and clinicians using Nadia Tranficante Australasian together geneticists, clinicians, Wen Qiu • Translation of basic research the kConFab biospecimen and data Research Officer Sarcoma Study Group surgeons, genetic counsellors, resource have contributed to a large Manasa Ramakrishna discoveries into clinical practice, Deborah Giles Executive Officer psychosocial researchers, pathologists number of prominent national and Georgie Ryland such as new targeted therapies Dr Sally Whyte and epidemiologists from all over international studies in the past 12 Research Assistants like the PARPi inhibitors. kConFab Australia and . They months, including: Leanne Bowes Project Officer • Development of a resource to promote believe the causes and consequences Laura Galetta Sophie Gatenby (to Aug) Research Manager collaborative basic, translational • The first large Genome-Wide of familial predisposition to breast and Joy Hendley Charelle Byrne (from Sept) Heather Thorne and clinical research into familial Association Studies (GWAS – ovarian cancer can be understood only Andreea Iuga breast, ovarian, prostate and published in Nature Genetics) to Executive Director by a national effort at both the basic Mira Liu Surgical Oncology pancreatic cancer. identify risk modifier SNPs in breast laboratory Prof. Joe Sambrook (to July) and clinical levels. Elizabeth Loehrer cancer. Prof. Stephen Fox (from August) Alexandria McGearey Head • Identifying novel moderate — to Traci Tanti Assoc. Prof. Wayne Phillips Research Assistants KEY 2010 RESEARCH ACHIEVEMENTS high-risk breast cancer predisposing Kirsty Baron Postgraduate Students Senior Research Officer The unique kConFab biospecimen genes that are likely to be incorporated Lana Djandjgava Kathryn Alsop and data resource has become of into clinical practice over the next Dr Nicholas Clemons Dragana Prodanovic few years, using next generation Joshy George increasing value to Australian and Research Officers Danni Surace Jaclyn Sceneay international breast, ovarian and prostate sequencing technology Kylie Scott Christina Wong Dr Kate Brettingham-Moore cancer researchers alike, as seen from • A stem cell breast cancer research Dr Ivan Ivetac Johanna Stoeckert the number of approved projects using program has gained international Honours Student Dr Vincent Roh Dr Amber Willems this resource and from its contribution recognition through kConFab’s Heloise Halse Dr Anjali Tikoo Lynda Williams to the number of high profile publications. supply of prophylactic mastectomy Summer Scholarship Students Research Assistants Data Manager In addition to facilitating basic and specimens and tumours that led to Eveline Niedermier clinical research, kConFab has been the discovery of an intrinsic defect in Anna Chen Karen Montgomery instrumental in networking with the luminal progenitor cells, which appear Sarah Ftouni Anita Sridhar Familial Cancer Centres around the to be the target cell that gives risk Yuan Gao Christina Tucci Melanie Hawksworth country to recruit high-risk multiple to BRCA1-associated breast cancer Postgraduate Students breast, ovarian and prostate cancer (Nature Medicine, 2009). Executive Assistant Lauren Hare families for research, and has played to Prof. David Bowtell Shze Yung Koh a key role in translating its research Reference: Antoniou AC, Wing X, Frederickson ZS, et al. A genome-wide association study identifies Linda Stevens Mr Charles Pilgrim findings to ensure high quality, a 19p13 locus that modifies the risk of breast cancer Dr Mirette Saad standardised clinical care throughout in BRCA1 mutation carriers and is associated Sarcoma Genomics Dr Henry To Australia. This has been achieved by with receptor-negative breast cancer and Genetics laboratory in the general population. Nature Genetics, Dr Thang Tran the organisation of annual scientific 42: 885–892, 2010. Head meetings that provide the Family Assoc. Prof. David Thomas Postdoctoral Researcher Dr Maya Kansara Research Assistant Tiffany Pang

Peter MacCallum Cancer Centre – Research Report 2010 Cancer Genomics program 39 1.3 Growth Control and Differentiation program 1.3 Growth Control and Differentiation program

Amee George is a postdoctoral research fellow at the University Understanding protein chemistry, signal transduction, of Queensland currently working on a collaborative project in the Growth cell biology and how these processes affect Control laboratory at Peter Mac. Her research focuses on understanding differentiation and cancer cell growth the mechanisms by which G protein- coupled receptors (GPCRs) hijack The Growth Control and Differentiation The program has recently made Growth Control laboratory other growth factor receptor signalling program brings together three groups ground-breaking discoveries linking Assoc. Prof. Ross Hannan pathways. By piecing together the with extensive and complementary signalling via the key PI3K/AKT/mTOR highly complex signalling networks expertise in areas ranging from and c-MYC growth control pathways Molecular Oncology laboratory involved in this process, Amee hopes proteomics and protein chemistry, to the regulation of ribosome synthesis Assoc. Prof. Grant McArthur to better understand the subsequent through signal transduction and cell and function. We aim to use this implications for cellular growth Protein Chemistry laboratory biology to the regulation of gene knowledge to develop novel therapeutic Assoc. Prof. Rick Pearson and malignant transformation. transcription and protein translation. approaches that target differentiation, cell cycle and cell growth. In addition, A major focus of our work is in together with the Cancer Therapeutics understanding the mechanisms of program (pg 62), we have established regulation of ribosome biogenesis, models of a range of tumours including and protein translation, and how these ovarian and prostate cancer and processes impact on differentiation lymphoma. These systems are being and are corrupted in tumour cells. used to investigate novel applications This is a critical area of cancer of targeted therapeutics and the research as accelerated cell growth program is ideally poised to translate and increased protein synthesis due to discoveries on fundamental aspects increased levels of functional ribosomes of cancer growth control into the clinic. are major features of tumour formation In particular, we have developed and progression. Conversely, cellular a completely new strategy for the differentiation is associated with based on disruption reductions in these processes and of RNA Polymerase I (Pol I) and we have often antagonises carcinogenesis. collaborated with Cylene Pharmaceuticals A number of current projects employ to develop the world’s first small molecule state-of-the-art biochemistry, molecular selective inhibitor of Pol I transcription and cell biology to characterise the CX-5461. We plan to begin the first-in- basis of the regulation of these human trials with this drug at Peter Mac fundamental processes. in cancer patients in 2012. This work represents a major scientific advance and paradigm shift in our understanding of one of the most fundamental and universally conserved cellular functions, ribosome biogenesis. We predict it will have major impact on the fields of cell biology and cancer.

Growth Control and Differentiation program 41 1.3.1 Growth Control laboratory 1.3.2 Molecular Oncology laboratory

RESEARCH FOCUS vRNA interference mediated knockdown RESEARCH FOCUS We examined the effects of CHK • Epigenetic mechanisms regulating of UBF or Rrn3 expression in Eμ-MYC • The interaction between the inhibitor treatment on lymphoma cells ribosomal gene transcription lymphoma cells reduced rDNA MYC oncogene and the PI3K with inherent DNA damage due to by RNA Polymerase I. transcription to the level in wild type pathway in regulating cancer MYC-driven replication stress. Eμ-myc B-cells. This resulted in a proliferative murine lymphoma cells showed a • Basic mechanisms underlying progression and maintenance. disadvantage of the lymphoma cells, dramatic increase in the extent of DNA cell growth control. • Fundamental mechanisms of both due to rapid cell death. To establish damage within an hour of treatment regulation of cell growth by MYC. • Dysregulation of ribosome whether this heightened dependence with PF-0477736. We observed biogenesis during cancer. on rDNA transcription could be exploited • Targeting of CHK1 kinase for cancer extensive caspase-dependent apoptosis • Functional screens for novel tumour as a therapeutic target for c-MYC driven treatment. and subsequent cell death in vitro and suppressors in breast cancer. cancer, we collaborated with Cylene • Targeting of BRAF Kinase for cancer in vivo. Apoptotic cell death was Pharmaceuticals to test a ‘first in class’ treatment. preceded by accumulation of DNA small molecule inhibitor of Pol I (CX- • Targeting of retinoic acid receptors damage and a DNA damage response KEY 2010 RESEARCH ACHIEVEMENT 5461) in this model. Treatment of the for the treatment of acute myeloid (DDR). In all cases, the level of DNA Research Leader: Assoc. Prof. Ross Hannan, Is dysregulation of ribosome animals with CX-5461 delayed sacrifice Research Leader: Assoc. Prof. Grant McArthur, leukaemia (AML). damage following treatment was the NHMRC Senior Research Fellowship biogenesis a necessary step due to disease of transplanted Eμ-MYC Cancer Council Victoria Sir Edward Dunlop most consistent indicator of sensitivity Clinical Cancer Research Fellow in malignant transformation? tumours, which was accompanied by to various CHK inhibitors. a period of complete remission with no KEY 2010 RESEARCH ACHIEVEMENT We propose that inhibitors of CHK The focus of the Growth Control The MYC-family of plays identifiable tumour cells in the peripheral The Molecular Oncology laboratory CHK inhibitor therapeutics can act in a synthetically lethal manner laboratory is to understand the a prominent role in cancer and has been blood. Importantly, death of malignant investigates new targets for cancer display efficacy as single agents in cancers with replication stress as molecular basis of the regulation of the implicated in the regulation of ribosome B-cells in response Pol I inhibition treatment that control cell growth, in MYC-driven lymphomas a result of these cancers being reliant ribosomal gene transcription by RNA assembly and function. We were the first occurred rapidly via apoptosis and division and differentiation. on a CHK-mediated DDR for cell survival. Polymerase I, and how dysregulation to demonstrate that c-MYC can regulate was not due to ribosome insufficiency. CHK proteins function as effectors of Our results suggest that CHK inhibitors of this process contributes to the transcription of the ribosomal RNA cell cycle checkpoint arrest following These data provide the first evidence would be beneficial therapeutic agents process of malignant transformation. genes (rDNA) by RNA Polymerase I DNA damage. Small molecule inhibitors that dysregulation of rDNA transcription in MYC-driven malignancies. (Pol I) through upregulation of the of CHK proteins such as PF-0477736 is required for MYC driven cancer essential Pol I transcription factor UBF. are under clinical evaluation in and is a therapeutic target for treatment combination with DNA damaging Interestingly, upregulation of rDNA of malignancy. Ongoing studies are chemotherapeutic agents. transcription is a frequent event during exploring the molecular mechanisms malignant transformation, leading us responsible for the selective therapeutic to propose the provocative hypothesis effectiveness of inhibiting Pol I that the oncogenic potential of MYC is transcription in Eμ-MYC lymphomas. directly related to its ability to modulate rDNA gene transcription. We have tested References: Sanij E, et al. UBF levels determine this hypothesis in a transgenic model of the number of active ribosomal RNA genes in mammals. J Cell Biol. Dec 29;183(7):1259 –74, 2008. B-cell lymphoma (Eμ-MYC) in which the malignancy is dependent on Sanij E, Hannan RD. The role of UBF in regulating the structure and dynamics of transcriptionally overexpression of c-MYC. This model active rDNA chromatin. Epigenetics. Aug;4(6): is associated with a robust upregulation 374 – 82, 2009. of rDNA transcription and increased expression of the rDNA transcription factors UBF and Rrn3.

Figure 1: Eμ-myc lymphoma cells following PF-0477736 treatment. A: Lymphoma sections stained with H&E and the Tunnel assay showing CHK inhibitor induced apoptotic cell death. B: Stained lymphoma cells displaying CHK inhibitor induced DNA damage by γH2AX staining and the Comet assay.

Figure 1: Fluorescent in situ hybridisation (FISH) analysis of ribosomal RNA (red) in Eμ-MYC lymphoma cells. rRNA synthesis is significantly reduced after 1hr treatment with 100μM CX-5461. Nuclei were visualised by DAPI (blue).

Peter MacCallum Cancer Centre – Research Report 2010 Growth Control and Differentiation program 43 1.3.3 Protein Chemistry laboratory Growth Control and Differentiation program – personnel

RESEARCH FOCUS The Protein Chemistry laboratory Growth Control Molecular Oncology Protein Chemistry laboratory laboratory laboratory • Understanding of the signal and other groups have shown that this transduction pathways underpinning pathway is activated in over 65 per cent Head Head Head cell growth control. of ovarian cancers and our research Assoc. Prof. Ross Hannan Assoc. Prof. Grant McArthur Assoc. Prof. Rick Pearson aims to take a range of complimentary • Biochemical and cell biology analysis cell biology, biochemical and genomic Research Officers Clinical Fellows Senior Research Officer of the role of deregulated cell growth approaches to characterise the role of Dr Amee George Dr Rachel Roberts-Thompson Dr Kate Hannan in cancer. activation of the pathway in Dr Nadine Hein Dr Prudence Scott Research Officer • Cell biology and genomic research tumorigenesis and to identify key Dr Elaine Sanij Senior Research Officers into the pathogenesis of ovarian pathways that also contribute to the Dr Megan Astle Research Assistants Dr Petranel Ferrao cancer. development of ovarian cancer. Research Assistant Analia Lesmana Dr Kathryn Kinross • High throughput functional screens It is hoped that these studies will Abigail Peck Dr Gretchen Poortinga Kim Riddell to identify novel genes important provide a basis for generation of new in breast and ovarian cancer. therapeutics useful for second-line Postgraduate Students Research Officer PhD Students Benjamin Green Research leader: Assoc. Prof. Rick Pearson, treatment of this cancer. Megan Bywater Dr Tiffany Somers-Edgar NHMRC Senior Research Fellow Maressa Bruhn Rachel Lee KEY 2010 RESEARCH ACHIEVEMENT In 2010, we have used specific inhibition Research Assistants Jane Lin of AKT to show it is necessary for rDNA Rachel Lee The role of the P13K/AKT signalling Greg Leong Patricia Bukczynska Mirette Saad The major focus of the Protein transcription independent of mTORC1 Margarete Kleinschmidt Chemistry laboratory is to understand in cancer signalling. Furthermore, expression of Jane Lin Honours Students Jaclyn Quin Rachel Ramsdale the molecular basis of the regulation The importance of deregulation of constitutively active AKT revealed AKT Frances Barber Nicola Janiel Cranna of the PI3K/Akt/mTOR/S6K signalling mTOR/S6K signalling in cancer became is sufficient to drive ribosomal RNA Laboratory Technician Don Cameron (The University of Melbourne) pathway, and to use this knowledge clear when it was shown to be a major synthesis, ribosome biogenesis and cell Kym Stanley Jennifer Devlin growth independent of growth factors. Jeannine Diesch to address how deregulation of this downstream mediator of signalling via Postgraduate Students Summer Scholarship Student AKT cooperates with c-MYC to hyper- (The University of Melbourne) process may contribute to cancer. the PI3K/AKT axis that is deregulated Dr Arun Azad Stephanie Munari activate rRNA synthesis and ribosome Omer Gilan in a high proportion of human tumours. Megan Bywater biogenesis identifying the AKT/mTORC1/ (The University of Melbourne) Indeed, small molecule PI3K and mTOR Dr Lynette Chee Growth Control and MYC network as a master controller of inhibitors are showing promise as Honours Student Dr Debbie Handolias Differentiation Program cell growth. Consistent with this concept, anti-cancer agents in clinical trials. Thus, Don Cameron Dr Paul Wood Laboratory Manager the second major theme of our research AKT activity is required for maximal Katrina Wilson is to understand the mechanisms by activation of rRNA synthesis in MYC Summer Scholarship Students Summer Scholarship Student which PI3K/AKT signalling contributes driven lymphoma cells. Importantly, Alison Boast Zhen Tao Li to cancer and to gauge the contribution AKT inhibition results in reduced rDNA Michael Issa Assistant to Grant McArthur made by the mTOR pathway and transcription that is associated with Anna Caldwell uncontrolled growth signalling. reduced lymphoma cell viability and apoptotic cell death. These data strongly implicate decreased ribosome biogenesis as a fundamental component of the therapeutic response to AKT inhibitors in malignant disease. This work was the subject of an invited oral presentation entitled ‘AKT cooperates with c-MYC to control ribosome biogenesis and growth via mTORC1-dependent and independent pathways’ by Assoc. Prof. Rick Pearson at the OzBio2010 conference in Melbourne in September 2010.

Figure 1: Akt increases rDNA transcription. (A) BJ-Tert cells labelled with EU, which incorporates into newly transcribed RNA, exhibit high EU signal in the nucleolus (arrow) marking the site of rDNA transcription. Nucleolar EU intensity is higher in Myr-Akt expressing cells compared to control cells reflecting enhanced rDNA transcription (arrowheads).

Peter MacCallum Cancer Centre – Research Report 2010 Growth Control and Differentiation program 45 1.4 Cancer Cell Biology program 1.4 Cancer Cell Biology program

Sue and Ygal Haupt were brought together by an interest in biological Utilising multidisciplined approaches to explore research. Research experience at the Weizmann Institute and the the cross-talk between cancer and surrounding cells, Hebrew University in Israel resulted in a milestone discovery delineating factors influencing cell growth, differentiation, survival how the most important tumour suppressor p53 is controlled. and senescence, with a strong focus on the genetic Their recruitment to Peter Mac two years ago brought us their control of cancer spread internationally recognised expertise to lead this field of research which The Cancer Cell Biology program is Recent advances in our ability to study Cell Cycle and Cancer has far reaching clinical implications, the most diverse program of research the growth, proliferation and of Genetics laboratory including the development of new at Peter Mac. The program spans epithelial tumour cells have come from Dr Patrick Humbert approaches to anti-cancer therapy. developmental to tumour biology and approaches that allow three dimensional Cell Cycle and Their relocation closes a personal connects investigators working with cultures of mammary, intestinal and Development laboratory circle in their family; Sue’s father, flies, mice and primary tissue from skin cells. These have provided new Assoc. Prof. Helena Richardson Dr. John Moody, while working cancer patients. opportunity to examine cells from mice in India in the 1950s, was visited that have been genetically manipulated The program focuses on the high Cell Growth and by his former pathology professor — on a gene by gene basis or by Proliferation laboratory incidence epithelial-derived tumours Sir Peter MacCallum, and accepted introducing agents that interfere with such as breast, prostate and colon. Dr Kieran Harvey his invitation to bring back to Australia endogenous gene function on a whole As tumours arise amid, and in Differentiation and his expertise in treating oral cancers. genomic scale. communication with, surrounding normal Transcription laboratory cells and the extracellular matrix, Exploiting these insights will be central Assoc. Prof. Rob Ramsay attention to the stromal and immune to how tumours can be effectively and environment is an important area of selectively targeted as well as how Epithelial Stem Cell Biology laboratory investigation. These non-tumour normal tissue can be spared adverse elements play a central role in promoting and lasting damage. Agents that are Dr Pritinder Kaur tumour growth and metastasis. aimed at addressing this direct clinical Metastasis Research laboratory need are also being developed within Epithelial cells demand tight, ordered Assoc. Prof. Robin Anderson the program. One of the most exciting connections with their neighbours and developments that is impacting the Molecular Radiation disruptions to these interactions affect Cancer Cell Biology program is the Biology laboratory cell polarity and these mark early events heightened interaction with clinical Assoc. Prof. Roger Martin in the transformation process. Similarly, researchers across Peter Mac. pathways that have been employed Tumour Suppression laboratory Structured and informal meetings across evolution that control the size Assoc. Prof. Ygal Haupt around tumour streams are now of organs also seem to be targeted early common place, opening opportunities Cell Polarity/Tissue Architecture in tumourigenesis. Much interest in the for clinic investigators to spend more Program properties normally attributed to stem time in laboratories and for researchers - Cell Cycle and Cancer Genetics cells such as self-renewal, impeded to refocus their investigations within (Dr Patrick Humbert) differentiation and extended proliferative the program. capacity have captured the attention - Cell Cycle and Development of cancer biology. Several program (Assoc. Prof. Helena Richardson) members have long standing interests - Immune Signalling (Dr Sarah Russell, in stem cell biology and accordingly see Cancer Immunology program have applied their laboratories to pg 28) address these properties.

Growth Control and Differentiation program 47 1.4.1 Cell Cycle and Cancer Genetics laboratory 1.4.2 Cell Cycle and Development laboratory

RESEARCH FOCUS How Scribble regulates oncogenic KEY 2010 RESEARCH ACHIEVEMENT These differences highlight the context • Cell biology and genetic analysis Ras signalling is currently unknown. The RhoGEF/Rho-family/JNK dependent nature of JNK in cooperative of cell polarity protein function We have conducted an unbiased pathway is an important driver tumourigenesis. We also found that + in 3D epithelial cell culture models. large-scale, functional genomics screen for cooperative tumourigenesis HER2 human breast cancers (where to identify the genetic requirements in Drosophila melanogaster human-epidermal-growth-factor-2 is • Generation and analysis of Genetically for Scribble to suppress Ras-driven overexpressed and Ras signalling Engineered Mouse Models (GEMMs) cell transformation, combining RNAi To identify novel genes that cooperate upregulated) show a significant V12 to investigate the role of polarity technology with Next Generation with Ras in tumourigenesis, we carried correlation with a signature representing proteins in cancer progression Sequencing. We have screened out a genome-wide screen for genes JNK pathway activation. Our genetic and organ development in vivo. approximately 20,000 shRNA constructs that when overexpressed throughout analysis in the Drosophila whole tissue • Analysis of cell polarity proteins and from the Open Biosystems human the developing Drosophila eye, system revealed that Rho1 and Rac V12 gene alterations in human cancers. genome-wide miR30-based lentiviral enhanced Ras -driven . are important for the cooperation V12 • Large Scale RNAi functional screens shRNA library, utilising the well defined Amongst the Ras -cooperating genes of RhoGEF2 or Pbl over-expression, to identify effectors of Scribble function. soft agar anchorage independent colony identified were Rho-family GTPases, and of mutants in polarity regulators, assay. Rho1 and Rac1, and their regulators, Dlg and aPKC, with RasV12 in the whole Research leader: Dr Patrick Humbert, • Collaborative analysis of tissue polarity Research leader: Assoc. Prof. Helena Richardson, NHMRC Senior Research Fellow RhoGEF2 and pbl (Ect2 homolog). tissue context. NHMRC CDA Research Fellow in cancer and development with the Through this approach, we have Russell and Richardson laboratories. identified more than 100 candidate In a clonal setting, which reveals genes Collectively our analysis reveals the conferring a competitive advantage over The Cell Cycle and Cancer Genetics genes that were significantly enriched The Cell Cycle and Development importance of the RhoGEF/Rho-family/ wild-type cells, Rac1, an activated allele laboratory investigates the fundamental in our selected sample sets, identifying program uses the model organism, the JNK pathway in cooperative KEY 2010 RESEARCH ACHIEVEMENT of Rho1 (Rho1V14), RhoGEF2 and pbl V12 role of tissue organisation and them as important regulators and vinegar fly, Drosophila, to dissect tumourigenesis with Ras . This cooperated with RasV12, resulting asymmetry on cancer progression, An extensive cell polarity network effectors of Scribble’s tumour the mechanism by which cell polarity research has important implications in reduced differentiation and large with the aim of identifying novel suppresses the oncogenic functions suppressive functions in mammalian (shape) regulators and Extra Cellular for understanding and developing novel of Ras through regulation of systems. We have subsequently invasive tumours. Expression therapeutic approaches to combat therapeutic strategies. Matrix (ECM) proteins affect signalling V12 sustained MAPK signalling performed both primary and secondary pathways to promote the hallmarks of of RhoGEF2 or Rac1 with Ras Ras-mediated human cancers. validation experiments for a number upregulated Jun kinase (JNK) activity, Scribble is a core polarity regulator first cancer — increased cell proliferation, Reference: Brumby, et al. Genetics 2011. of key targets, confirming not only their and JNK upregulation was essential identified in Drosophila and shown to survival, prevent differentiation and Upper image: Identification of Novel Ras- requirement for the inhibition of Ras- for cooperation. However, in the whole have important roles in the regulation of induce invasion. We also are examining Cooperating Oncogenes in Drosophila driven oncogenesis by Scribble but also how cell polarity regulators cooperate tissue system upregulation of JNK alone melanogaster: A RhoGEF/Rho-Family/JNK tissue architecture and cell proliferation. Pathway Is a Central Driver of Tumorigenesis. their ability to cooperate with oncogenic with oncogenes in tumourigenesis, was not sufficient for cooperation with In addition, Scribble loss cooperates V12 Brumby AM, Goulding KR, Schlosser T, et al. Ras to drive invasive phenotypes in vitro. Ras , whilst in the clonal setting JNK with activated oncogenes Ras or Notch and are carrying out screens to identify Genetics. 2011 May;188(1):105-25. Epub The top ranked hits are also independent upregulation was sufficient for RasACT- 2011 Mar 2. to give rise to invasive and metastatic small molecule inhibitors of tumour predictors of outcome in breast cancer mediated tumourigenesis. tumours in Drosophila. growth in vivo. Lower image: Lgl, the SWH pathway patients. One common function of these and tumorigenesis: It’s a matter of context JNK upregulation was also & competition! Grzeschik NA, Parsons LM, Our laboratory has recently shown top hits appears to be the regulation sufficient to confer invasive growth of Richardson HE. Cell Cycle. 2010 Aug 15;9(16): that loss of the mammalian homologue V12 of sustained MAPK signalling. RESEARCH FOCUS Ras -expressing mammalian MCF10A 3202-12. Epub 2010 Aug 10. of Scribble can similarly cooperate breast epithelial cells, but did not affect • Mechanism by which cell polarity with activated H-Ras to drive invasion proliferation in culture. of mammary epithelial cells in 3D regulators, including the junctional organotypic culture. Conversely, we also neoplastic tumour suppressor genes, Figure 1: Top Panels: Cooperation of Rac1 lgl/scrib/dlg, affect cell proliferation, with RasV12. Clones are marked by GFP (green). observe suppression of Ras-mediated Rac1 + RasV12 clones massively overgrow and cell transformation phenotypes survival and tumourigenesis. invade between the brain lobes (BL), relative to through ectopic expression of Scribble, • Role of the extracellular matrix protein wild type control clones in the developing eye. including loss of polarity, invasion Sparc as an invasion/metastasis- Bottom Panels: Blocking JNK in lgl mutant in 3D culture and importantly, suppressor. clones results in an invasive phenotype. Clones are marked by GFP (green). When JNK is blocked anchorage independent growth. • Modelling cooperative tumourigenesis using a dominant negative transgene (BskDN) in lgl mutant clones the mutant tissue overproliferates in Drosophila — epithelial and and becomes highly invasive, as evidenced by GFP+ paediatric brain tumours: tissue throughout the body of the developing fly. - The mechanism of cooperation of cytoskeletal regulators with oncogenic Ras in tumourigenesis — role of JNK signalling. - The mechanism of cooperation of BTB/POZ domain Zn finger proteins in cooperation with polarity mutants. - Building models of paediatric brain tumours in Drosophila, and investigation of the cytoskeleton in tumourigenesis. - Screening for anti-cancer drugs Peter MacCallum Cancer Centre – Research Report 2010 using Drosophila cancer models. Cancer Cell Biology program 49 1.4.3 Cell Growth and Proliferation laboratory 1.4.4 Differentiation and Transcription laboratory

RESEARCH FOCUS Using Drosophila melanogaster RESEARCH FOCUS When Myb is mutated profound stem • Developmental organ size control imaginal discs we found that Salvador- • Gastrointestinal epithelial tissue cell recovery defects are marked. Warts-Hippo pathway activity is repressed in the vinegar fly, Drosophila homeostasis and early events These defects are most severe in regenerating tissue and that Yorkie melanogaster. that initiate cancer. when mice are subjected to radiation is rate-limiting for regeneration of • Functional characterisation of • Mammary development, stem exposure. The second unanticipated the developing wing. We found that the Salvador-Warts-Hippo tumour cells and carcinogenesis. discovery is that when we delete Myb, regeneration is compromised in Dachs suppressor pathway in Drosophila. specifically in the mammary gland, mutant wing discs, but that proteins • Control of transcriptional elongation. tumourigenesis is essentially ablated • Investigation of the Salvador-Warts- in addition to Fat and Dachs are likely • Chromosome stability, radiation without any lasting effect on mammary Hippo tumour suppressor pathway to modulate Yorkie activity in responses and DNA Repair. gland function. This is of considerable in human cancer. regenerating cells. • Translation of basic research note, as our observation suggests there Our findings reveal the importance of discoveries into new therapies is a critical Myb-dependent window KEY 2010 RESEARCH ACHIEVEMENT Yorkie hyperactivation for tissue and vaccines. that affects mammary cancer. This may regeneration and suggest that multiple speak to the epidemiological data in The Salvador-Warts-Hippo organ- Research leader: Dr Kieran Harvey, upstream inputs, including Fat- Research leader: Assoc. Prof. Rob Ramsay, women that suggests that some key size control pathway controls Viertel Senior Research Fellow Dachsous signalling, sense tissue NHMRC Senior Research Fellow KEY 2010 RESEARCH ACHIEVEMENT events in setting up mammary cancer regenerative tissue growth damage and regulate Yorkie activity The role of Myb in the regulator of occur in or around puberty. Finally, we The Cell Growth and Proliferation During tissue regeneration, cell during regeneration. The Differentiation and Transcription stem and progenitor cell populations have a strong interest in chromosome proliferation replaces missing structures cohesion mediated by proteins that laboratory studies mechanisms that Reference: The Salvador/Warts/Hippo pathway laboratory investigates mechanisms The laboratory had previously proposed to restore organ function. Regenerative controls regenerative tissue growth in Drosophila hold chromatids together during mitosis. control organ size during development, of transcriptional control of differentiation a direct role for Myb in regulating stem potential differs greatly between organs melanogaster. Grusche FA, Degoutin JL, One of these, Rad21, is very important in and how deregulation of these processes Richardson HE, et al. Dev Biol. 2011 Feb and carcinogenesis in epithelial cells in the GI. The most evident GI stem and organisms; for example some this function and we now have confirmed contributes to human cancer. 15;350(2):255-66. Epub Nov 25, 2010. tissues. These include gastrointestinal, cell gene is Lgr5 which we have now amphibians can re-grow entire limbs that it is over-expressed, and is of mammary, epidermal and neurogenic confirmed is a direct Myb target. whereas mammals cannot. The process tissues. We are particularly interested prognostic significance in breast cancer. of regeneration relies on several signalling in stem and progenitor cell regulation pathways that control developmental in these compartments. tissue growth, and implies the existence of organ size-control checkpoints that regulate both developmental, and regenerative, growth. The Salvador-Warts-Hippo pathway limits tissue growth by repressing the Yorkie transcriptional coactivator. Several proteins serve as upstream modulators of this pathway including the atypical cadherins, Dachsous and Fat, whilst the atypical myosin, Dachs, functions downstream of Fat to activate Yorkie. Figure 1: Tissue injury is induced in cells marked in green through expression of a pro-death gene, leading to apoptosis of some cells, marked by staining for Caspase 3 in blue. Remaining cells of the tissue can regenerate the missing structures. Our laboratory has shown that the Hippo pathway, whose output is shown in red, is important for this regenerative response.

Figure 1: Growing the gut in plastic dishes. Recent advances in the culturing of small intestinal (SI) stem cells are serving the DT lab in their study of signalling pathways that affect stem cell function and cancer development. Images show organoid cultures at different times of culture and the cartoon indicates the position of the crypt-like structures (blue cells) that feed into the red region that ultimately form villi. Thus the organoids have all the cell types of the SI epithelium including the stem cells.

Peter MacCallum Cancer Centre – Research Report 2010 Cancer Cell Biology program 51 1.4.5 Epithelial Stem Cell Biology laboratory 1.4.6 Metastasis Research laboratory

RESEARCH FOCUS We have demonstrated a novel role RESEARCH FOCUS complexes to repress gene expression • Tissue reconstitution ability of epidermal for these cells as CAFs. Specifically, • Development of animal models and has recently been found to stem cells and their cycling progeny. ovarian cancer patients carrying the of tumour growth and spontaneous associate with enhancer regions to pericyte gene signature are predisposed promote transcription of genes nearby. • Role of pericytes in homeostasis, metastasis. to having a higher risk of relapse and Not surprisingly, emerging evidence tissue repair and cancer. • Identification of genes that control lower overall survival, suggesting that implicates aberrantly expressed ncRNA the process of metastasis. • Molecular profiling of epidermal pericyte involvement is a strong predictor in the development of diseases, stem cells and their progeny. of recurrent cancer and mortality. • Development of molecular including cancer. Importantly this high-risk patient group targeted therapies to prevent • Molecular and cellular cross-talk Dr. Richard Redvers in our laboratory was distinct from the groups identified or treat metastatic disease. between the epidermis and dermal has further developed a model of by an angiogenic signature, suggesting microenvironment during homeostasis spontaneous breast cancer metastasis, a more direct role for pericytes in and cancer. isolating many independent sublines increasing tumour growth. Consistent KEY 2010 RESEARCH ACHIEVEMENT representing a wide spectrum of with this, co-injection of an ovarian A functional genomics screen metastatic capacity and sites of distant KEY 2010 RESEARCH ACHIEVEMENT cancer cell line (OVCAR-5), with implicates a novel class of molecules Research Leader: Dr Pritinder Kaur, Research leader: Assoc. Prof. Robin Anderson, dissemination. Using these lines, NHMRC Senior Research Fellow pericytes resulted in accelerated National Breast Cancer Foundation Career Fellow in breast cancer metastasis Dermal pericytes can act as cancer he has recently completed a functional tumour-forming ability in vivo. Pericytes associated fibroblasts For almost 50 years after the discovery genomics screen to identify genes were also able to enhance the intrinsic of DNA, it was universally accepted regulating the spread of tumour cells The Epithelial Stem Cell Biology Cancer associated fibroblasts migratory and invasive capacity of to other organs in the body, is a that large regions of the genome to lungs and bone. Significantly, a long laboratory studies the role of skin (CAFs) are a heterogeneous population OVCAR-5 cells in vitro. major cause of cancer related deaths. stem cells and their microenvironment of cells with a broadly similar phenotype, Our research aims to identify the amounted to ‘junk DNA,’ exhibiting ncRNA was the most upregulated in tissue renewal and carcinogenesis. but with the common ability to promote Taken together, these results suggest molecular events that control neither transcription nor function. transcript in vivo in tumour cells (311- The benefits of this research to patients cancer growth. We have studied the that CAFs can originate from pericytes metastasis to enable the development It has recently become apparent that fold, p=2.82x10-4) derived from the include a greater understanding of the role in cancer progression of a particular and the genes they express may be of new therapies that prevent transcription of the human genome metastatic cohort. Importantly, his mechanisms by which the mesenchymal stromal cell type: the pericyte. Pericytes useful prognostic tools in predicting metastasis from occurring or that is far more pervasive than originally screen also revealed a role for numerous microenvironment promotes normal are wellknown to stabilise blood-vessel patient survival. Current work is aimed kill secondary tumours before they thought. There is now virtual consensus other long ncRNAs whose functional role tissue replacement which will endothelial cell function both during at identifying the cellular and molecular cause organ failure and death. on the existence of a novel class of in metastasis has yet to be determined. events by which pericytes contribute to transcripts known as long non-coding be useful in designing tissue homeostasis and tumour-associated Clearly, this novel class of molecules tumour development. The data obtained RNAs (ncRNAs). regenerative therapies; and how the angiogenesis. represents an important area of will assist in developing potential targets microenvironment can be hijacked Numerous approaches have revealed metastasis research that we and others for anti-cancer therapy. to achieve cancerous growth. an abundance of transcripts with low are only just uncovering. Ongoing Knowledge gained in the latter Metastasis, or the spread of cancer or no protein-coding potential, many research will focus on the underlying aspect is being used to develop of which exhibit temporal and tissue- mechanisms of action of these potential better diagnostic tools for patients with specific expression patterns, are highly modulators of metastasis, with the aggressive epithelial cancers including conserved across species and have potential to uncover new therapeutic ovarian and head and neck cancers. demonstrable functionality in a variety strategies for patients with advanced of contexts. ncRNA transacts breast cancer, whose prognosis transcriptional and post-transcriptional is currently very poor. regulation, guides chromatin-modifying

Figure 1: Pericytes promote promote the growth of OVCAR-5 tumours in vivo. (a) Co-injection of ovarian cancer cells (OVCAR-5) cells with cultured pericytes p4 (T+P) at a 10:1 ratio results in accelerated tumour growth compared to ovarian cells alone (T) in a subcutaneous xenograft model in nude mice with time taken to reach a volume of 200 mm3 being 7 days earlier (n=3; 15 mice per group). (b) Representative images of tumours excised from mice at end point of experiment.

Figure 1: Measurement of breast cancer growth in the mammary glands of mammalian models with or without treatment with a new experimental compound designed to inhibit primary tumour growth and metastasis. The tumour cells have been engineered to express luciferase which releases light when the enzyme substrate, luciferin, is injected into the models.

Peter MacCallum Cancer Centre – Research Report 2010 Cancer Cell Biology program 53 1.4.7 Molecular Radiation Biology laboratory 1.4.8 Tumour Suppression laboratory

RESEARCH FOCUS KEY 2010 RESEARCH ACHIEVEMENT RESEARCH FOCUS Interplay between mutant p53 • Continuing development of a new Development of new DNA-binding • Identification of key determinants of and PML in cancer development class of DNA-binding radioprotecting radioprotector drugs regulation of the tumour suppressors Mutations in p53 are found in nearly drugs, exemplified by the initial lead p53 and the promyelocytic leukemia During 2010,the laboratory made good 50 per cent of human cancers. Certain methylproamine, to identify improved (PML) protein: implication to the progress in the project aimed at mutations in p53 provide a ‘gain radioprotectors, in a program of treatment of lymphomas. developing new radioprotecting drugs of function’, including the induction research supported by that could be applied to normal tissues • Definition of the regulatory mechanisms of chemoresistance, and enhanced a Licensing Agreement with Sirtex to reduce the side effects of cancer and function of mutant forms of p53. proliferative and metastatic potential, Medical.The new analogues are being radiotherapy. • Investigation of the involvement of the thereby making them attractive evaluated as topical radioprotectors. therapeutic targets. We have recently Starting with the lead drug E6AP-PML axis in cancer development, • Design and synthesisi of minor with a focus on prostate cancer. identified physical and functional groove-binding DNA ligands labelled methylproamine, more than 150 interaction between PML and mutant • Identification of novel pathways of with Auger-emitting isotopes, evaluated new analogues have been designed, p53. A loss of PML and acquisition cellular stress response using for DNA breakage efficacy and synthesised and evaluated. The initial of mutant p53 correlates with poor functional screen and mouse models Research leader: Assoc. Prof. Roger Martin cytotoxicity. evaluation, using cultured cells, provides Research Leader: Assoc. Prof. Ygal Haupt, NHMRC survival of prostate cancer patients, data for radioprotective activity and Senior Research Fellow and VESKI Fellow for cancer. • Preparation and evaluation of and of mice in animal models. cytotoxic activity. Mapping these values • Exploration of the regulation of cellular In two separate approaches to conjugates of the labelled ligands Use of copper ionophores to on a graph, in which each data point aging (senescence) and its link improving radiation treatment with tumour targeting proteins, both in selectively target cancer cells represents one analogue, provides a to tumour suppression. of cancer, the Molecular Radiation vitro (cytotoxicity) and in vivo The Tumour Suppression laboratory visual indication of progress. Increasing Prostate cancer cells accumulate Biology laboratory is developing (distribution in tumour-bearing mice). studies the regulation and function radioprotective activity is reflected in high levels of copper. We have taken a topical radioprotector to protect of tumour suppressors, with the aim the vertical dimension, and cytotoxicity KEY 2010 RESEARCH ACHIEVEMENTS advantage of this phenomenon and normal tissues, and a strategy to to explore new therapeutic strategies reduces from left to right. It is immediately Involvement of the E6AP/PML used copper ionophore, clioquinol, target radioactivity to tumours. based on restoration of tumour apparent that more than 40 drugs are suppression in cancer cells. axis in cancer development that transport copper into cells, to both better radioprotectors and selectively kill prostate cancer cells. The laboratory has recently identified a less cytotoxic (red symbols), than This provides a proof of principle new regulatory pathway of tumour methylproamine (green triangle). for this therapeutic approach, which suppression. We found that the One recent analogue (open red circle) we will test in animal models. is particularly promising. Some of E3 ligase E6AP controls the protein the new analogues have been shown stability of PML, a major known tumour to protect mouse oral mucosa after suppressor. We have demonstrated topical application. in mouse models for cancers that aberration in the regulatory axis of E6AP/ Attention is now focused on formulating PML promotes cancer development, strategies to improve the efficiency of and that inverse correlation between Figure 1: Each of more than 150 new delivery of such drugs to basal cells methylproamine analogues has been assessed E6AP and PML is associated with poor by clonogenic survial assays, generating a pair in oral mucosa, after topical application. survival of patients with prostate cancer. of values for each drug. One of these values is a dose modification factor (DMF), derived from the increase in survival conferred by the drug, at the optimal concentration, after a radiation dose of 12Gy. A DMF value of 1 corresponds to null radioprotective activity; <1 to radiosensitisation. The other value is a measure of cytoxicity — an estimate of the drug concentration (C50) corresponding to a decrease in survival of un- irradiated cells by 50 per cent after a one-hour exposure. The green triangle depicts the values for methylproamine, the first lead drug. The red circles correspond to the 41 drugs (as of December 2010) that are both less cytotoxic (lower C50) and better radioprotectors (higher DMF). The ‘target zone’ is the top right-hand corner of the diagram, so on this basis, the most promising analogue depicted by the open red circle. The experiments were done with a cell line derived from human keratinocytes.

Figure 1: Immunofluorescence staining of freshly isolated bone marrow cells for PML. The nuclear dots represent the PML nuclear bodies, structures that regulate cell death and cell aging (senescence). We found that in cells lacking the E3 ligase E6AP, the levels of PML and PML nuclear bodies increased significantly leading to enhanced growth suppression.

Peter MacCallum Cancer Centre – Research Report 2010 Cancer Cell Biology program 55 Cancer Cell Biology program – personnel Cancer Cell Biology program – personnel

Cell Cycle and Cancer Cell Growth and Epithelial Stem Cell Molecular Genetics laboratory Proliferation laboratory Biology laboratory Radiation Biology Head Head Head Head Dr Patrick Humbert Dr Kieran Harvey Dr Pritinder Kaur Prof. Roger Martin Research Officers Senior Research Officers Research Officers Senior Research Scientist Dr Nathan Godde Dr Joffrey Degoutin Dr Stuart Mills Dr Pavel Lobachevsky Dr Helen Pearson Dr Jane Lin Dr Holger Schlueter Visiting Scientist Dr Claire Martin Dr Claire Milton Postgraduate Student Dr Carole Poon Dr Olga Sedelnikova Research Assistants Lynn Chong Dr Kevin Watt Research Officer Allison Ogden Dr Xiaomeng Zhang Visiting Postdoctoral Fellow Tanja Schlosser Dr Andrea Smith Technical Officer Dr Carla Brohem Postgraduate Students Post-doctoral Fellow Lauren Hicks Imogen Elsum Metastasis Research Dr Alesia Ivashkevich laboratory Ryan Galea Postgraduate Students Research Assistants Lorey Smith Felix Grusche Head Chloe Pandeli (part-time) Ashesha Sinha Assoc. Prof. Robin Anderson Technical Officer Laboratory Assistants Olivia Cakebread Honours Students Peter Mac Research Fellows Natasha Deprez Samantha Williams Lucas Dent Dr Belinda Parker Jwan Daniel Dr Normand Pouliot Cell Cycle and Summer Scholarship Student Honours Students Development laboratory Kiryu Kee-Long Yab Postdoctoral Fellows Laura Munforte Dr Bradley Bidwell Nyan Kapadia Head Differentiation and Dr Richard Redvers Assoc. Prof. Helena Richardson Transcription laboratory Dr Cameron Johnstone Tumour Suppression Senior Research Officers Head Dr Clare Slaney laboratory Dr Anthony Brumby Assoc. Prof. Robert Ramsay Research Associate Head Dr Nicola Grzeschik Senior Research Officers Assoc. Prof. Ygal Haupt Dr Linda Parsons Dr Izhak Haviv Dr Jordane Malaterre Research Assistants Senior Research Officer Research Officers Dr Lloyd Pereira Dr Sue Haupt Dr Karen Doggett Dr Huiling Xu Judy Doherty Dr Nathalie Martinek Erin Lucas Postdoctoral Fellows Research Assistants Rebecca Pelzer Dr Michael Cater Research Assistants Sally Lightowler Christina Restall (NHMRC Biomedical Research Fellow) Melinda Allott Shienny Sampurno Kathryn Visser Dr Mariam Mansour Karen Goulding Postgraduate Students Postgraduate Students Dr Kamil Wolyniec Samuel Manning Lisa Mckenzie Dilara Akcora Allan Burrows Research Assistant Lee Willoughby Sandra Carpenteri Yuan Cao Vincent Corneille Dane Cheasley Rachel Carter Postgraduate Students Duy Huynh Nicole Kusuma Postgraduate Students Felix Grusche Yu Rebecca Miao Yu Rebecca Miao Daniel Brown Peytee Khoo Yan Yuqian Nimali Withana Ai-Leen Chan Nezaket Turkel Honours Students Summer Scholarship Student Honours Student Technical Officers Ryan Cross Lauren Burton Simone Woods Peter Burke Suh-youn Ko AMS Student (2010–11) Technical Assistants Alexandra Cussen Summer Scholarship Student Joel Greaney Summani Dharmatilleka Chloe Georgiou Ryan Cross (2009–10) (The University of Melbourne) Stephanie Munari Cristina Murphy Scholar Sabbatical visitor John Daly Rayner Dr Elizabeth Vincan Dr. Gunbjørg Svineng Visiting Postgraduate Student Visiting Postgraduate Student Annika Bijenhof Yvonne Smith

Peter MacCallum Cancer Centre – Research Report 2010 Cancer Cell Biology program 57 1.5 Tumour Angiogenesis program 1.5 Tumour Angiogenesis program

Tumour angiogenesis is the process by which tumours generate the blood Determining the molecular mechanisms that regulate vessels they need to secure their blood supply and survive. Tumours the formation of blood vessels and lymphatic vessels also recruit lymphatic vessels (lymphangiogenesis) which can during normal development and tumourigenesis facilitate metastatic spread, the most lethal aspect of cancer. Under the RESEARCH FOCUS KEY RECENT RESEARCH supervision of Associate Professors ACHIEVEMENTS Steven Stacker and Marc Achen, • Large-scale genomic screens to Steve Williams uses siRNA from determine the signalling pathway The Tumour Angiogenesis program Peter Mac’s Functional Genomics networks in endothelial cells. has been involved in the discovery and characterisation of growth factors facility to screen the genome and • Development of discovery platform and receptors involved in promoting to identify molecules that can be for predictive biomarkers of clinical human cancer. We have also generated targeted therapeutically to block response and resistance to anti- specific reagents and inhibitors to allow lymphatic metastasis. neovascular agents. the development of therapeutics and • Characterisation of lymphatic vessel diagnostics for application to human subtypes and their relationships diseases including cancer. These to human disease. discoveries include: • Determining the role of proteases in • Cloning and characterising novel the regulation of vascular endothelial members of the vascular endothelial Heads of Tumour Angiogenesis program: growth factors and formation of Assoc. Prof. Marc Achen, NHMRC Principal growth factor (VEGF) family. tumour stroma. Research Fellow, and Assoc. Prof. Steven Stacker, • Identifying VEGF-D as a key mediator NHMRC Senior Research Fellow • Development of mouse models of tumour lymphangiogenesis to understand human lymphatic and metastasis via lymphatic vessels. disorders and disease. The Tumour Angiogenesis program • Developing inhibitors of VEGF-D for was established at Peter Mac in • Structure-function analysis of vascular use as anti-cancer agents. endothelial growth factors and July 2010. The program is led by • Using adenoviral delivery of the receptors. Associate Professors Marc Achen VEGF-D gene to prolong the patency and Steven Stacker, highly respected • Characterisation of the role of novel of vascular access grafts and treat and internationally recognised growth factor receptors (e.g. the Ryk cardiovascular diseases. researchers whose work covers the receptor) in human cancer, and • Generating VEGF-D antibodies; range of lab-based cell biology through development of modulators of their such antibodies are now used in to pre-clinical cancer models and function. human clinical trials. Marc and Steven the first blood-based diagnostic test jointly hold a NHMRC Program Grant for lymphangioleiomyomatosis (LAM), and each is supported at a senior level a devastating neoplastic disease through the NHMRC Fellowship Scheme. effecting women. Research conducted under the • Advancing our understanding Tumour Angiogenesis program is of lymphatic biology through the focused on growth factors, cell surface characterisation of new molecules receptors and signalling pathways and pathways associated that regulate growth and differentiation with lymphatic endothelium. of endothelium and other cell types • Defining the roles of novel growth associated with the vasculature in factor receptors and their role solid tumours. in Wnt signalling. We aim to use this information to develop therapeutics that block tumour angiogenesis and lymphangiogenesis, and thereby restrict the growth and spread of cancer. This information will also be used to develop diagnostics Figure 1: Lymphatic and blood vasculature of a for applications in cancer and other mouse ear: whole-mounts of the ear were performed human diseases. to immunostain the lymphatic endothelial cells, using the LYVE-1 marker (green), and the blood endothelial cells, using the CD31 marker (red).

Tumour Angiogenesis program 59 1.5 Tumour Angiogenesis program – overview Tumour Angiogenesis program – key publications & personnel

Research into the molecular control This work was further validated in human Some of the resulting studies have Program Publications Baldwin ME, Catimel B, Nice EC, et al. PERSONNEL The specificity of receptor binding by vascular of blood and lymphatic vessel formation cancer patients by studies which now progressed to clinical trials in the Davydova N, Roufail S, Streltsov VA, endothelial growth factor-D is different in mouse Program and Group Heads started in the program over 15 years correlated the expression of VEGF-C USA and Europe. Stacker SA, et al. The VD1 neutralizing and man. J. Biol. Chem. 276: 19166 – 19171, Assoc. Prof. Marc Achen ago with the initial cloning of growth and VEGF-D in primary human tumours antibody to vascular endothelial growth factor-D: Since relocating to Peter Mac in 2010, 2001. (cit.=77) Assoc. Prof. Steven Stacker factor receptors involved in angiogenesis. with disease outcome and measures binding epitope and relationship to receptor our program has continued with These receptors (e.g. VEGFR-2 and of metastasis. To directly address binding. J. Mol. Biol. 407:581 – 593, 2011. Stacker SA, Caesar C, Baldwin ME, et al. Research Officers advances in the development of the first Vascular endothelial growth factor-D promotes Tie-2) were a starting-point to understand whether VEGF-D was responsible for Harris NC, Paavonen K, Davydova N, blood-based diagnostic test for LAM the metastatic spread of cancer via the Dr Natalia Davydova et al. Proteolytic processing of vascular the control of angiogenesis in the the formation of new vessels and the lymphatics. Nature Med. 7:186 – 191, 2001. Dr Rae Farnsworth which utilises antibodies to VEGF-D. endothelial growth factor-D is essential for its context of developmental biology spread of tumour cells, we also (cit.=552) Dr Michael Halford LAM is a debilitating, progressive and capacity to promote the growth and spread of and cancer. developed a monoclonal antibody Dr Tara Karnezis often lethal neoplastic lung disease cancer. FASEB J., volume 25, 2011, in press. Veikkola T, Jussila L, Makinen T, et al. to VEGF-D which blocked its interaction Signalling via vascular endothelial growth factor Dr Maria Macheda At the time it was evident that other effecting women of child-bearing age. Francois M, Caprini A, Hosking B, et al. with both of its receptors, VEGFR-2 and receptor-3 is sufficient for lymphangiogenesis in Dr Sophie Paquet-Fifield receptors and ligands must exist to The diagnostic test, developed from Sox18 induces development of the lymphatic VEGFR-3 (Achen et al., Eur. J. Biochem., transgenic mice. EMBO J. 20:1223 – 1231, 2001. mediate the array of different functions intellectual property generated in our vasculature in mice. Nature 456:643-7, 2008. Research Assistants 2000; Davydova et al., J. Mol. Biol., (cit.=290) served by specialised vessels in different program, is aiding in the diagnosis (cit.=51) Carol Caesar 2011). The successful inhibition of both Halford MM, Armes J, Adams MT, et al. organs of the body, and by vessels of LAM, and is an excellent example McColl BK, Paavonen K, Karnezis T, et al. Sally Roufail primary tumour growth and metastasis RYK-deficient mice exhibit craniofacial defects which form in response to human of the translation of our scientific Proprotein convertases promote processing with this antibody was the first including a cleft palate associated with loss of Dr You-Fang Zhang diseases. Using techniques of gene discoveries for the benefit of patients. of VEGF-D, a critical step for binding the demonstration of an anti-metastatic crosstalk between RYK and Eph receptors. discovery combined with specialised angiogenic receptor VEGFR-2. FASEB J. Postgraduate Students approach based on inhibition of Nature Genet. 25:414 – 418, 2000. (cit.=74) bioassays for endothelial growth factors, 21:1088-98, 2007. (cit.=15) Nicole Harris a lymphangiogenic growth factor Stacker SA, Stenvers K, Ceasar C, et al. new members of the VEGF family were Achen MG, McColl BK, and Stacker SA. Dr Sidney Levy Biosynthesis of vascular endothelial growth (Stacker et al., Nature Medicine, 2001). Focus on lymphangiogenesis in tumor Steven Williams isolated. The cloning and characterisation factor-D (VEGF-D) requires proteolytic metastasis. Cancer Cell 7:121 – 127, 2005. of VEGF-D (Achen et al., Proc. Natl. Detailed biochemical analysis of the processing which generates non-covalent Casual Research Assistant Acad. Sci. USA, 1998), and the VEGF-D polypeptide in our program (cit.=103) homodimers. J. Biol. Chem. 274:32127 – 32136, Katie Ardipradja demonstration that this soluble revealed two protein domains which Baldwin ME, Halford MM, Roufail S, et al. 1999. (cit.=147) Vascular endothelial growth factor-D is growth factor activates both VEGFR-2 can be cleaved to generate the fully Stacker SA, Vitali A, Caesar C, et al. Surgical Associate dispensable for development of the lymphatic and VEGFR-3 on blood vessels bioactive growth factor (Stacker et al., A mutant form of vascular endothelial growth Dr Ramin Shayan system. Mol. Cell. Biol. 25:2441-9, 2005. (cit.=66) and lymphatics opened new doors J. Biol. Chem., 1999). These studies factor which lacks VEGFR-2 activation but for understanding the biology of not only confirmed how the activity Baluk P, Tammela T, Ator E, et al. retains the ability to induce vascular permeability. the vasculature. Combined with the of VEGF-D could be regulated in vivo, Pathogenesis of persistent lymphatic vessel J. Biol. Chem. 274:34884 – 34892, 1999. (cit.=67) hyperplasia in chronic airway inflammation. J. discovery of a related growth factor, but showed that it is similarly regulated Wise LM, Mercer AA, Veikkola T, et al. Clin. Invest. 115:247-57, 2005. (cit.=109) VEGF-C, in the laboratory of Professor to VEGF-C, and indicated potential The vascular endothelial growth factor Kari Alitalo in Helsinki, Finland, a avenues to target the protein via the Rissanen TT, Markkanen JE, Gruchala M, (VEGF)-like protein from Orf Virus NZ2 binds subfamily of VEGFs capable of driving proteases that release its fully bioactive et al. VEGF-D is the strongest angiogenic to VEGF receptor-2 and neuropilin-1. Proc. Natl. Acad. Sci. USA 96:3071 – 3076, 1999. (cit.=145) the formation of new lymphatic vessels domain (McColl et al., J. Exp. Med., and lymphagiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Achen MG, Jeltsch M, Kukk E, et al. was identified. These findings opened 2003; McColl et al., FASEB J., 2007). Circ. Res. 92:1098-106, 2003. (cit.=143) the way for studies in the field of Vascular endothelial growth factor-D (VEGF-D) is In 2006, a family of patents generated lymphangiogenesis (the formation Stacker SA, Achen MG, Jussila L, Baldwin a ligand for the tyrosine kinases VEGF receptor-2 in our program, describing the ME, et al. Lymphangiogenesis and cancer (Flk-1) and VEGF receptor-3 (Flt-4). Proc. Natl. of new lymphatic vessels) and VEGF-D gene, inhibitory VEGF-D metastasis. Nature Rev. Cancer 2:573 – 583, Acad. Sci. USA 95:548 – 553, 1998. (cit.=588) importantly, the role of lymphangiogenic antibodies and therapeutic and 2002. (cit.=313) signalling in human disease. Gilbert, RE, Vranes D, Berka JL, et al. diagnostic approaches for cancer and Stacker SA, Baldwin ME and Achen MG. Vascular endothelial growth factor and its Our interest in tumour biology and other diseases based on these reagents, The role of tumor lymphangiogenesis in receptors in control and diabetic rat eyes. the function of vessels in the metastatic was acquired by Circadian Technologies PC3 cells (prostate tumour cells) endogenously metastatic spread. FASEB J. 16:922-934, 2002. Lab. Invest. 78:1017 – 27, 1998. (cit.=94) expressing VEGF-C and VEGF-D were implanted (cit.=129) spread of cancer led us to examine (an Australian publicly-listed company) as xenograft tumour to study the lymphogenous the role of VEGF-D in the growth and for development primarily in the area spread of prostate tumour cells to regional lymph Achen MG, Williams RA, Minekus MP, et al. nodes. (work of Tara/Maria). Top: Metastasis of Localization of vascular endothelial growth spread of cancer. We demonstrated that of cancer. A phase I clinical trial testing PC3 cells have been observed in an axillary lymph VEGF-D induces both new blood vessels an antibody to VEGFR-3 (a receptor for node. (40% of the lymph node was invaded by factor-D in malignant melanoma indicates a role and new lymphatic vessels in a tumour. VEGF-D) in cancer was initiated in 2011. tumour cells, shown by H & E staining). Bottom: in tumour angiogenesis. J. Pathol. 193:147 – 154, IHC of LYVE 1 has shown lymphangiogenesis 2001. (cit.=83) Further, VEGF-D promoted the spread Companies have taken licenses within a PC3 cells induced tumour. of the primary tumour to regional lymph to discoveries from our program nodes, whereas tumours that did not to examine the therapeutic potential express VEGF-D grew slowly and of the VEGF-D gene in angina, foetal never spread to lymph nodes (Stacker growth restriction and peripheral et al, Nature Medicine, 2001). These vascular disease, and for prolonging experiments showed the importance the patency of vascular access grafts. of the lymphangiogenic growth factors for the metastatic spread of tumour cells.

Peter MacCallum Cancer Centre – Research Report 2010 Tumour Angiogenesis program 61 1.6 Cancer Therapeutics program 1.6 Cancer Therapeutics program

Integrating basic research activities, platform technologies, and pre-clinical model systems to discover, develop, characterise and refine novel cancer therapeutics for clinical use

The Cancer Therapeutics program, Key technologies involved include Gene Regulation laboratory combined with the Molecular Imaging functional genomics, next generation Assoc. Prof. Ricky Johnstone and Translational Medicine program, sequencing, molecular imaging — is designed to integrate various basic PET, CT and optical, mouse models Melanoma Research laboratory research activities, platform technologies, of cancer, and drug development. Dr Mark Shackleton and pre-clinical model systems available Scientists and clinicians within these Molecular Imaging and Targeted within Peter Mac to discover, develop, programs use basic research, clinical Therapeutics laboratory characterise and refine novel cancer trials and collaboration with industry to Prof. Rod Hicks therapeutics for clinical use. maximise the future impact of research Translational Research Laboratory Basic research within the program findings for cancer patients. Assoc. Prof. Grant McArthur is focused on: Pfizer / Peter Mac Cancer • Increased understanding of the Genomics program biological, genetic and genomic Assoc. Profs. Rick Pearson basis of cancer onset. and Wayne Phillips • Development and clinical responses to treatment. CCV Venture Grant Initiative • Pre-clinical testing of novel Assoc. Prof. Ricky Johnstone therapeutics, development of CRC for Cancer Therapeutics imaging methods and biomarker Translational Research laboratory assays to follow treatment efficacy. Dr Mark Devlin • Investigation of molecular pathways involved in response to anti-cancer therapies.

After obtaining a PhD in Pharmacology from The University of Melbourne, Mark Devlin worked in a variety of roles focused on academic-based drug discovery and development. He then joined Peter Mac in 2008 to head the CRC for Cancer Therapeutics (CTx) Translational Research Laboratory. Mark conducts his research as part of a larger, multidisciplinary drug discovery and development team, involved in the development and validation of target-specific biomarkers, in vitro functional assays and in vivo cancer models. These proof-of-concept studies provide an important foundation for further development towards new targeted therapies for cancer.

Cancer Therapeutics program 63 1.6.1 Gene Regulation laboratory 1.6.2 Melanoma Research laboratory

RESEARCH FOCUS These studies have provided OVERVIEW RESEARCH FOCUS • Basic and pre-clinical characterisation important information regarding the In Australia, melanoma causes the • Elucidating mechanisms of melanocyte of novel apoptosis-inducing therapeutic fundamental molecular mechanisms second most years of lost productive development and transformation. of IFN signalling and the complex agents used alone and in combination. life of any cancer. Our research program • Identifying mechanisms of melanoma molecular and biological interplay • Determination of the effects of aims to identify ways to reduce the progression and metastasis. between Type I and II IFNs. incidence of melanoma and to improve combining novel agents designed • Developing clinically relevant models the outcomes of patients with to specifically kill breast cancer cells We used syngeneic pre-clinical of melanoma biology and treatment. with other agents that stimulate a host models of human solid cancers established disease. 2010 OVERVIEW anti-tumour immune response. to demonstrate that the HDACi We underpin molecular studies • Development and use of genetically panobinostat can sensitise tumour of melanoma development and Since our genesis in January 2010, engineered models of haematological cells to apoptosis mediated by the progression with detailed biological the Melanoma Research laboratory malignancies and solid cancers anti-mouse TRAIL receptor antibody investigations, using in vivo models. has been successful in attracting for pre-clinical studies. MD5-1. We showed that the combination Our main focus is currently on studying independent funding for our research of panobinostat and MD5-1 can the growth of human using and in establishing key and logistically Research leader: Assoc. Prof. Ricky Johnstone, • Use of functional genomics-based eradicate tumours grown subcutaneously Research leader: Dr Mark Shackleton NHMRC Senior Research Fellow screens to identify novel tumour NHMRC CDA Fellow in vivo models that are highly permissive complex in vivo assays that form the and orthotopically in immunocompetent for revealing the malignant potential of basis of our work. Initial developments suppressor genes and genes that mice, while single agent treatment had regulate the apoptotic response to human cancer cells. The in vivo assay focused on restructuring of the The Gene Regulation laboratory minimal effect. However, escalation of Newly established in 2010 following the new anti-cancer agents. we use is remarkably efficient, allowing laboratory space and on acquisition of performs fundamental and pre-clinical the dose of panobinostat to enhance recruitment of medical oncologist and tumour formation from single melanoma major equipment items, including a new • Characterisation of novel signal research aimed at defining the molecular anti-tumour activity resulted in on-target VESKI Fellow Dr Mark Shackleton, the cells and providing a unique vehicle FACS Aria II cell sorter through support transduction pathways stimulated and biological processes required gastrointestinal that were fatal Melanoma Research laboratory aims to for studying human cancer biology. from the Peter Mac Foundation and the for anti-cancer drug action and drug by Type I and II interferons and the to the treated mice. Given that clinical identify molecular mechanisms that drive Flow Cytometry facility. The first research Through identifying tumours that vary resistance, and the mechanisms role of interferon signalling in tumour studies using HDACi and activators of melanoma initiation and progression. staff appointments were made in March/ in their abilities to propagate disease, of interferon signal transduction. immune surveillance. the TRAIL pathway have been initiated, April and experimental work commenced we aim to identify molecular determinants our pre-clinical data highlight the in May. Key to the development of of melanoma growth and metastasis. potential toxicities that could limit our program has been the building KEY 2010 RESEARCH ACHIEVEMENT Our close links with the Melanoma the use of such a treatment regimen. of relationships with the Melanoma Unit at Peter Mac and the Melbourne Defining the molecular mechanisms Unit at Peter Mac, the Victorian Biobank For more information on related Melanoma Project provide us with of action of anti-cancer agents and the Melbourne Melanoma Project. research, see: clinically annotated human tumour We determined that regulated basal These relationships provide us with fresh specimens that have been kindly donated expression of Type I interferon (IFNβ) - Cancer Immunology program (pg 24) melanoma tumor tissue from patients in by patients for study. This enables us production by c-Jun is necessary a way that enables translation to the to link our laboratory findings directly to to maintain the levels of transcription clinic of findings from in vivo disease patient characteristics and outcomes. factor STAT1 within cells and ‘prime’ modelling. cells for subsequent responses to IFNγ and other cytokines that utilise STAT1. References: Quintana E, Shackleton M, Sabel MS, et al. Efficient tumour formation by single human melanoma cells. Nature. Dec 4;456(7222):593–8, 2008. Quintana E, Shackleton M, Foster HR, et al. Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organised. Cancer Cell. 18: 510-523, 2010.

Figure 1: Pieces of melanoma tumour obtained freshly at surgery from a Peter Mac patient who consented to donate tumour tissue for research. The specimen was taken immediately and freshly to Pathology. Peter Figure 1: Mammalian models with established subcutaneous mammary were treated Mac pathologists separated parts of the tumour not required for clinical management and gave them to staff with an agonistic monoclonal antibody to DR5, a pan histone deacetylase inhibitor or a combination from the Victorian Biobank for initial processing and forwarding to the Melanoma Research laboratory. As a of both, the latter treatment causing regression and/or long term cures with no toxic side effects. result of such co-ordination, the total time from surgical removal of the tumour to its delivery to the lab was only 30 minutes. Melanoma cells were then dissociated from the tumour, stained to enable identification of dead and contaminating cells, and evaluated by flow cytometry (dot plot shown to right, enclosed region indicates melanoma cells).

Peter MacCallum Cancer Centre – Research Report 2010 Cancer Therapeutics program 65 1.6.3 Molecular Imaging and Targeted 1.6.4 Translational Research Laboratory Therapeutics laboratory

RESEARCH FOCUS RESEARCH FOCUS double-strand breaks (as measured • Targeting molecular pathways involved • Investigation of inhibitors of protein by γ-H2AX immunofluorescence) and in metabolism, amino acid transport and lipid kinases using laboratory the induction of accelerated senescence and apoptosis for cancer imaging and clinical studies. (terminal growth arrest) in vitro and in vivo. BEZ235 also exhibits potent and therapeutic monitoring. • Identification and validation of tissue inhibition against a key DNA repair • Developing novel agents and and imaging biomarkers to predict protein, DNA-dependent protein kinase technologies for imaging melanoma, response to targeted therapeutics. (DNA-PK). Significantly, DNA-PK neuroendocrine cancers and lymph • Understanding of the mechanism of knockdown using either a selective node metastasis. action of therapeutics targeting pharmacological inhibitor (KU57788) • Imaging receptor activation signalling, cell cycle and cell surface or small interfering RNA replicates the and hypoxia in tumours to guide receptors. effects of BEZ235 on DNA repair and therapeutic intervention. Figure 1: 18F-D-FPHCys uptake into cancer • Understanding of the role of hypoxia in senescence, suggesting that DNA-PK • Developing advanced chemistries cells correlates with expression of amino acid tumour responses to cancer therapies. is a key therapeutic target of BEZ235 transporter subclass LAT1. Research Leader: Prof. Rod Hicks and automation procedures to Research Leader: Assoc. Prof. Grant McArthur, CCV following radiation. Using p53-inducible produce radiopharmaceuticals Sir Edward Dunlop Clinical Cancer Research Fellow cells, we also demonstrate that KEY 2010 RESEARCH ACHIEVEMENT for clinical cancer applications. Until now, these imaging agents functional p53 is required for BEZ235 As part of the Centre for Cancer • Participating in clinical trials of new have been labelled with the PET isotope BEZ235 targets the DNA to induce senescence in irradiated cells. Imaging, the Molecular Imaging As part of the Centre for Cancer treatments and imaging modalities carbon (11C) which has a very short damage response leading to We conclude that BEZ235 modulates and Targeted Therapeutics laboratory Imaging and Translational Medicine, to enhance translation of research half-life of 20 minutes, making transport radiosensitisation and senescence DNA double strand break repair and uses in vivo imaging of tumour the Translational Research Laboratory finding to clinical practice. and multi-centre trials impractical. promotes p53-dependent accelerated biology in models of human cancers investigates the application of novel Activation of the phosphatidylinositol senescence after radiation by inhibiting to develop new therapies and improved To overcome this limitation, we, together targeted cancer therapies by integrating 3-kinase (PI3K)/mammalian target of DNA-PK. These data highlight that imaging technologies for application with collaborators at the Australian cell biology, molecular biology, rapamycin (mTOR) pathway confers KEY 2010 RESEARCH ACHIEVEMENT DNA-PK is an attractive therapeutic in cancer patients. Nuclear Science and Technology functional imaging and clinical trials. resistance to ionising radiation. Imaging cancer with radio-labelled Organisation (ANSTO) and the Therefore, pharmacological inhibition target for enhancing tumor radio- amino acid derivatives Cooperative Research Centre for of signalling through the PI3K/mTOR sensitivity and identify accelerated senescence as an important determinant Cancer cells have a high demand for Biomedical Imaging Development pathway is a promising strategy for of outcome when DNA-PK inhibitors are glucose and other nutrients in order (CRC-BID), have developed a novel enhancing the cytotoxicity of radiation. 18 combined with radiation. to support their rapid growth and methionine analogue, F-D-FPHCys, In this project, we are investigating the 18 proliferation. Since the 1980s, the high labelled with Fluorine which has therapeutic consequences of combining For more information on related glucose consumption of tumour cells a significantly longer half-life (109 a novel PI3K/mTOR inhibitor (BEZ235) research, see: has been exploited to image cancers minutes). 18F-D-FPHCys has shown with radiation. Treatment with BEZ235 - Molecular Oncology laboratory (pg 43) by Positron Emission Tomography excellent imaging properties in animal cause significant radiosensitisation as (PET) using the glucose analogue models of human tumours. This tracer evidenced by clonogenic survival assays - Molecular Imaging and Targeted fluorodeoxyglucose 18( FDG). However, has great potential to become an in a panel of human cancer cell lines Therapeutics laboratory (pg 66) effective clinical PET imaging agent despite its proven usefulness in cancer including non-small cell lung cancer - Centre for Cancer Imaging (pg 110) management, 18FDG has some and improve the localisation and cells. Importantly, BEZ235 also reduces - Medical Oncology and Early Phase limitations, in particular for brain tumour characterisation of cancers, in particular tumor growth following radiation Clinical Trials (pg 82) imaging. Indeed, glucose is also the brain tumours. First-in-human clinical treatment of tumour xenografts in vivo. preferred source of energy for normal trials will commence in 2011. The enhanced radiation response - Gastrointestinal Service (pg 84) brain cells which, therefore, have Our pre-clinical work in developing produced by BEZ235 coincides with 18 - Head and Neck Service (pg 87) a high uptake of FDG. In addition new imaging tracers in association delayed repair of radiation-induced DNA to high glucose utilisation, cancer cells with the CRC for Biomedical Imaging - Melanoma and Skin Service (pg 89) require high amounts of amino acids Development has moved into the for the protein production necessary clinical domain with commencement to maintain their continuous proliferation. of human studies of Mel050, a highly Thus, radio-labelled amino acid specific melanoma imaging agent. derivatives are another type of metabolic probes that can be used as alternative to 18FDG imaging.

Figure 1: γ-H2AX immunofluorescence in cells after treatment with radiation alone (A) and radiation plus BEZ235 (B). Note increased staining with addition of BEZ235. γ-H2AX (green), DAPI – nuclear staining (blue).

Peter MacCallum Cancer Centre – Research Report 2010 Cancer Therapeutics program 67 1.6.5 Pfizer / Peter Mac Cancer Genomics program 1.6.6 CCV Venture Grant Initiative

RESEARCH FOCUS RESEARCH FOCUS important role in regulating tumour • Screening tumour cells for drug • RNAi screening to identify novel onset and progression. We have shown sensitivity, focusing on melanoma genes involved in breast cancer that altered activity of the ARL4D/ELMO and ovarian cancer. onset and the response of breast pathway affects the biological activity of breast cancer cells and have • Using genomic and proteomic cancer cells to apoptosis mediated identified the biochemical processes profiling to obtain a predictive by novel therapeutics. that are involved. signature of drug response and • Characterisation of the genes gain insight into drug resistance. identified as novel tumour suppressors The CCV Venture Grant Initiative • Functional genomic RNAi screening and modifiers of responses to cancer was supported by the John T Reid to identify genes associated with therapeutics. Charitable Trusts, through the resistance to specific drugs and • Development of novel RNA-based Cancer Council of Victoria. to enable rational development of Figure 1: Heat map of the 28 gene signature functional genomics screening For more information on related that was 87 per cent accurate in classifying ovarian novel combinational drug therapies. tumour cells as either resistant or sensitive to PF502. technologies including the use research, see: of next generation sequencing. Research leaders: Assoc. Prof. Rick Pearson, Research Leaders: Assoc. Prof. Ricky Johnstone, › Cancer Immunology program (pg 24) NHMRC Senior Research Fellow and Assoc. NHMRC Senior Research Fellow (pictured), Prof. Wayne Phillips KEY 2010 RESEARCH ACHIEVEMENT Assoc. Prof. Ross Hannan, NHMRC Senior › Growth Control and Differentiation For more information on related Research Fellow, Assoc. Prof. Rick Pearson, • Ovarian cancer included as KEY 2010 RESEARCH ACHIEVEMENT program (pg 40) research, see: NHMRC Senior Research Fellow and The goal of the Pfizer / Peter Mac one of the tumour types selected Assoc. Prof. Grant McArthur, CCV Sir Edward Identification of novel putative tumor › Cancer Genetics and Genomics Dunlop Clinical Cancer Research Fellow Cancer Genomics program is to identify for clinical trials of PF502 (PI3Kinase/ suppressor genes laboratory (pg 34) tumour signatures that will guide the mTOR inhibitor), with potential targets We have validated the role of eight use of chemotherapy to cancer patients for combination therapies in PF502 › Cancer Immunology program (pg 24) The Cancer Council Victoria new potential tumour suppressor who are most likely to respond. resistant ovarian cancer identified. (CCV) Venture Grant Initiative focuses genes identified in our initial RNAi-based › Growth Control and Differentiation on the identification of novel breast functional genomics screen. Two of One of the major challenges in treating program (pg 40) cancer is the selection of the most cancer tumour suppressors and genes these genes (ARL4D and ELMO1) have effective chemotherapy agents for that regulate sensitivity to cancer been previously shown to function in the individual patients. To address this therapeutics using whole-genome same biochemical pathway, indicating challenge, the aim of the Pfizer/Peter RNA interference (RNAi) screens. that this pathway may play a very Mac Cancer Genomics Program is to generate Proteomic and Genomic Profiles of human tumour cells, correlate these with response to targeted therapies and use this information to predict drug effectiveness in patients. We have successfully screened 35 Ovarian cell lines and 100 Melanoma cell lines with drugs that are currently pre-clinical or in clinical trials. We have successfully generated a ‘gene signature’ that is 87% accurate in classifying cells as either resistant or sensitive to PF502, a drug that targets the PI3 kinase pathway. In addition we have identified potential mechanisms that confer drug resistance. These studies have led to the inclusion of ovarian cancer as one of the tumour types selected for PF502 clinical trials and also identified potential targets for combination therapies in PF502 resistant disease.

Figure 1: Knockdown of ARL4D and ELMO1 confers anchorage independent growth in HMEC-LTR cells.

Peter MacCallum Cancer Centre – Research Report 2010 Cancer Therapeutics program 69 1.6.7 CRC for Cancer Therapeutics Cancer Therapeutics program – personnel Translational Research laboratory

RESEARCH FOCUS Once accepted as a project, a Gene Regulation laboratory Molecular Imaging and Pfizer / Peter Mac Cancer Targeted Therapeutics Genomics program • Investigation of the effects of small multidisciplinary project team consisting Head of scientists from various organisations laboratory molecule inhibitors targeting proteins Assoc. Prof. Ricky Johnstone Scientific Manager involved in cell migration, invasion is assembled to advance the project Head Dr Karen Sheppard and metastasis. through a series of pre-clinical Postdoctoral Researchers Prof. Rod Hicks development milestones. Molecular Dr Amber Alsop Project Leaders • Identification and validation of targets arising from research carried Dr Michael Bots Project Leaders Assoc. Prof. Rick Pearson biomarkers to predict response out at Peter Mac are currently the focus Dr Ailsa Frew David Binns Assoc. Prof. Wayne Phillips to targeted therapeutics. of some CTx projects. Dr Carleen Cullinane Dr Nicole Haynes Chief Investigators • Development of non-invasive Dr Geoff Matthews Dr Donna Dorow Peter Mac is an important contributor at Assoc. Prof. Ross Hannan small animal fluorescent and Dr Jessica Salmon both a strategic and operational level to Research Postdoctoral Fellows Assoc. Prof. Grant McArthur bioluminescent imaging technologies. Dr Vanessa Solomon the drug discovery and development Dr Delphine Denoyer Assoc. Prof. Ricky Johnstone Dr Inge Verbrugge activities of CTx. We have Dr Titaina Potdevin representatives on both the CTx Portfolio Dr Michaela Waibel Postdoctoral Scientists KEY 2010 RESEARCH ACHIEVEMENT Research Assistants Research leader: Dr Mark Devlin Management Group, that helps select Research Assistants Dr Joanne Chan Progression of a major CTx project Laura Kirby Dr Richard Tothill and review new and existing projects, Kellie Banks to the late lead optimisation phase Richard Young of development and on individual project teams involved Leonie Cluse Research Assistants in overseeing the day-to-day science. As a participant in the Co-operative Peter Mac is well-placed to contribute Ben Martin Radiopharmaceutical Chemists Patricia Bukczynska Moreover, the guiding principles of CTx Research Centre for Cancer to the development of new small Christina Neff Dr Oliver Neels Allen Foo and its participant organisations permit Therapeutics(CTx), Peter Mac employs molecule therapies for cancer through its Rachael Ralli Wayne Noonan Amelia Neilsen commercial-inconfidence information to a team to help develop small molecules broad range of activities in laboratory Andrea Reitsma Dr Peter Roselt Gwyneth Ng be shared with researchers at Peter Mac for cancer treatment by integrating research, clinical and translational Ashley Robertson who are not directly involved in project Postgraduate Student Animal Technician in vitro assays, in vivo studies and research programs and its involvement Kym Stanley teams, ensuring CTx has access to Peter Dr Damien Kee Kerry Ardley small animal imaging. The knowledge in clinical trials. gained from these studies assists the Mac’s cancer-focused expertise, Postgraduate Students Translational Bioinformatics Analyst development of new cancer therapies. The identification of new proteins and personnel and platform technologies, Helen Arthur Research Laboratory Jason Ellul the elucidation of the role of these important to its drug development Mark Bishton Katrina Falkenberg and known proteins in complex cellular activities. Head CCV Venture Grant Initiative signalling pathways involved in cancer is Nicole Messina For more information on related Assoc. Prof. Grant McArthur a focus of many researchers at Peter Andrea Newbold Heads research, see: www.cancercrc.com Co-head Mac. These proteins, once validated Jake Shortt Assoc. Prof. Ricky Johnstone using a variety of genetic and functional Alison West Prof. Rod Hicks Assoc. Prof. Ross Hannan Assoc. Prof. Grant McArthur screens, have the opportunity to become Honours Student Scientific Manager the focus of proposals put forward to Assoc. Prof. Rick Pearson Marcus Lefebure Dr Carleen Cullinane CTx for consideration as drug targets. Postdoctoral Fellows Executive Assistant Physician Scientist Dr Christine Hauser Dr Ben Solomon Linda Stevens Dr Kathy Jastrzebski Postdoctoral Scientists Melanoma Research Postgraduate Student Dr Petranel Ferráo laboratory Gregory Leong Dr Kathryn Kinross Head Dr Titaina Potdevin Summer Scholarship Student Dr Mark Shackleton Dr Jeanette Raleigh Maria Selvadurai Research Assistants Dr Kelly Waldeck CRC for Cancer Therapeutics Pacman Szeto Research Assistants Elisha Wybacz Ekaterina Bogatyreva Scientific Manager Dr Mark Devlin Summer Scholarship Students Athena Hatzimihalis Jessalyn Sukamto Margarete Kleinschmidt Research Assistants Richard Young John Yek Judy Doherty Technical Assistants Anthony Natoli Kerry Ardley Kathryn Visser Susan Jackson Cancer Immunology Program Alison Slater Rachael Walker Administrative Assistant Jeannette Valentan Belinda Kelly Postgraduate Student Laboratory Manager Dr Arun Azad Jason Brady Dr Damien Kee

Peter MacCallum Cancer Centre – Research Report 2010 Cancer Therapeutics program 71 2 Clinical and Translational Research 2 Clinical and Translational Research 2

Assoc. Prof. Declan Murphy moved to Melbourne in January 2010 to take up appointments as consultant urological surgeon at both Peter Mac and The Royal Melbourne Hospital, and Director of Outcomes Research at the Australian Prostate Cancer Research Centre, Epworth Richmond. Trained in all aspects of open and endoscopic urology — with particular interest in laparoscopic and robotic- assisted surgery — Declan has a strong academic background and has published extensively in the field of minimally-invasive urology for the management of prostate, renal and bladder cancer. Declan is also leading the establishment of the first Academic Robotic Cancer Surgery Program in Victoria’s public health system, available to patients at Peter Mac. This will provide our patients with better treatment options and better outcomes — an excellent example of translating research developments into clinical practice. 2 Clinical and Translational Research

Developing novel, evidence-based approaches to cancer care and cure, and providing patients with new and better treatment options by participating in cutting-edge research studies.

Based on the principle that cancer Division of Cancer Medicine patients are best treated under the care Prof. John Zalcberg, OAM of a multidisciplinary team focused on a particular type of cancer, Peter Mac Division of Cancer Surgery has 11 ‘tumour streams’. The philosophy Assoc. Prof. Alexander Heriot of these tumour streams is to provide Division of Radiation Oncology integrated patient-focused care, based and Cancer Imaging on evidence-derived treatment protocols, Prof. Gillian Duchesne in a supportive and compassionate environment. This clinical service model has led Tumour Streams and Medical to a focus on research efforts along Oncology Research site-specific tumour lines. This scope Medical Oncology is wide-ranging, from early phase and Early Phase Clinical Trials clinical studies which allow our patients Assoc. Prof. Danny Rischin access to novel anti-cancer drugs to international randomised controlled Breast Service trials designed to answer key clinical Assoc. Prof. Michael Henderson questions in cancer care. Gastrointestinal Service Our clinical and translational Assoc. Prof. Michael Michael research aims to drive the translation Gynae-oncology Service of our laboratory and clinical research into best clinical practice: to improve Assoc. Prof. Kailash Narayan cancer survival, provide new diagnostic Haematology Service and treatment options, and reduce Prof. John Seymour the impact of cancer on patients and their carers. Head and Neck Service Assoc. Prof. June Corry Lung Service Prof. David Ball Melanoma and Skin Service Assoc. Prof. David Speakman Paediatrics and Late Effects Service Dr Greg Wheeler Sarcoma Prof. Peter Choong Uro-oncology Service Dr Farshad Foroudi

Peter MacCallum Cancer Centre – Research Report 2010 Clinical and Tranlsational Research 75 2 Cancer Medicine 2 Cancer Medicine

RESEARCH HIGHLIGHTS Collaborative familial cancer Clinical trials into high-risk cutaneous studies investigating BRCA gene squamours cell carcinoma (CSCC) mutations in ovarian cancer of the head and neck A collaborative genotyping study Under the leadership of Peter Mac’s between the Familial Cancer Centre Assoc. Profs. Danny Rischin and June (FCC) and the Australian Ovarian Corry, and coordinated by the Trans- Cancer Study (AOCS), both based at Tasman Radiation Oncology Group Peter Mac, is determining the number (TROG), this trial is a first for looking of women presenting with ovarian at new treatment strategies for CSCC, cancer who have BRCA gene mutations. the second most common form of The findings of this study are providing non-melanoma skin cancer. Involving insights into the mechanisms underlying researchers from across Australia the development of ovarian cancer, and have the potential to change the way Executive Director: Prof. John Zalcberg OAM and New Zealand, and led by study co-chairs from Medical Oncology and women with ovarian cancer are selected the Head and Neck Service at Peter for BRCA genetic testing. Mac, this clinical trial is emblematic Also under Cancer Medicine are the of the layered collaborative relationships departments of Pathology, Clinical that are fostered to strengthen cancer Psychology, Nutrition, Occupational research, underpinning improvements Therapy, Physiotherapy, Social Work and in cancer care. Speech Pathology; each with their Haematological own thriving programs, working together translational research as interdisciplinary research platforms to support the entirety of Peter Mac’s Pursuing a broad and varied clinical clinical and translational research. and translational research program, incorporating Peter Mac initiatives, cooperative group trials — particularly those of the Australasian Leukaemia and Lymphoma Group (ALLG) — and OVERVIEW The research conducted is closely linked Figure 1: Registered Nurse Laura Pyszkowski pharmaceutical industry studies, our to the affiliated clinical and basic science and Research Nurse Carrie Donohoe with a patient The Division of Cancer Medicine in the Chemotherapy Day Unit. Joint appointments clinician researchers facilitate important programs, including strong links with the comprises Medical Oncology, between the divisions of Cancer Medicine links with relevant oncological groups Immunology and Cancer Therapeutic and Cancer Research help facilitate early drug Haematology, Pathology, Pharmacy, development research, while close cooperation nationally and internationally. Pain and Palliative Care, Psychiatry, laboratory programs. with the Translational Research laboratory permits They lead studies for the early phase Allied Health, Centre for Blood Cells Notable research achievements bench to bedside research, and opportunities to return to the laboratory to explore observations development of novel therapeutics, Therapies, Clinical Trials Unit and the representative of the breadth of made in the clinic. including clinical investigations into Centre for Biostatistics and Clinical Trials. translational research within Cancer therapies for multiple myeloma, Medicine are outlined in the following Staff all work in multidisciplinary leukaemia and lymphoma. teams — regarded as a best practice highlights and in the tumour stream and model. With a focus on evidence-based medical oncology sections (pg 82). practice, all staff members are committed to clinical research and improving treatments for patients. Cancer Medicine is also committed to ensuring that patients receive optimal supportive care (including psychosocial care).

Peter MacCallum Cancer Centre – Research Report 2010 Clinical and Tranlsational Research 77 2 Cancer Surgery 2 Cancer Surgery

RESEARCH HIGHLIGHTS Aberrant epithelial-mesenchymal hedgehog signalling characterises Initiation of the academic Barrett’s metaplasia robotic surgery program In collaboration with researchers at In 2010, robotic surgery was introduced Johns Hopkins University, Baltimore, to Peter Mac with the installation of USA, the Surgical Oncology laboratory a da Vinci© Surgical System, a first for recently demonstrated that the a Victoria public hospital. The da Vinci© hedgehog signalling pathway, a system was delivered as part of the key pathway important for the normal Academic Cancer Robotic Cancer development of many organs including Surgery Program directed by Assoc. the , may play an Prof. Declan Murphy, who has been important role in Barrett’s Oesophagus, awarded a two-year grant from the a benign precursor to oesophageal Victorian Policy Advisory Committee adenocarcinoma. This study revealed on Technology to enable a detailed that the hedgehog pathway is aberrantly Executive Director: Assoc. Prof Alexander Heriot evaluation of the clinical and health- activated in Barrett’s Oesophagus economic impact of using this compared to normal oesophagus, and technology within the public hospital that activation of this pathway in mouse Acting Executive Director system. This research evaluation of oesophageal cells in a novel 3-D in vivo robotic surgery will assess all aspects Assoc. Prof. Michael Henderson tissue reconstitution model resulted in of the utilisation of robotic surgery, (Until Oct 2010) morphologic changes and expression including oncological outcome, of columnar genes, reminiscent of Executive Director quality of life, and health economics Barrett’s Oesophagus. This work Assoc. Prof Alexander Heriot and the impact on society. (From Oct 2010) highlights the translational research program between the Division of Research and Cancer Surgery. Reference: Wang DH, Clemons NJ, Miyashita T, et al. Aberrant epithelial-mesenchymal Hedgehog signalling characterises Barrett’s metaplasia. Gastroenterology. May;138(5):1810-22, 2010.

OVERVIEW hepatobiliary, clinical trials and basic Cancer Surgery has successfully The Division of Cancer Surgery is science (with a focus on Barrett’s implemented fortnightly translational committed to providing high quality Oesophagus and the PI3-kinase research meetings to allow cross healthcare and optimal outcomes signalling pathway). fertilisation of research ideas among clinicians and research scientists, for all patients and their families. Cancer Surgery is committed to a leading to greater collaboration and We strive to ensure that the model of research focus in all its activities improved quality research. We also care is evidence-based, safe, efficient and encompasses a wide area of actively encourage and support junior and effective. Surgical Oncology is research activity. This includes, though medical staff to conduct clinical research committed to ensuring that the services not limited to, the clinical science projects, undertaking full time research we provide for our patients are the most and technical aspects of surgery within the division. effective available. We continually and anaesthesia, the evaluations of monitor and evaluate our processes, outcomes after surgical management, Notable research achievements which redesign our services and implement an understanding of tumour behaviour, are representative of the breadth of changes where required so that patient particularly when relevant to the discipline translational research within Cancer safety and clinical effectiveness become of surgery, and an understanding of Surgery are outlined in the following part of our every day routine as we pre-malignant disease and those at highlights and in the tumour stream continue to work toward achieving genetically high risk of development achievements. the most appropriate surgical service of cancer. In addition, a variety of profile for Peter Mac. Figure 1: The da Vinci© Surgical System laboratory-based programs in basic progressed through trial phases in 2010 The research conducted is oncological science are conducted, in preparation for its launch in 2011. closely linked to the affiliated in particular, utilising molecular and clinical and basic science programs, cellular approaches to understand particularly in the following areas: the development and progression gastro-oesophageal, colorectal of gastrointestinal cancers and to cancer and lower gastrointestinal, identify new treatments. breast, melanoma, head and neck,

Peter MacCallum Cancer Centre – Research Report 2010 Clinical and Tranlsational Research 79 2 Radiation Oncology and Cancer Imaging 2 Radiation Oncology and Cancer Imaging

RESEARCH HIGHLIGHTS Gated Radiotherapy Our research achievements are Gated Radiotherapy is Improving the highlighted below, in the tumour stream delivery of radiotherapy to tumour research and in the Enabling Technology volumes which move with respiration. Platforms sections. This research aims to assess and detect the range of tumour movement with Radiation therapy in prostate cancer respiration and delivery of radiotherapy Scott Williams was awarded a Prostate only when the tumour is present within Cancer Foundation of America Creativity the target zone. This approach, known Award, to conduct research aiming to as gated treatment delivery, aims to provide new insights into improve the dose delivered to cancerous how to optimally treat prostate cancer cells whilst minimising the effect to with radiation therapy. healthy tissues. PET imaging and tumour response Managing organ deformation Executive Director: Prof. Gillian Duchesne PET imaging is being used in the and patient compliance assessment of tumour volume and This is being studied via the response to radiation in lung cancer implementation of a structured patients, which involves staff working in patient preparation program for daily all disciplines including imaging. Our radiotherapy for men with localised PET program has influenced the prostate cancer. management of lung cancer worldwide, with six papers cited in the American eLearning Society of Clinical Oncology lung cancer A Victoria-wide web based electronic treatment guidelines; our criteria for learning (eLearning) program has response assessment after been developed for Image Guided chemoradiation in non-small cell lung Radiotherapy. This program brings cancer (NSCLC) have now been widely together all Victorian Radiation Oncology adopted by clinicians worldwide. departments in creating and utilising this resource. Recent treatment results for Peter Mac OVERVIEW Significant change and increase of and response assessment, together chemoradiation patients with NSCLC The Division of Radiation Oncology and complexity of radiotherapy treatment with the development of clinical dose show that the use of PET/CT for patient Cancer Imaging comprises Radiation technology is enabling further refinement escalation and body stereotactic selection and treatment planning has Oncology, Physical Sciences, Radiation of brachytherapy and external beam irradiation approaches using PET/CT led to survival that is among the best Therapy Services and Diagnostic radiotherapy methods, the development defined target volumes and gated ever reported anywhere in the world. and Molecular Imaging. Our integrated of image guided radiotherapy and acquisition of target volumes and research efforts range from basic patient motion management, use of with gated therapy delivery. novel ‘diagnostic imaging devices’ to science in cancer biology and physics, We are also actively involved assess the impact of organ motion on through translational research using in clinical trials. We have strong links planning dosimetry and target volume molecular biological and imaging with the Trans Tasman Radiation assessments. Increased integration of methods to clinical trials of innovative Oncology Group (TROG) and have imaging into the radiotherapy process treatment strategies. recently become a member of the is a key focus. Radiation Oncology and Cancer Radiation Therapy Oncology Group Imaging is a rapidly evolving discipline. The research efforts continue to grow, (RTOG), one of only three groups Consequently, to ensure patient particularly at the satellites, with outside of North America. We have treatments implemented at Peter Mac increasing emphasis on multidisciplinary affiliations with Melbourne University, are based on world’s best practice and team programs. As well as radiation RMIT, Monash and Wollongong enable Peter Mac to be actively involved oncologists, we have a very active group Universities and there are collaborations in clinical research, the department is of radiation medical physicists and with both applied and basic research. radiation therapists who are increasingly structured into ten specialist clinical units Figure 1: Recipient of the 2010 Prostate that focus on the various types of cancer. involved in collaborative projects. Much Cancer Foundation of America Creativity Award, of the research is investigator-initiated Assoc. Prof. Scott Williams is investigating if better Our focus of is to enhance the treatment and multidisciplinary, and is increasingly use of radiation therapy can more effectively treat prostate cancer. of cancer patients, using radiotherapy, attracting peer-reviewed funding. both as a single modality and in combined modality therapy with novel Major areas of research include chemotherapy and targeted therapy the successful program assessing the agents. utility of molecular imaging in staging, biological characterisation and treatment

Peter MacCallum Cancer Centre – Research Report 2010 Clinical and Tranlsational Research 81 2.1 Medical Oncology and Early Phase Clinical Trials 2.2 Breast Service

RESEARCH FOCUS Publication highlights included RESEARCH FOCUS Randomised trial of accelerated partial breast irradiation (RAPID) • New drug development and a population-based cohort study • Breast cancer genetics. early phase clinical trials focused of over 3,000 breast cancer patients This active trial evaluates if partial • Breast . on targeted therapies. which examined the association breast irradiation using external beam between reproductive risk factors and • Early stage breast cancer. 3D conformal radiotherapy is as effective • Establishing benefit of new death. Women who had had a full-term as the more protracted conventional therapies in phase 2 and 3 clinical pregnancy within two years prior to their • Locally advanced breast cancer. whole breast irradiation after breast trials including investigator initiated breast cancer diagnosis had a 2.75 • Metastatic breast cancer. conserving surgery for early breast cooperative group trials. times higher death rate (Phillips et al. cancer. If confirmed, partial breast • Survivorship issues. • Supportive care research Cancer Epidemiol Biomarkers Prev irradiation will improve convenience including survivorship. 18: 1792–1797, 2009). of care for patients and radiotherapy resource utilisation. • Familial cancer including risk In another study Peter Mac investigators 2010 RESEARCH ACHIEVEMENTS management and chemoprevention. found that the Australian general public International randomised wants to be informed about expensive A phase 3 study of radiation controlled trial to compare dose escalation and fractionation Head: Assoc. Prof. Danny Rischin anti-cancer drugs as potential treatment Head: Assoc. Prof. Boon Chua targeted intra-operative radiotherapy schedules in non-low risk ductal with conventional post-operative 2010 RESEARCH ACHIEVEMENTS options, even if they are not willing or carcinoma in-situ (DCIS) of the breast readily able to pay for them (Mileshkin radiotherapy after conservative The Department of Medical Oncology The Breast Service is actively This is a TROG (Trans Tasman Radiation Members of the department gave et al, J Clin Oncol Dec 1;27(34):5830-7, breast surgery for women with runs a large clinical research program progressing a strategic planning Oncology Group)-led trial in collaboration early stage breast cancer (TARGIT) a number of significant presentations 2009). that includes clinical trials of cancer at the American Society of Clinical and service development framework with the Breast International Group, The study showed that a single fraction therapeutics from early phase trials Oncology Annual Meeting. Assoc. Kelly Phillips won the award for best to establish national and international NCI Canada Clinical Trials Group of intra-operative radiotherapy targeted (with a focus on targeted therapies) Prof. Danny Rischin gave an oral oral presentation by a consultant at the leadership in research-driven (NCIC CTG), European Organisation to the tumour bed (partial breast to definitive phase III trials, studies presentation on the prognostic Medical Oncology Group of Australia multidisciplinary clinical programs for Research and Treatment of Cancer irradiation) is equivalent to standard exploring the clinical relevance of significance of human (MOGA), 30th Anniversary Annual for optimal patient outcomes. (EORTC), UK Breast Intergroup and post-operative whole breast radiotherapy new biologic findings, supportive care Scientific Meeting for her work on virus and p16 status in patients with Our strong and diverse research International Breast Cancer Trials after breast conserving surgery in women research including survivorship and Breast Cancer Prognosis In BRCA1 oropharyngeal cancer treated on a program, which encompasses Group (IBCSG). This active trial aims with early breast cancer, in terms of local psycho-social interventions, adolescent and BRCA2 Mutation Carriers: An large international phase 3 trial and laboratory, translational and clinical to individualise radiation therapy for control. The first results were published and young adult oncology research and International, Prospective, Population- Assoc. Prof. David Thomas reported research, draws on the collective women with DCIS of the breast and in The Lancet in 2010. familial cancer research including risk Based Cohort Study. is underpinned by an international on the activity of denosumab for the academic strengths of our members For more information on related management and chemoprevention. translational research program that treatment of giant cell tumour Grant highlights included a survivorship in collaboration with other leading research, see: of bone in an oral session. project in bowel cancer survivors led Peter Mac researchers and major investigates the biological profiles of by Assoc. Prof. Michael Jefford funded national and international clinical DCIS predictive of a high risk of invasive - Familial Cancer Centre (pg 114) Peter Mac investigators were co-authors breast cancer recurrence. on two of the most exciting trials with by Cancer Australia/Beyond Blue and trials groups. - kConFab Follow-Up Project (pg 116) new drugs presented at the meeting: the Victorian Cancer Agency (VCA); A phase 3 study of regional radiation a NHMRC project grant led by Assoc. therapy for early breast cancer • Assoc. Prof. Grant McArthur on Prof. Michael Michael to investigate This study evaluates if regional nodal the phase 1 trial of a BRAF inhibitor genomics and functional imaging irradiation in addition to whole breast which has shown significant activity to predict pharmacokinetics and radiation after breast conserving surgery in melanoma. pharmacodynamics; translational and systemic therapy improves overall • Dr Ben Solomon on a phase I study cancer research grants from VCA in survival for early breast cancer. The first of a drug that inhibits the ALK receptor melanoma led by Assoc. Prof. Grant results of the study will be presented at which has shown very promising McArthur and in sarcoma led by the American Society of Clinical Oncology activity in patients with ALK positive Assoc. Prof. David Thomas. Annual Scientific Meeting in 2011. lung cancer.

Peter MacCallum Cancer Centre – Research Report 2010 Clinical and Tranlsational Research 83 2.3 Gastrointestinal Service 2.4 Gynae-oncology Service

RESEARCH FOCUS 2010 RESEARCH ACHIEVEMENTS RESEARCH FOCUS Adjuvant chemotherapy • Translational and multi-modality The GastrointestinaI Service aims to Assessing and improving in endometrial cancer approaches of surgery, radiation optimise and individualise the treatment the treatment of: The PORTEC 3 study aims to assess with chemotherapy and/or biological of GI malignancies through several the role of adjuvant chemotherapy • Cervical cancer. agents in the treatment of all research initiatives: for patients receiving post-operative gastrointestinal (GI) malignancies, • Endometiral carcinoma. radiation treatment for high risk The evaluation of novel endometrial cancer; Peter Mac is in particular rectal, gastric and combined modality therapies • Ovarian carcinoma. anal cancers. the highest recruiting site to this large with the commencement of novel international study which is supported chemoradiotherapy trials for • Predicting the efficacy of by a grant from the NHMRC. Dr Linda rectal cancer chemoradiotherapy through 2010 RESEARCH ACHIEVEMENTS Mileshkin is the study chair for the This involves the evaluation of novel genomic approaches in rectal Australia New Zealand Gynaecological combinations of agents to both optimise Nurse led interventions and oesophageal cancers. Oncology Group (ANZGOG). Dr Pearly the control of local disease and micro- Peter Mac’s Gynae-oncology Service Khaw is the radiation oncology lead • Phase 1 to 3 studies of new drugs and and macroscopic metastatic disease is dedicated to developing and for the study who is working with TROG Head: Assoc. Prof. Michael Michael novel combined modality regimens. as well as increasing radiosenstisation Head: Assoc. Prof. Kailash Narayan delivering improved supportive care. to perform quality assurance for the • Participation in national and in rectal cancer. Led by Prof. Penny Schofield, behavioural researcher, a national study. The Gastrointestinal Service is multinational phase 2–3 clinical trials The Gynae-oncology Service The evaluation of functional imaging study into the role of nurse led a multidisciplinary therapeutic is a multidisciplinary program If positive, OUTBACK and PORTEC 3 • Predicting chemotherapy drug handling, and pharmacogenomics in several interventions supported by trained program for patients with upper settings to predict prognosis, tumour with a research focus directed will change the standard of care for toxicity and efficacy by functional cancer peers is underway. Recruiting and lower gastrointestinal cancers. response and normal tissue toxicity at understanding and improving women with high-risk endometrial imaging, pharmacogenomics (normal patients nationwide into a process Our research focus is directed, from for several malignancies to systemic the management and treatment and cervical cancers. host tissues and tumour tissues) with of education and support, this study the institutional to international level, and combined modality therapies of gynae-oncology patients. the aim of individualising treatment. is unique in that it includes peer support The value of PARP inhibitors towards the evaluation of new These will hopefully enable us to in treatment of ovarian cancer In particular in colon cancer and from carefully chosen long- therapeutic strategies to provide individualise therapy (agents used gastrointestinal stromal tumours term survivors, offering them a role in Several open studies are assessing optimal individualised care for and treatment intensity) to increase (GISTs). supporting newly diagnosed patients on the value of PARP inhibitors in the our patients. tumour control, whilst reducing their journey through cancer treatment. treatment of women with relapsed toxicity and to improve patients overall ovarian cancer. These targeted agents survival. Specific work is being carried Adjuvant systemic chemotherapy are particularly effective in women out in oesophageal cancer, colorectal in cervical cancer treatment known to have a genetic predisposition cancer and anal cancers. The OUTBACK randomised phase 3 to ovarian cancer due to a BRCA1 Technological evaluation study being developed by Dr Linda or BRCA2 mutation. Their value is also Mileshkin and Assoc. Prof. Kailash The evaluation of novel technologies being assessed in women with sporadic Narayan aims to assess the value such as Robotics, IORT, stereotactic ovarian cancer. In addition, our patients of additional adjuvant systemic radiotherapy to optimise local treatment participate in phase 1 trials open through chemotherapy for patients who have of GI malignancies. of Cancer Medicine. completed definitive chemo-radiation These have led to several ongoing treatment for locally advanced cervical trials supported by research funding cancer. This trial will be run internationally and postgraduate research fellows. through the Gynaecologic Cancer The program has been supported Intergroup and led by the Australia by competitive grants from post- New Zealand Gynaecological Oncology graduate research scholarships, Group (ANZGOG) in collaboration with the NHMRC and Cancer Australia the NHMRC Clinical Trials Centre. as well as industry support.

Peter MacCallum Cancer Centre – Research Report 2010 Clinical and Tranlsational Research 85 2.5 Haematology Service 2.6 Head and Neck Service

RESEARCH FOCUS • Detailed exploration of the mechanism RESEARCH FOCUS Radiotherapy with Humidification in Head & Neck Cancer (RadioHum) • Novel therapies for multiple myeloma, of action of immunomodulatory drugs • Improving clinical outcomes and their immunologic basis of activity. revlimid and thalidomide used in for head and neck cancer patients. A randomised Phase III trial of TROG in multiple myeloma, and the detrimental collaboration with Fisher and Paykel • Early phase development of novel effects of the commonly used • Investigating novel head and neck Healthcare. This study uses simple therapeutics, particularly monoclonal agent dexamethasone. cancer treatments with a focus humidification aiming to reduce the antibodies and epigenetic therapies. on hypoxia. severity and duration of patients painful • Presentation and publication of the mucositis. Study principal investigators • Enhancing the efficacy and safety first study demonstrating the benefits • Minimising treatment side-effects are Dr Andrew McCann (NZ) and Dr of nucleoside analogue combination of maintenance treatment with the with a focus on Intensity-Modulated Tsien Fua from Peter Mac. therapies in indolent monoclonal antibody Rituximab as Radiation Therapy (IMRT). lymphoproliferative disorders. part of the initial chemo-immunotherapy A Phase I/II Study of Cetuximab, • A state-wide referral centre for treatment program for patients with Carboplatin and Radiotherapy the management of cutaneous follicular lymphoma. 2010 RESEARCH ACHIEVEMENTS in patients with locally advanced head and neck cancer lymphomas and investigation of • Confirmation of the superior Peter Mac’s Head and Neck Service Head: Prof. John Seymour Head: Assoc. Prof. June Corry This study focuses on a unique group novel therapies for these diseases. therapeutic activity of the has 25 clinical research projects of head and neck cancer patients not hypomethylating agent currently in progress. Some examples • A recognised centre of excellence previously studied — those unable to The Haematology Service conducts a over conventional therapies in elderly Peter Mac’s Head and Neck Service of institutional, national and international for management of myelodysplastic have cisplatin treatment. Study co-chairs broad range of clinical and translational patients with acute myeloid is the largest in Australia and offers collaborations include: syndromes and myeloproliferative are Assoc. Profs. Danny Rischin and research studies focused on patients leuekaemia. comprehensive diagnostic and disorders, including the development Trans-Tasman Radiation Oncology June Corry. with haematologic malignancies — treatment services to cancer patients of novel treatments such as Jak-2 • Confirmation of the activity of the Group study on Post-operative on pathogenesis, supportive care and throughout Victoria. Patient care IHN01 Study — Randomised study inhibitors. immunotoxin conjugate deileukein concurrent chemo-radiotherapy the enhancement of long-term quality of is provided by an experienced of cisplatin-RT ± nimotuzumab diftotox in cutaneous T-cell lymphomas, in high risk cutaneous squamous life. Key conditions on which we focus multidisciplinary team of radiation cell carcinoma of the head and neck A collaboration with Singapore National in a study which supported the include multiple myeloma, non-Hodgkin oncologists, medical oncologists, Cancer Centre (NCC), this is a study 2010 RESEARCH ACHIEVEMENTS licensing of this agent internationally. This study is the first looking at new lymphoma, chronic lymphocytic surgeons, diagnostic radiologist, treatment strategies for high risk skin intensifying adjuvant treatment after leukaemia and the myelodysplastic The focus of our research is • Demonstration of the activity of nursing, radiotherapists, social workers, cancer. Study co-chairs are Assoc. Prof. surgery using a new biological drug syndromes. improving our understanding of the epidentic agent romidepsin dietitians, dental oncologists and Sandro Porceddu, and Assoc. Profs. in addition to chemotherapy and disease pathogenesis, improving in patients with T cell lymphomas, speech pathologists. A key feature Danny Rischin and June Corry from radiotherapy. Study principal treatments, enhancing supportive care, which are very difficult to treat with of our service is expertise in the Peter Mac. The primary objective of investigators are Prof. Khee Chee and enhancing the long-term health conventional agents. complex and technically challenging the trial is to determine, in patients Soo (Singapore NCC) and Assoc. status of patients with haematologic • Early phase development of novel planning of head and neck radiotherapy who have undergone surgery with Prof. June Corry. malignancies. We have pursued treatment. We also offer expertise therapeutics. This high priority area curative intent for high-risk cutaneous a broad and varied clinical and of research includes the following and on-site delivery of concurrent squamous cell carcinoma (CSCC) of translational research program, clinical investigations: chemo-radiotherapy and, when the head and neck, whether there is which incorporates our own initiatives, appropriate, the availability of novel a difference in time to loco-regional cooperative group trials — particularly - A co-ordinated suite of ongoing agents through phase I/II studies. relapse between patients treated those of the Australasian Leukaemia studies into novel therapies The Head and Neck Service has a with post-operative concurrent chemo- and Lymphoma Group (ALLG) — for multiple myeloma. strong international profile based on its radiotherapy (consisting of Carboplatin) and pharmaceutical industry studies. - Ongoing trials of the novel pro- published record of clinical research, and patients treated with post-operative At every opportunity we seek to apoptotic agent ABT263 in patients which underpins optimal patient care. radiotherapy alone. enhance translational research with chronic lymphocytic leukaemia. productivity and collaborate with laboratory-based research colleagues, - Optimising therapeutic approaches particularly in the Cancer Therapeutics, for indolent lymphoproliferative Cancer Immunology, and Haematology disorders. Immunology Translational Research - Exploration of the novel laboratory programs. Jak-2 inhibitor SB15158 in 2010 was very successful, with myeloproliferative disorders. more than 30 international conference For more information on related presentations, and 52 peer-reviewed research, see: publications by the medical, nursing, › Cancer Immunology program (pg 24) and laboratory staff of the Haematology, Service including numerous influential › Cancer Therapeutics program (pg 62) reports: › Haematology Immunology Translational Research Laboratory (pg 30)

Peter MacCallum Cancer Centre – Research Report 2010 Clinical and Tranlsational Research 87 2.7 Lung Service 2.8 Melanoma and Skin Service

RESEARCH FOCUS FLT PET study RESEARCH FOCUS Biopsy • Molecular imaging and prognostic A study of tumour cell kinetics during • Evaluation of novel therapeutics The focus of our Surgical Oncology team factors. radical radiotherapy using the novel in melanoma. remains centered around the ever- tracer FLT was completed in 2010, with evolving role of Sentinel Lymph Node • Development of novel therapies NHMRC funding secured by Dr Sarah • Integration of molecular analysis Biopsy. We continue to participate in the for non-small cell lung cancer. Everitt to continue this work into 2011. of melanoma with clinical care. MSLT 2 International Multi Centre Trial regarding the ongoing management of • Symptom palliation. 4D PET/CT • Targeted therapies in skin cancer. patients with positive Sentinel Lymph • Psychosocial research. • Role of radiotherapy in melanoma The influence of 4D PET/CT on Nodes in Melanoma. The unit has also and other skin cancers. radiotherapy planning is under presented significant data on the role of investigation. staging, in particular with PET scans in 2010 RESEARCH ACHIEVEMENTS SAFRON study stage 3A disease, 2010 RESEARCH ACHIEVEMENTS The CHISEL randomised trial A pilot study of single dose stereotactic and also in patients with high risk primary A Cancer Australia funded trial radiotherapy for patients with secondary The Melbourne Melanoma Project lesions. We continue to investigate Head: Prof. David Ball comparing conventional radiotherapy lung cancers is being led by Dr Shankar Head: Assoc. Prof. David Speakman This is a tissue banking and database ways to avoid the morbidity of radical (33 treatments) with hypofractionated Siva. The cancers will be studied using program with the potential to unlock the lymphadenectomy. stereotactic radiotherapy (three perfusion CT to determine if the tumour further molecular secrets of melanoma Peter Mac’s Lung Service promotes The Melanoma and Skin Service treatments) for stage I peripherally killing effect of this treatment is achieved and with significant potential to develop and facilitates clinical, translational undertakes translational and clinical located lung cancers. This is now through an effect on its blood supply. improved therapeutic strategies for For more information on related and supportive care research directed research in melanoma and non- a collaborative national study of the management by identifying specific research, see: at improving outcomes for patients FGFR1 amplification melanoma skin cancer with a focus Trans-Tasman Radiation Oncology targets related to melanoma. We have Clinical Trial Unit (pg 112) with lung cancer and other thoracic in squamous cell carcinoma on integrating research with - Group (TROG) and the Australasian expanded the range of local therapies malignancies. This project, conducted in multidisciplinary care of patients - Translational Research Laboratory Lung Cancer Trails Group. This study to combat locoregional disease with the conjunction with St Vincent’s Hospital with skin cancer. (pg 67) may lead ultimately to the availability use of photodynamic and microwave and international collaborators based of an effective non-surgical treatment There have been significant therapies and focused laser along in Cologne, Germany, has identified option for patients with early stage developments in the treatment options with the standards of surgery and overexpression of a factor (FGFR1) lung cancer. Work on Quality Assurance for patients with advanced skin radiotherapy for patients in whom in a common type of lung cancer for the CHISEL Trial was presented cancers, and we are in the fortunate progressive disease has a high impact which may make the cancer susceptible by Natalie Clements at the 52nd position of being at the forefront of the on their daily lives and routines. to inhibition of FGFR1. This is the first Annual meeting of the American newest agents to control this disease. time a factor of this type has been BRAF inhibitors in Association of Physicists in Medicine detected in patients with squamous melanoma treatment in Philadelphia, USA. cell carcinoma. This study was funded The Melanoma and Skin Service has in part by the Peter Mac Foundation, been involved in trials of PLX4032 — and published in Science Translational a highly promising BRAF inhibitor to Medicine in December 2010. combat melanoma in its more advanced stages. This work provides the strongest Chemotherapy studies light yet for patients with progressive Peter Mac’s Lung Service has a number disease, and we continue to be involved of active chemotherapy studies, including: in first-line trials of this agent (see Clinical • The Canadian led BR29 randomised Trials Unit, pg 112). study of chemotherapy with and without AZD 2171. • A phase 3 study of chemotherapy and crizotinib in patients with ALK mutations. • The GATE study of erlotinib and gemcitabine in elderly or poor performance status patients.

Peter MacCallum Cancer Centre – Research Report 2010 Clinical and Tranlsational Research 89 2.9 Paediatrics and Late Effects Service 2.10 Sarcoma Service

RESEARCH FOCUS 2010 RESEARCH ACHIEVEMENTS RESEARCH FOCUS The Livestrong Young Adult Alliance • Understanding and improving the Peter Mac’s Paediatrics and Late Effects • The identification and characterisation Osteosarcoma Meta-analysis treatment of children with cancer. Service is developing guidelines and of a novel tumour suppressor gene In collaboration with co-operative protocols that will, over the next few in osteosarcoma, Wif1 (see Sarcoma oncology groups internationally, we have • Cooperative research into childhood years, result in the development Genetics and Genomics laboratory, conducted the world’s largest meta- brain tumours. of research protocols. We are also pg 35). analysis of outcomes for patients with • Novel supportive care interventions developing an important network of curable osteosarcoma. This study, • The role of the immune system for children undergoing radiotherapy. supportive care projects to investigate involving over 4,000 patients from 26 in osteosarcoma. clinical trials, has shown that there are • Physical and psychology health of the effects of the process of radiotherapy • Clinical trials of denosumab in important gender- and age-related the ‘survivors’ attending the clinic. on children. These projects include music therapy, information books Giant Cell Tumour of bone, and differences in side effects and treatment Our main research focus is to participate and video creation. of antiangiogenic agents in soft-tissue response for patients with osteosarcoma. in international cooperative group sarcoma. Denosumab and Giant Cell studies. Our portfolio of local studies is Recent local protocols, guidelines and collaborations have started to bear • Understanding inherited cancer risk Tumour(GCT) of bone Head: Dr Greg Wheeler also expanding. Head: Prof. Peter Choong fruit, with two Public Health Care Awards in sarcoma families. Peter Mac has played a key role in the and a VCA Supportive Care Research development of denosumab in GCT, The Paediatrics and Late Effects Capacity Building grant awarded in The Sarcoma Service provides resulting in a lead author publication of the Service is contributing to developments 2010. Further research initiatives are access to leading treatments through 2010 RESEARCH ACHIEVEMENTS first clinical study in Lancet Oncology in in a number of institutional, national being developed in both technical and an active clinical trials program, 2010. Denosumab has shown remarkable The Australian Sarcoma biological and clinical activity in GCT, and and international clinical and translation supportive care fields so that we may and supports basic and translational Study Group(ASSG) better care for children as they undergo research programs in osteosarcoma is now being explored in follow up studies. trials into the treatment and clinical The ASSG, a national cooperative aiming radiation therapy and subsequently and liposarcoma, and adolescent outcomes of children with cancer. to facilitate access to leading treatments Sarcoma Service Nursing highlights throughout their lives. and young adult cancer. through translational and clinical research, Regular nursing education forums, held We remain committed to participation is hubbed at Peter Mac. The group’s chief in conjunction with staff at St Vincents in the Children’s Oncology Group aim is to develop and coordinate cohesive Hospital, begun in 2010. These forums Cooperative trials in conjunction with clinical trials and basic research while still focus on the medical and psychosocial The Royal Children’s Hospital and the St focusing on community education and care of sarcoma patients undergoing Jude Meduoblastoma consortium in the patient advocacy of sarcomas. In the last multimodal therapy between Peter Mac SJMB03 study. This study investigates 18 months, Peter Mac has enrolled over and St Vincent’s. the genetic makeup of tumours related 250 patients on the national sarcoma- For more information on related research, to treatment outcomes and cognitive specific clinical database. see: Sarcoma Genetics and Genomics effects of treatments of patients with The Rainbows for Kate International laboratory (pg 35) newly diagnosed childhood brain Sarcoma Kindred Study tumours known as medulloblastoma, Sarcomas are uncommon cancers that supratentorial primitive neuroectodermal disproportionately affect young people tumour (PNET), or atypical teratoid with a high mortality and significant rhabdoid tumour (ATRT). morbidity. The Rainbows for Kate International Sarcoma Kindred Study (ISKS) is creating a resource to investigate the familial aspects of adult-onset sarcoma. After 12 months, we have over 400 fully consented participants across five states, above the projected rate, and we expect to meet the national target of 600 index cases within three years. We are now opening sites in India, France and New Zealand, making this a global study. Early data confirm powerful underlying genetic factors present in families with sarcoma. In the coming years the ISKS resource will be invaluable in elucidating these factors and improving outcomes for those families affected by sarcoma.

Peter MacCallum Cancer Centre – Research Report 2010 Clinical and Tranlsational Research 91 2.11 Uro-oncology Service Clinical and Translational Research – personnel

RESEARCH FOCUS Recent research highlights include: Cancer medicine Medical Physicist Gynae-oncology Service • Multidisciplinary care. • The introduction of robotic surgery Prof. John Zalcberg, OAM Prof. Tomas Kron Chair • Nursing interventions to Peter Mac with the installation of Radiation Therapists Assoc. Prof. Kailash Narayan a da Vinci© Surgical System, a first cancer surgery and supportive care. Katie Davidson Medical Oncologist for a Victoria public hospital. The da Assoc. Prof. Alexander Heriot Brigid Moran • Image guided and adaptive Dr Linda Mileshkin Vinci© system was delivered as part David Willis radiation oncology radiotherapy. of the Academic Cancer Robotic Radiation Oncologists AND Cancer imaging • Testicular cancer. Cancer Surgery Program directed Gastrointestinal Service Dr David Bernshaw Prof. Gillian Duchesne by Assoc. Prof. Declan Murphy, who Chair Dr Pearly Khaw • Prostate, bladder and renal cancer. has been awarded a two-year grant Assoc. Prof. Michael Michael Dr Bronwyn King from the Victorian Policy Advisory Breast Service Committee on Technology to enable Chair Deputy Chair Brachytherapist 2010 RESEARCH ACHIEVEMENTS a detailed evaluation of the clinical Assoc. Prof. Boon Chua Mr Bruce Mann Sylvia van Dyk The research of Peter Mac’s Uro-oncology and health-economic impact of using Medical Oncologists Medical Oncologists Visiting Fellow Head: Dr Farshad Foroudi Service is aimed at improving the clinical this technology within the public Dr Alex Boussioutas Dr Joanne Alfieri outcomes of patients. Through surgical hospital system. Dr Ian Collins, Fellow Dr Prudence Francis Assoc. Prof. Michael Jefford The Uro-oncology Service is a innovations we aims to reduce Haematology Service • Assoc. Prof. Scott Williams continues Dr Marisa Grossi Prof. John Zalcberg, OAM multidisciplinary clinical unit offering perioperative stay and pain as well as to alead a project that brings together Dr Sandra Harvey (Breast Cancer Dr Alan Zimet Chair treatment for all forms of uro-oncology shorten the time needed to return unique data from Peter Mac’s Genetics and Survivorship Fellow) Prof. John Seymour malignancies. Our Service offers tertiary to work. Developments in radiation Radiation Oncologists excellence in imaging, biology, external Dr Ross Jennens care including all forms of surgical oncology should have the dual benefits Dr Julie Chu Consultant Haematologists beam radiation and brachytherapy Dr Gillian Mitchell management, radiation oncology of reducing toxicity in terms of Dr Trevor Leong Dr Kate Burbury fields to provide new insights into Assoc. Prof. Kelly Phillips techniques and systemic therapy. surrounding normal tissues as well as how to optimally treat prostate cancer Assoc. Prof. Sam Ngan Dr Dennis Carney We have links to co-operative research the improving local control. Involvement with radiation therapy. Radiation Oncologists Dr Kirsty Wiltshire Dr Simon Harrison in multiple clinical studies will help Dr Kirsten Herbert (CCV Fellow) groups and laboratory based research. Dr Jill Ainslie Surgical Oncologists provide the basis of future therapies. Dr Michelle Bishop Dr Henry Januszewicz Our Service is also involved in a Mr Simon Banting Dr Steven David Prof. Miles Prince number of supportive care programs Mr Cuong Duong Dr Roslyn Drummond Assoc. Prof. David Ritchie and patients are offered co-ordinated Assoc. Prof. Sandy Heriot Dr Mary Dwyer Dr Stephen Ting care. Mr Craig Lynch Dr Tracie Gleisner Dr David Westerman Assoc. Prof. John Mackay Dr Bronwyn King Assoc. Prof. Max Wolf Mr Bruce Mann Dr Chen Liu Mr John Spillane Research Fellows Dr Claire Phillips Mr Ben Thomson Dr Michael Dickinson Dr Phillip Tran Dr Amit Khot Anatomical Pathologists Surgical Oncologists Dr Bill Murray (Head) Nurse Coordinators Assoc. Prof. Michael Henderson Dr Catherine Mitchell Odette Blewitt Miss Jane O’Brien Sharna Debham Miss Cathie Poliness Nuclear Medicine Physicians Catherine Grima Miss Anita Skandarajah Prof. Rod Hicks Kristen Houdyk Assoc. Prof. David Speakman Mr Michael Hoffman Trish Joyce Miss Chantel Thornton, Fellow Dr Grace Kong Yvonne Panek-Hudson Pathology Dr Kate Moodie Prof. Stephen Fox Radiologists Dr Catherine Mitchell Dr Nick Ferris Cancer Imaging Surgical Oncology laboratory Prof. Rod Hicks Assoc. Prof. Wayne Phillips (Head) Dr Alexander Cochet, PET Fellow Postgraduate Students Dr Kate Moodie Dr Brooke Sawyer Dr Charles Pilgrim Dr Henry To Familial Cancer Centre Dr Gillian Mitchell

Peter MacCallum Cancer Centre – Research Report 2010 Clinical and Tranlsational Research 93 Clinical and Translational Research – personnel

Head and Neck Service Lung Service Research Manager Paediatrics and Sarcoma Service Uro-oncology Service Late Effects Service Chair Chair Virginia Tuckwell Chair Chair Assoc. Prof. June Corry Prof. David Ball Study Coordinator Chair Prof. Peter Choong Dr Farshad Foroudi Dr Greg Wheeler Medical Oncologists Medical Oncologists Deborah Cruickshank Surgical Oncologists Radiation Oncologists Assoc. Prof Danny Rischin Assoc. Prof. Michael Michael Research Division Radiation Oncologists Assoc. Prof. Michael Henderson Prof. Gillian Duchesne Dr Annette Lim Assoc. Prof. Linda Mileshkin Assoc. Prof. Alex Dobrovic Dr Kate Cardale Mr Gerard Powell Dr Sarat Chander Dr Ben Solomon Dr Ben Solomon Dr Mary Dwyer Dr Farshad Foroudi Consultants Melanoma and Skin Service Dr Keen Hun Tai Radiation Oncologists Radiation Oncologists Radiation Therapists Assoc. Prof. Samuel Ngan Assoc. Prof. Scott Williams Assoc. Prof June Corry Prof. David Ball Chair Katie Davidson Assoc. Prof. David Thomas Dr Andrew Coleman Dr Belinda Campbell Assoc. Prof. David Speakman Julia McAlpine Dr Jayesh Desai Urologists Brigid Moran Dr Ieta D’Costa Dr Steven David Medical Oncologists Dr Ken Khamly Assoc. Prof. Laurence Cleeve Dr Tsien Fua Assoc. Prof. Michael Mac Manus David Tongs Dr Sarat Chander Mr Jeremy Goad Dr Ben Brady Dr Chen Liu Dr Nikki Plumridge David Willis Dr Julie Chu Assoc. Prof. Declan Murphy Dr Damien Kee Dr Mark Lee Dr Mark Shaw Assoc. Prof. Grant McArthur Nurse Coordinators Paediatric Oncologist Medical Oncologist Dr Greg Wheeler Surgical Oncologists Dr Mark Shackleton Priscilla Gates Assoc. Prof. Andrew Wirth Dr Lisa Orme Assoc. Prof. Guy Toner Mr Sorway Chan Natalie Goroncy Radiation Oncologists Australian Sarcoma Study Group Nursing Mr Stephen Kleid Thoracic Surgeons Frances Ness Dr Vanessa Estall Prof. Andrew Sizeland Mr Phillip Antippa Jessy Thambiraj Dr Sally Whyte (Executive Officer) Mary Leahy (Coordinator) Dr Andrew Hui Mr Gavin Wright Dr Mandy Ballinger (Project Manager, Katherine Schubach Dietitian Dr Mark Lee Music Therapist ISK Study) Research Radiation Therapists Nicole Kiss Respiratory Dr Mathew Seel Pip Barry Assoc. Prof. Lou Irving Daniel Pham Nurse Coordinator Surgical Oncologists Neurologist Dr Renee Manser David Tongs Wendy Poon Mr Felix Behan Dr Richard Stark Cancer Imaging Mr Simon Donahoe Anatomical Pathologist Psychology/Psychiatric Service Prof. Rod Hicks Assoc. Prof. Michael Henderson Dr Catherine Mitchell Annabel Pollard Mr Miki Pohl Diagnostic Radiologist Kate Neilson Psychosocial Mr John Spillane Dr Jeremy Cooper Assoc. Prof. Penny Schofield Dr Colin Styles Pathologist Research Fellow Radiotherapy Charge Nurse Coordinator Dr Sarah Swain Sue Walsham Mary Duffy Suki Gill Speech Pathologist Structural Imaging Statistician Louise Dobbie Dr Brooke Sawyer Alan Herschtal Translational Research Physicists Assoc. Prof. Alex Dobrovic Prof. Tomas Kron Richard Young (Principal Research Physicist) Assoc. Prof. Annette Haworth (Clinical Research Physicist) Radiation Therapists Yolanda Aarons Dr Sarah Everitt Radiologist Assoc. Prof. Eddie Lau Nuclear Medicine Physician Dr Michael Hofman Statisticians Assoc. Prof. Richard Fisher Alan Herschtal Radiation Oncology Fellow Danny Duplan Radiation Oncology Registrar Dr Shanker Siva

Peter MacCallum Cancer Centre – Research Report 2010 Clinical and Tranlsational Research 95 3 Enabling Technologies and 3.1 Enabling Technology Platforms Interdisciplinary Research Platforms 3 Across Peter Mac, there is a breadth of expertise and resources that form the foundations of our laboratory, clinical and translational research, facilitating and identifying new research directions and achievements.

Dr Richard Tothill, Manager of the Collaborative projects are central Molecular Genomics technology to Peter Mac’s research ethos. platform, is also co-leader of several ‘When the brightest minds come collaborative Peter Mac projects, together from differing perspectives, including identifying the molecular there is stronger potential to generate characterisation of lymphoma arising new therapeutics, better predicative in a transgenic mammalian model diagnostics, and more chances (with Assoc. Prof. Ricky Johnstone, to effectively supplement existing Gene Regulation laboratory) anti-cancer treatments.’ and discovering novel mutations associated with rare neuroendocrine cancers (with Prof. Rod Hicks, Translation Research Laboratory).

Peter MacCallum Cancer Centre – Research Report 2010 3.1 Enabling Technology Platforms 3.1.1 Functional Genomics facility

The application of this technology The high-end instruments that we house, Our enabling technologies are the backbone is limited only to the imagination of all of which are fully automated and bar the researcher and, as such, the facility code reader enabled, include: of our laboratory research, providing the is dedicated to assisting researchers • Cellomics ArrayScan VTi microscope. meet their goals. Our team provides cutting-edge technology needed to facilitate critical advice on experimental design, • BioTek 406 for liquid handling and research, and the expertise to identify, import assay development, high throughput cell dispensing. workflows, ongoing instrument training • BioTek Synergy 4 plate reader which and develop vital new resources. and support and bioinformatics analysis reads absorbance and fluorescence of data. and has a monochromator to measure The facility currently operates three assays at any wavelength, kinetic An extensive enabling base Functional Genomics facility main platforms; assay option, luciferase reading of platform technologies and Dr Kaylene Simpson and low volume DNA quantitation. interdisciplinary research completes 1) A lentiviral-based short hairpin Molecular Genomics facility microRNAi (shRNAmir) strategy, • Calliper ALH3000 liquid handling robot the research structure that underpins Head: Dr Kaylene Simpson our nationally and internationally Dr Richard Tothill enabling the shRNA sequences to be for library management and transfection. recognised research. Bioinformatics facility delivered to human cell lines and primary • Liconics 220 tower incubator. The Functional Genomics facility cells using a viral infectivity approach. Dr Gian Sberna With a focus on developing and provides cutting edge, high-end Such an approach allows for short or • Velocity 11 Plate Loc automated implementing advanced technologies, Flow Cytometry facility technology infrastructure and expertise long term gene knockdown. Human plate sealer. our enabling research platforms are Ralph Rossi to enable researchers to analyse and mouse genome-wide viral pools Over the course of this year, the led by experienced specialists and gene function using high throughput or boutique gene family collections supported by highly trained teams who Microscopy facility Functional Genomics facility has RNA interference approaches. are available. welcomed a large number of users help drive our key scientific directions Sarah Ellis and fulfil our strategic focus. 2) Synthetic siRNAs (short interfering) and two genome-wide siRNA screens Media and Laboratory in the form of SMARTpool reagents were initiated, whilst many are in the Services facility OVERVIEW (four sequences targeting one gene in a assay development phase. A number Lara Sekhon The Functional Genomics facility houses single well) are transiently transfected of high profile researchers in the field visited PeterMac, presented a seminar Tissue Bank facility the Victorian Centre for Functional into cell lines and analysed 72-96 hours and held discussion time with members Sam Cauberg Genomics and the Australian Cancer later. The functional effects of gene Research Foundation Victorian Centre knockdown are evaluated at the cellular of the facility. Dr Simpson initiated the for Functional Genomics in Cancer. level using high throughput microscopy inaugural RNAi Australia meeting in July The facility offers unprecedented access or by using a fluorescence plate reader and also co-organised the Australian to evaluate the function of all the genes for overall measurement of cell survival High Content Screening meeting, both in the human and mouse genomes by or reporter gene expression. Following of enormous relevance to the facility. using gene knockdown technology. the primary screen, validation libraries For more information on the comprising the individual SMARTpool The ability to assess the function of Functional Genomics facility, visit: sequences arrayed in single wells are each gene in the human genome will then interrogated to create a subset of www.petermac.org/Research/ACRF allow researchers to discover genes gene ‘hits’ that are high confidence and CentreforFunctionalGenomicsinCancer that play critical roles in disease states, suitable for more detailed biochemical such as cancer. Open to medical and molecular analysis. We house human researchers Australia-wide, we provide and mouse genome-wide SMARTpool expertise in the use of high throughput and individual siRNA libraries. technologies and unparalleled access to RNAi interference reagents and 3) Synthetic microRNA screening imaging technology. reagents, allow parallel over-expression and knockdown of all the individual The Functional Genomics facility human miRNAs currently encoded in enables researchers to perform the human genome. Cell transfection unbiased gene discovery experiments protocols follow a similar process using RNA interference that would as for siRNAs and permit short term otherwise be impossible to do in a assays (generally inside one week). regular laboratory.

Peter MacCallum Cancer Centre – Research Report 2009 Enabling Technologies and Interdisciplinary Research Platforms 99 3.1.2 Molecular Genomics facility 3.1.3 Bioinformatics facility

OVERVIEW One large project funded by the OVERVIEW We have subsequently placed a Next generation sequencing is a Peter Mac Foundation involved The Bioinformatics facility at Peter Mac substantial focus on meeting this sharp revolutionary genomics platform that has collaboration of more than ten provides statistical and computational rise in the demand for bioinformatics a number of applications including DNA laboratories with the aim to sequence support for researchers to analyse support by recruiting additional resequencing, transcriptional profiling 250 cancers across more than and interpret the results of their personnel, expanding computational and epigenomics. The sequencing core 500 genes of interest. This work was biological data, including gene capacity and establishing strategic offers PCR clean laboratory space and completed in 2010 with data made expression and genotyping microarray collaborations with external access to all reagents and equipment available to researchers through a data, next generation sequencing data bioinformatics and high performance required for library preparation, while web-based database also developed and high throughput siRNA screening computing groups. within the Molecular Genomics facility. the sequencing process itself is based data. The analysts in the Bioinformatics We also provide and maintain computer on a fee-for-service model. Alternatively, Other notable research projects facility work closely with experimental workstations with commercial and open users have a full service option, starting included: a VBCRC funded project from scientists and clinicians to ensure the source bioinformatics specialty with submission of nucleic acids taken the VBCRC Cancer Genetics laboratory biological assumptions and subsequent software packages. Workshops are right through to data output. focusing on a genome-wide screen translational relevance of their studies regularly held by core staff for training Head: Dr Richard Tothill Head: Dr Gian Sberna are fully considered when building or The microarray laboratory also for mutations predisposing to breast in the use of these software packages. selecting an appropriate analysis model. provides access to necessary cancer in kConFab family cohorts, The use of these workstations and a study searching for novel cancer bioinformatics consulting services The Molecular Genomics facility microarray instrumentation as well as The Bioinformatics facility provides The Division of Cancer Research genes in ovarian cancer (VBCRC are cost recovered. at Peter Mac provides state-of-the-art complete Affymetrix microarray services statistical and computational support currently operates an Illumina GAIIx Cancer Genetics laboratory pg 37) facilities and expertise in the use of to both internal and external researchers. for the analysis of high-throughput sequencer and also has access to For more information on the and a project focusing on the mapping further next generation sequencing next generation sequencing, microarray The facility is committed to protocol biological data including, but not Bioinformatics facility, visit: of the ribosomal transcription factor instruments offsite. These platforms technologies and associated development, provision of reagents limited to, DNA microarray and next www.petermac.org/Research/ UBF in mouse fibroblasts (Growth produce large-scale amounts of data instrumentation to facilitate genetic/ for new methodologies and is generation sequencing data. Bioinformatics Control laboratory, pg 42). that require advanced bioinformatics genomics related cancer research. continuously surveying the genomics analysis. Picture courtesy of Bio21 Cluster technology arena for new genomics More than 900 Affymetrix microarrays related technologies, tools and products, were processed through the facility in facilitating their introduction into Peter 2010, with completion of several studies Mac to ensure our research remains including a large pharmacogenomics internationally competitive. study in ovarian cancer as part of the Pfizer genomics program. Demand The Molecular Genomics facility for microarrays remains strong with principally offers access to the Illumina an increase in interest from external GAIIx sequencing platform, and providers following advertising of the Affymetrix microarray platform but also facility through the Victorian Platform supports other microarray platforms Technologies Network (VPTN). including Agilent. For more information on related A significant amount of development research, see: work was invested in the next generation sequencing facility during 2010 including - Cancer Genetics program (pg 32) the development of a fully integrated - Cancer Therapeutics program (pg 62) LIMS system for pipeline sample - Growth Control and Differentiation submission, processing and data program (pg 40) management and development of robotics protocols for automated For more information on the Molecular sample preparation. Genomics facility, visit: www.petermac.org/Research/Microarray The core facility generated more andNextGenerationDNASequencing than 500 gigabases of sequence data during 2010. Principal application for the sequencing instrument was targeted resequencing from cancer samples using hybridisation enrichment strategies, epigenomic profiling (ChIP-seq, MeDIP-seq) and transcriptome profiling (RNA-seq).

Peter MacCallum Cancer Centre – Research Report 2010 Enabling Technologies and Interdisciplinary Research Platforms 101 3.1.4 Flow Cytometry facility 3.1.5 Microscopy facility

OVERVIEW to advancing the understanding of OVERVIEW The excellence of the Microscopy facility The aim of the Flow Cytometry facility how cancer occurs and how it can be The Peter Mac Microscopy facility was is well-known throughout Australia, is to give researchers access to, prevented or treated. developed in 1999 as the Microscopy resulting in extensive collaborations between Peter Mac and leading medical and offer support with, the modern Assistance provided by the Flow Research and Imaging Core by merging research institutes and universities. cytometric technologies that enable Cytometry facility includes simple the existing electron microscopy / histology We aim to maintain our reputation them to conduct their work. Our facility screening and sorting of transfected facilities with the optical microscopy and to continue to meet the current provides professional consultation cells, complex multiparameter analysis facility. Laser capture microscopy was and future needs of researchers by and technical assistance with samples, and sorting, and cell function assays. added in 2001. The core has enlarged continually updating our equipment appropriate instrumentation, data analysis There is a strong demand for sorting through the purchase of new equipment and extending our knowledge base. capabilities and data interpretation. with an emphasis on low frequency funded by competitive grants. We are now recognised as a world-class facility The major areas of support are: populations. Education and training is an important component of the facility encompassing all aspects of biological • Sorting samples that are brought and tutorials and one-to-one advice optical and electron microscopy. KEY 2010 RESEARCH ACHIEVEMENT to the facility. are provided on a regular basis. The aim of the Microscopy facility is In 2010 we evaluated a number Head: Ralph Rossi Head: Sarah Ellis • Technical assistance with protocols. This facility incorporates eight two-fold: to provide researchers with of newly released equipment including a slide scanner for the automated • Advice on instrumentation. instruments: three cell sorters a dedicated research histology facility, The Flow Cytometry and Cell (two Vantage SE Divas, and an Aria2 The Microscopy facility is a world- sophisticated microscopy equipment imaging, analysis, and archiving of Sorting facility provides investigators • Data interpretation. Sorp model), an LSR2, two Canto2s, class facility, providing sophisticated and software to facilitate their research, sections on slides. We also evaluated four different confocal microscopes. with access to state-of-the-art • Education and tutorials. an Automacs magnetic cell separator microscopy equipment and software and to educate, train and supervise equipment and expertise in all aspects and a Luminex 200. supported by technical expertise to researchers using the facility. In addition, With the exciting addition of three of flow cytometry and cell sorting for facilitate research integral to a wide the Microscopy team advises researchers new research laboratories to Peter Mac, Both of the Diva sorters have been the analysis and separation of cell range of cancer research projects. on imaging and sample processing and the demand for confocal microscope CAPABILITIES AND ACTIVITIES configured to have maximum flexibility populations stained with fluorescent conducts regular tutorials and workshops. usage has outstripped supply. As a in the scope of work that they can compounds. As the biological sciences become By organising regular trials and consequence we are purchasing perform. The Aria2 is a special order increasingly technologically dependant, evaluations of newly developed a new confocal to add to our suite product that has a maximum capability it is important to have sufficient microscopes and software, we ensure of microscopes. The new confocal of 17 parameter aquisition; additionally technology to allow researchers to that Peter Mac researchers have access will be commissioned in early 2011. conduct their work in a competitive it can perform high speed sorting, large to the latest technology. Histology has also experienced an manner with other leading institutes. particle sorting and has a FSC PMT increase in workload and we have Peter Mac’s Flow Cytometry facility detection option that allows detection Currently the Microscopy facility houses increased the EFT of several staff achieves this; our services are used of microparticles. The LSR2, is capable microscopes and equipment to facilitate members to cope with this. We are heavily by most Peter Mac researchers, of more complex analysis and includes a wide range of cancer research also endeavouring to increase our contributing to a large variety of a plate reader, while the other analysers projects, including four confocal laser range of services offered to introduce innovative research projects dedicated conduct simpler work. The Automacs scanning microscopes, six wide-field Magnetic cell separator (Miltenyi microscopes, a transmission electron new technologies to researchers. Biotech, Germany) is an adjunct to microscope (TEM), a laser capture the other sorters. This instrument allows microscope, and digital recording and the separation of magnetically labelled analytical software for each microscope. cells. This technology is ideal for quick Three of the microscopes, two confocal separations where very high purity is and one wide-field, are dedicated to not required. The Luminex 200 is a the capture of live cell data through bead-based multiplexing instrument the addition of gas-controlled, heated and is used in fields such as genetic environmental chambers, motorised disease diagnosis, immunodiagnostics stages, and specialist objectives. applications, gene expression, protein A complete array of ancillary equipment analysis and drug discovery. required for the processing of tissues and cells for both optical and electron microscopy is also provided; for histology work this includes a tissue processor, embedding centre, auto- stainer, coverslipper, rotary microtomes, and immunostainer, and, for electron microscope, high pressure freezer, ultramicrotomes with cryoattachments, freeze substitution system, and immunostainer for electron microscopy grids.

Peter MacCallum Cancer Centre – Research Report 2010 Enabling Technologies and Interdisciplinary Research Platforms 103 3.1.6 Media and Laboratory Services facility 3.1.7 Tissue Bank facility

OVERVIEW OVERVIEW The Tissue Bank facility also supports The Media and Laboratory Services Tissue Bank facility offers researchers clinical trial activity and project-specific facility is separated into two areas: centralised access to a broad collection requests. Researchers make a single Media Kitchen and Laboratory Services. of ethically-collected human tissue application to the Victorian Cancer and blood derivatives from more than Biobank to access services or The Media Kitchen maintains a cost 17,000 donors. specimens held in tissue banks across effective, consistent and reliable store the partner sites: Melbourne Health, of commonly used sterile media and In 2010, 855 specimens from 1098 Austin Health, Southern Health and buffers for Cancer Research and the consenting donors were added to Peter Mac. Department of Pathology. Peter Mac’s collection of tissue samples. The facility supports the needs of The figure below details the number and The Tissue Bank facility also offers individual research groups who may breadth of specimens banked in 2010 a digital slide scanning service; have a specific media or buffer stock for each cancer type. scanned images can then be viewed, maintained for them and Media analysed, shared and archived across Donors provide broad consent for their Kitchen staff can also supply specific multiple sites. Head: Lara Sekhon Head: Sam Cauberg biospecimens to be used in unspecified non-stock requests on demand. future research. This includes consent The Victorian Cancer Biobank resource The facility steam sterilises all Cancer to access medical record information of readily available tissue has been Research liquids and retrovirus linen The Media and Laboratory Services The Tissue Bank facility at Peter Mac enabling the Tissue Bank facility crucial for researchers securing major and maintains the x-ray developer facility provides an essential service is one of four consortium members to provide up to eleven years clinical research grants from bodies such as and water ultra filtration unit. to Cancer Research, serving the needs of the Victorian Cancer Biobank follow-up data on individual specimens. NHMRC and international funding of Peter Mac laboratory researchers Laboratory Services provides a providing scientists with high quality, Consequently, the ability to provide agencies such as US Department of by supplying high quality liquid and convenient and consistent system ethically-collected human tissue clinical outcome data together with Defense. solid media and sterile laboratory ware samples for research studies. of cleaning, dry heat and steam the breadth of the specimen collection For further information on the in a cost efficient manner under strict sterilising and returning of reusable (across ten of the 11 main tumour Victorian Cancer Biobank please visit quality control. laboratory items to Cancer Research streams, including rare tumour types) www.viccancerbiobank.org.au across all laboratories and to sets our bank apart from other tissue For more information on the Tissue the Department of Pathology. banks in Australia. Bank facility, visit: www.petermac.org/ For more information on Media Research/TissueBankCore and Laboratory Services, visit: www.petermac.org/Research/ MediaandLaboratoryServices

Figure 1: Specimens banked from Consenting Donors 2010

Peter MacCallum Cancer Centre – Research Report 2010 Enabling Technologies and Interdisciplinary Research Platforms 105 Enabling Technology Platforms – personnel 3.2 Interdisciplinary Research Platforms

Functional Genomics facility Media and Laboratory Services facility Head Dr Kaylene Simpson Head Lara Sekhon Research Assistants Katrina Gouramanis Media Kitchen Kai Syin Lee Helen Braun Yanny Handoko Menka Kyriakou Daniel Thomas Laboratory Services Kate Gould Emily Breninger Molecular Genomics facility Elzbieta Gajewska Graham Heffernan Head Suh-youn Ko Dr Richard Tothill Paul McPherson Research Assistants Patrick Murray Aga Borcz Nicole Robb Aidan Flynn Belinda Whitby Tim Holloway Tissue Bank facility Bioinformatics facility Head Head Samantha Cauberg Dr Gian Sberna Tissue Bank Scientists Bioinformaticians Paul Pinto Correia Jason Ellul Jeremy Hoglin Jason Li Rhonda Mawal Kimberly Ong Flow Cytometry facility Amanda Ross Head Resource Enhancement Scientist Ralph Rossi Kylie Scott Senior Flow Cytometrist Data Managers Ralph Rossi Leanne Bowes Samara Rosenblum Cytometrist Sophie Kotsakidis

Microscopy facility Head Sarah Ellis Research Assistants Leah Adolf Stephen Asquith Judy Borg Agnes Gany Dhanya Menon Basia Pryzbylowski Matthew Reardon Karin Sedelies Claire Tan Assoc. Prof. Penny Schofield is the and improves the quality of life for Simon Yoong Research Director of the Nursing and patients who are undergoing and Supportive Care Research Department completing cancer treatment. at Peter Mac. Nursing and Supportive Penny develops and tests evidence- Care Research (N&SC Research) is based psycho-educational programs firmly embedded across each of Peter that can be readily adopted into clinical Mac’s tumour streams and Penny practice, and the rigorous assessment leads a multi- disciplinary program of of quality of life outcomes in clinical supportive care research that assesses trials of novel therapies for cancer.

Peter MacCallum Cancer Centre – Research Report 2010 3.2 Interdisciplinary Research Platforms 3.2.1 Centre for Blood Cell Therapies

RESEARCH FOCUS Recent research highlights include: Our interdisciplinary research platforms • Development and production • Expanded cell tracking program are the foundation upon which clinical of novel cell therapy treatments. to include the use of 19F and • Innovative regenerative medicine nano-Fe materials on Peter Mac’s medicine is practised. and immunotherapies. 3T MRI machine. • Cell tracking studies. • For the second year in a row Peter Mac’s Apheresis Unit achieved The research conducted by our Centre for Blood Cell Therapies Molecular Pathology laboratory • Autologous peripheral blood stem NATA accreditation (NPAAC standard interdisciplinary research platforms Prof. Miles Prince cell transplants. Prof. Stephen Fox HPC-A) and completed audit with is crucial to our cancer care; it is the • Collaboration with the Cancer and Assoc. Prof. Alex Dobrovic no recommendations or conditions. source of new approaches to difficult Centre for Cancer Imaging Immunology program (pg 109) management issues, involves managing Prof. Rod Hicks Nursing and Supportive Care and the Haematology Immunology • Cell Therapies entered into a Prof. Sanchia Aranda patients according to world best practice, Centre for Biostatistics Translational Research Laboratory collaboration agreement with delivers state-of-the-art diagnostic and and Clinical Trials Nutrition (pg 30). National University Hospital of treatment options, and strives to improve Assoc. Prof. Dina Neiger Janelle Loeliger Director: Prof. Miles Prince Malaysia in Kuala Lumpur (HUKM) treatment outcomes. and successfully trained HUKM staff Clinical Trials Unit onTrac@Peter Mac RESEARCH DIRECTIONS in cGMP compliance and quality The multidisciplinary nature of our The Centre for Blood Cell Therapies Shannon Uren Dr Lisa Orme The Peter Mac CBCT focuses on systems management. clinical services has facilitated a valuable (CBCT) provides standard of care developing, testing and applying new multidisciplinary focus in our research, Clinical Psychology Pain and Palliative Care treatments for cancer patients via •  Secured a TGA manufacturing license treatments based on the use of patient with all clinical and allied health Annabel Pollard Dr Odette Spruyt two collection sites and a central (a world first) for a commercial client cells to control their cancer, and to professionals in all areas of the hospital processing facility in East Melbourne. using mesenchymal precursor cells. Familial Cancer Centre Pharmacy restore function that has been lost engaged in important collaborative The centre manufactures cell and Dr Gillian Mitchell through disease or injury. We do this • Secured a number of subsidies for both research. The scope is wide-ranging, Sue Kirsa tissue-based treatments arising work in the context of strict government Peter Mac and outside researchers from early phase clinical studies which Infectious Diseases Physical Sciences from both our own discoveries and regulation and international standards to progress their activities up to allow our patients access to novel anti- Assoc. Prof. Monica Slavin the discoveries of our clinical and Jim Cramb to ensure patient safety. regulatory compliance for clinical trials. cancer drugs to international randomised commercial partners. kConFab Follow-Up controlled trials designed to answer key Radiation Therapy CBCT also uses novel cell imaging For more information on related Through Cell Therapies Pty Ltd, clinical questions in cancer care. Assoc. Prof. Kelly-Anne Phillips Aldo Rolfo technology to provide unique data research, see: the commercial interface for the CBCT, on the distribution and function of Social Work we expedite the translation of cellular - Cancer Immunology program (pg 24) these modified cells in targeting Alison Hocking therapy research from the bench into cancer in patients. - Haematology Immunology Translational the clinic and in some cases through Research laboratory (pg 30) to standard of care therapies. - Haematology Service (pg 86)

Peter MacCallum Cancer Centre – Research Report 2010 Enabling Technologies and Interdisciplinary Research Platforms 109 3.2.2 Centre for Cancer Imaging 3.2.3 Centre for Biostatistics and Clinical Trials

RESEARCH FOCUS medical physics, genomics and medical RESEARCH FOCUS tissue samples obtained from the • Improvement of diagnostic paradigms oncology groups at Peter Mac. The BaCT has expertise in all phases marker sub-study component of for . Royal Children’s Hospital and RMIT of clinical trials as well as specialist the phase 3 trial. University in the pre-clinical imaging • Establishment of optimal timing and diagnostic trials and treatment planning • BaCT is working with Assoc. Prof. Jane domain. This research aims to provide tracer combinations for therapeutic studies with the research focus on: Turner (UQ, Medicine) and Beyond insights into potential therapeutic targets response assessment to novel • Provision of high quality biostatistical Blue on the PROMPT (Promoting for neuroendocrine cancers. molecular targeted therapies. and data management support to Optimal Outcomes in Mood through • Development of novel PET Other research projects conducted cooperative oncology groups and Psychosocial Therapies) study, imaging agents. in 2010 include: researchers at Peter Mac. a multi-centre randomised controlled trial to evaluate the effectiveness • New trials looking at radiation • Collaboration in clinical trials, including of a systematically-introduced brief dose and quality of life outcomes in phase 1 trials, translational research psychosocial intervention in cancer RESEARCH DIRECTIONS neuroendocrine tumour (NET) patients. programs and supportive care. services to reduce and An initial report detailing the safety • Our pre-clinical work in developing • Biostatistical and clinical trial depression, which affects up of the combination of radiosensitising Head: Prof. Rod Hicks new imaging tracers in association Director: Assoc. Prof. Dina Neiger methodological research. to one-third of cancer patients. chemotherapy with peptide receptor with the CRC for Biomedical Imaging BaCT staff have specific expertise There is limited detection of distress radionuclide therapy using Lu-177 Development has moved into the in the design, conduct, analysis and The Centre for Cancer Imaging is by clinicians and most centres do not octreotate was published in 2010; clinical domain with commencement interpretation of cancer clinical trials a consultative and research oriented The Centre for Biostatistics and Clinical systematically identify patients who are Peter Mac has pioneered this approach of human studies of Mel050, a highly as well as retrospective studies, and service, providing advice on the best Trials (BaCT) is a leading Australian distressed. Even when implemented, internationally. specific melanoma imaging agent. are experienced in the analysis of other test or combination of tests to answer coordination centre for clinical trials screening for distress is not always clinical and laboratory research data. specific needs to cancer patients Reflecting ongoing developments For more information on related in oncology, providing a full range supported by defined clinical referral The trial centre supports approximately and their management team, and in this field, the Centre for Cancer research, see: of services to clinical trials and pathways. There is also limited access 100 phase 1 to 3 trials involving over to integrate the results of those tests Imaging was successful in achieving other clinical research projects, to specialist psychosocial service - Cancer Therapeutics program (pg 62) 5,500 patients. into multidisciplinary management a Victorian Cancer Agency Translational including assistance with protocol providers. The trial will take advantage selection and planning. Research Grant. This grant of almost development, study design, database Trial centre statisticians are actively of an eCRF system introduced by $1.6 million over three years will design, randomisation and registration involved in research into statistical BaCT last year, improving efficiency The Centre applies its experience and accelerate discoveries regarding services, management of data, central methods applicable to clinical trials and by facilitating on-line data entry research in the use of multi-modality the genetic drivers of neuroendocrine trial coordination, statistical analysis, the analysis of medical data, as required and multi-site system access. correlative imaging to provide advice cancers and our understanding of interpretation and reporting of data. by clinical projects. • BaCT staff currently manage a on the best test or combination of tests new treatment targets to improve multi-site, international, randomised to answer the specific needs of cancer patient outcomes. The research will Through a continuing commitment phase 3 study investigating radiation patients and their management team. involve a close collaboration with the to high quality research, BaCT RESEARCH DIRECTIONS contributes to improved outcomes doses and fractionation schedules for patients currently participating • BaCT successfully applied for a in non-low risk Ductal Carcinoma In in specific clinical trials as well as continuation of Cancer Australia Situ (DCIS) of the breast. The DCIS for cancer patients in the future. funding support of clinical research study has grown considerably since trial development services to the ASSG international collaboration was The centre is home to the Operations from 1 July to 30 June as part of the introduced in 2008. BaCT staff Office of the Australasian Leukaemia Cancer Clinical Trials Development currently manage 70 active sites and Lymphoma Group (ALLG) — Unit (CTDU). Established in July 2008, globally (more than double the original Australasia’s leading clinical trials CTDU is a collaboration between number of Australian sites) across and translational research group the NHMRC Clinical Trials Centre and Singapore, New Zealand, Canada in haematological malignancies. BaCT, providing expert advice, support and Europe. The number of active and trial development services for sites is expected to reach 110 by the the newly established multi-site, end of 2011, following introduction collaborative national cancer clinical of new collaborative groups, including trials groups. the International Breast Cancer Study • BaCT staff collaborate in the Group (IBCSG), the Scottish Cancer international phase 3 head and neck Trials Breast Group (SCTGB), and trial (HEADSTART) with Assoc. Prof. the Ireland Cooperative Oncology Danny Rischin and Prof. Lester Peters Research Group. The increase as principal investigators. The results in site activation since international of this trial have demonstrated the collaboration has contributed critical importance of radiotherapy to an almost three-fold increase in quality on the outcome of chemo- the total annual accrual in 2010. radiotherapy in head and neck cancer. International collaboration initiated The trial has also generated many the development of a web-based studies, involving BaCT, into randomisation system, which was the role of markers in head and neck released globally in June 2010. cancer using data from blood and

Peter MacCallum Cancer Centre – Research Report 2010 Enabling Technologies and Interdisciplinary Research Platforms 111 3.2.4 Clinical Trials Unit 3.2.5 Clinical Psychology

RESEARCH FOCUS • Playing a key role in the development RESEARCH FOCUS Head and Neck Study of PF-02341066 in ALK positive Our clinical research program covers • Develop and drive the implementation We are involved in a three-year Non-Small Cell Lung Cancer from prevention, diagnosis and management of an overarching psycho-oncology prospective observational study Phase 1 – Phase 3. and extends from early to advanced research strategy. of people with head and neck cancer. stages of disease. Our research includes • Phase 1 studies in LY2874455, • Facilitate statewide and national The study has highlighted the incidence investigations of novel treatments ABT-199 & NPI-0052. research collaborations. of psychological morbidity (anxiety and or new approaches in medical oncology, depression and quality of life) in patients • A Pilot Study — LITTVAC in Multiple • Drive the clinical application of haematology, radiation oncology and undergoing treatment for head and Myeloma. The LITVAC study is unique evidence-based improvements surgery. The end goal of all our work is neck cancer. in its approach to treating patients with in psycho-oncology care. improved outcomes for our patients. an incurable malignancy of the blood • Raise the awareness of psycho- The Breast Cancer Survivors’ called multiple myeloma. The immune oncology as a collaborative field of Healthy Lifestyle Study RESEARCH DIRECTIONS investigations are generating some research. A Randomised Controlled Pilot very new findings that are being using Study To Test The Effects of a Behavioural In 2010, Peter Mac’s CTU was involved • Keep abreast of and disseminate to design further therapies for patients. Intervention (Theory-Based Information Manager: Shannon Uren in over 180 active clinical trials, including Head: Annabel Pollard information about new developments The LITVAC study has been extended and Advice) on Uptake of Physical the following: and resources. to look at the effects of higher doses Activity in Breast Cancer Survivors. Under the auspices of the Division • A phase 1 study in the oral AKT of lenalidomide and no steroid on The aim of Clinical Psychology is • Develop education and training This study has highlighted the effects of Cancer Medicine, the Clinical Trials Inhibitor GSK2110183 in the myeloma and the immune system, to be a national centre of excellence opportunities for clinical researchers. of a psycho-behavioural intervention Unit (CTU) underpins clinical research Haematological malignancies. to inform optimum combinations in clinical interventions, research • Contribute to national advocacy efforts on uptake of exercise in breast cancer across cancer types. The unit is involved for future studies. and implementation of specialist related to survivorship research issues. • Playing a key role in the development survivors. in the co-ordination and management evidence-based psychological of MUC1 Dendritic Cell Vaccine (CVac) For more information on related • Seek external funding to sustain For more information on related of clinical trials, providing a key service and psychiatric care for people for Epithelial Ovarian Cancer Patients. research, see: and grow our clinical interventions research, see: to both internal and external bodies. with cancer and their families. and research program. With a focus on Ph I, II and III trials and • Playing a key role in the development - Haematology Service (pg 86) - Breast Service (pg 83) the provision of ongoing education and of PLX4032/ RO5185426 a BRAF - Lung Service (pg 88) - Head and Neck (pg 87) support to clinician investigators and inhibitor molecule in melanoma from RESEARCH DIRECTIONS trial participants and their carers we - Melanoma and Skin Service (pg 89) phase 1 – phase 3, including the follow- Our overarching aim is to focus on are the largest single oncology clinical on phase 1 study of RO5185426 in research that has the potential to trials unit in Victoria. With more than 180 combination with GDC-0973. improve the psychological and clinical active clinical trials currently underway, Peter Mac staff developed outcomes for people with cancer and growth of our unit has been rapid. sophisticated molecular screening their families. Our current research tests to identify patients with mutations program seeks to establish and develop in the BRAF gene that allowed Peter evidence-based improvements in the Mac to join with cancer centres in psychological care of patients such as the USA to lead the development of effective psychological interventions. a new class of anticancer treatment that has established a new way The research program is explicitly of treating melanoma. collaborative. Aiming to build knowledge and understanding of psychological issues across the organisation, our research program involves working directly with patients through collaborative projects with the multidisciplinary teams in the Head and Neck (pg 87) and Breast (pg 83) tumour streams.

Peter MacCallum Cancer Centre – Research Report 2010 Enabling Technologies and Interdisciplinary Research Platforms 113 3.2.6 Familial Cancer Centre 3.2.7 Infectious Diseases

RESEARCH FOCUS Recent research highlights include: RESEARCH FOCUS Randomised Control Trial (RCT) for Invasive Aspergillosis Our research portfolio covers • Understanding that the clinical • Development of local and national many aspects of familial cancer information we hold on our patients evidence based clinical guidelines This RCT is evaluating an early with a particular emphasis on: is a rich resource for familial cancer for the management of the treatment strategy for invasive aspergillosis in high risk haematology • Finding new cancer predisposition research while reducing the burden of immunocompromised patient. patients. This national study in bone genes. research fatigue on our unique group • Development of epidemiological marrow transplant recipients and of patients. We have developed an tools for the surveillance of infections • Evaluating new technology patients undergoing treatment for for genetic testing. integrated clinical / research database, in cancer patients. transferring all paper records into acute leukaemia is comparing an early • Investigating new cancer treatments • Study and report on the outcomes of diagnostic strategy based on serological an electronic format, permitting rapid infections in cancer patients, including targeted to the mutated genetic interrogation and data queries and testing and PCR to the standard empiric pathway. newly emerging infections such as antifungal therapy approach. speeding up the time taken to influenza H1N1 (swine flu). • Streamlining the care and follow up complete our research projects. Our research group comprises • Study of the clinical, molecular of families at risk. infectious diseases physicians who • Developing an FCC consumer and infection control factors Head: Dr Gillian Mitchell • Investigating the wider impact of Head: Assoc. Prof. Monica Slavin have appointments across multiple research group to help us set a associated with healthcare-associated hereditary cancer syndromes and their institutions. We are therefore able to research agenda that is responsive infections, including infection due management on the psychosocial perform high quality clinical research The Peter Mac Familial Cancer to our patients’ and their families’ to multi-resistant organisms in the functioning of individuals as well as The Department of Infectious projects that influence care of patients Centre (FCC) is a comprehensive needs, evaluating research proposals immunocompromised patient. cancer genetics centre with a their wider family. and helping us draft the patient Diseases and Infection Control aims across haematology/oncology units • Development of new strategies for commitment to clinical service and information documents associated to minimise the impact of community across the state. improving outcomes of infection research. The FCC provides cancer with specific projects. and healthcare-associated infections RESEARCH DIRECTIONS in cancer patients. All current Infectious Diseases projects risk assessment, genetic counselling in patients and healthcare workers. • Holding a Research Strategic Planning focus on best practice and surveillance. and genetic testing, medical advice and Our research is focused on finding Our services involve preventing Day in November involving the FCC, For more information on related management as well as psychological better ways to identify people at risk and managing infections among molecular pathology, representatives RESEARCH DIRECTIONS research, see: support to individuals and their family of hereditary cancer syndromes and immunocompromised patients and from tumour streams and the Division who have concerns about their personal then reduce the morbidity and mortality we provide care across outpatient, Antimicrobial Stewardship – - Pharmacy (pg 122) of Research. Its purpose was to and/or family . Our aim associated with these syndromes. ambulatory care and inpatient settings. Guidance DS® ensure close collaboration across is to reduce the morbidity and mortality In addition to patient clinical care, we Antimicrobial therapy plays an important these groups that will result in effective from cancer associated with hereditary perform epidemiological surveillance, role in the prevention of adverse patient translation of research from the cancer syndromes. outbreak management and policy outcomes related to underlying research labs into the clinic and for development. We also conduct immunocompromised diseases or the clinical needs of the FCC patients research on prevention and treatment their treatment. Electronic decision to drive future laboratory research of infections. support tools are a necessary and directions. The success of this day important way of optimising clinical leads us to hold one or two such practice, preventing antibiotic resistance, meetings per year from now on. auditing prescribing practices and monitoring the use of restricted antimicrobial agents. Guidance DS® — a computerised clinical decision support system — involves electronic real-time monitoring of inpatient prescribing of restricted antimicrobials. Febrile Neutropenia Guidelines Consensus and evidence based guidelines for the treatment and management of febrile neutropenia were developed in collaboration with specialists from haematology, oncology and pharmacy.

Peter MacCallum Cancer Centre – Research Report 2010 Enabling Technologies and Interdisciplinary Research Platforms 115 3.2.8 kConFab Follow-Up Project 3.2.9 Molecular Pathology laboratory

RESEARCH FOCUS adequate surgery RESEARCH FOCUS faults in this gene. In about three to four • Prospective evaluation of the effect if they were operated on by a specialist • Translational and clinical research per cent of young women, their BRCA1 of non-genetic potential risk modifiers gynaecologic oncologist (rather than into cancers including breast, lung, gene has been made less capable of such as risk-reducing surgery, a general gynaecologist or general colorectal and urological cancers preventing breast cancers, placing them chemoprevention, reproductive surgeon), and if they were younger. and haematological malignancies. at a 3.5-fold increased risk of breast Reassuringly, the adequacy of the cancer. factors, exogenous , • Identification of predictive markers surgery performed seemed to have alcohol, cigarettes and exercise. enabling appropriate stratification The discovery of this epimutation in improved over time. We are now working • Prospective determination of of patients for individualised treatment. the peripheral blood indicated that with peak bodies to ensure that our penetrance of BRCA1 and BRCA2. it was present in many tissues of the results are disseminated to women • Development of clinical diagnostics. body. This is highly significant for the • Evaluation of prevalence and and surgeons, so that the adequacy • Adoption of novel molecular understanding of mechanisms of breast predictors of use of various cancer risk of risk-reducing surgery and pathology platforms and methodologies for cancer development as it could drive management strategies, including risk- can be further improved. genetic and epigenetic analysis. reducing surgery, chemo-prevention the development of breast cancer and cancer screening. Reference: Kiely BE, Milne RL, Burnham L, et al. in the same way as a mutation. Head: Assoc. Prof. Kelly-Anne Phillips Prospective Study of Adequacy of Risk-Reducing Heads: Prof. Stephen Fox and Assoc. Prof. Many questions remain unanswered, in Alex Dobrovic KEY 2010 RESEARCH ACHIEVEMENT Salpingo-oophorectomy in Australasian BRCA1/2 particular what triggers this epimutation Carriers and Women at High Familial Risk of New Risk Factor for Developing The kConFab Follow-Up Project kEY 2010 RESEARCH ACHIEVEMENT Ovarian Cancer in the Kathleen Cuningham and whether women carrying this risk Consortium Foundation For Research Into Familial Breast Cancer factor can reduce their risk by dietary researches the clinical consequences Prospective Study of Adequacy The Molecular Pathology laboratory Breast Cancer (kConFab) (2011). Familial Cancer, aims to perform basic and translational or pharmacological intervention. Testing of having a hereditary predisposition of Risk-Reducing Salpingo- published online 22 March 2011, DOI 10.1007/ The risk factor involves a special type for this risk factor will be unavailable until to breast cancer and the non-genetic oophorectomy in Australasian s10689-011-9435-0 research with the goal of achieving of alteration (DNA methylation) of the personalised cancer medicine. BRCA1 gene. This study has been answers to these and other questions factors that might modify cancer risk. BRCA1/2 Carriers and Women at For more information on related published in Cancer Prevention are known. Data on the risk management High Familial Risk of Ovarian Cancer research, see: behaviours and outcomes of kConFab Research, where it also featured in an This study is the first to report on the - kConFab (pg 38) Reference: Wong EM, Southey MC, Fox SB, et al. participants are collected every three editorial. Constitutional methylation of the BRCA1 promoter adequacy of risk-reducing gynaecologic years. The Follow-Up Project is funded - Breast Service (pg 83) is specifically associated with BRCA1 mutation- surgery undertaken in Australian women Women with mutations in the BRCA1 associated pathology in early-onset breast cancer. separately from the kConFab core. at high familial risk for ovarian cancer. gene are predisposed to breast cancer. Cancer Prevention Res. 2011 4:23–33. Such surgery should include removal The DNA methylation modification is of both ovaries and fallopian tubes, known as an epimutation. It is not a and the removed tissue should all be mutation but it acts to turn off the BRCA1 submitted for pathology examination gene leading to the loss of its protective to ensure that undiagnosed cancer, function against breast cancer. that might require additional treatment, The study involved women diagnosed is not present. The study was prompted with breast cancer before the age of 40 by anecdotal reports of high risk women years for whom BRCA1 mutations had receiving inadequate surgery. We not been identified. The epimutation reviewed the surgical and pathology was found in the blood of some women reports of 201 high risk women who with breast cancer, especially those who underwent surgery between 1998 and develop the same type of breast cancer 2008. We showed that 9 per cent of that develops in women with a BRCA1 Figure 1: Poorly differentiated adenocarcinoma women had inadequate surgery and 77 mutation. Factors that triggered of the oesophagus illustrating amplification of per cent had inadequate pathology. epimutations that stopped the gene the MET gene (red) in relation to chromosome Women were most likely to have BRCA1 from doing its usual job of 7 centromere (green) by fluorescent in situ hybridisation (FISH) in formalin fixed paraffin preventing breast cancer seem to cause embedded (FFPE) tissue. the same proportion of early-onset breast cancers (10 per cent) as do inherited For more information on related research, see: - Familial Cancer Centre (pg 140) - Medical Oncology and Early Phase Clinical Trials (pg 82)

Peter MacCallum Cancer Centre – Research Report 2010 Enabling Technologies and Interdisciplinary Research Platforms 117 3.2.10 Nursing and Supportive Care 3.2.11 Nutrition

RESEARCH FOCUS guidelines, this novel program was Nutrition is involved in the education and RESEARCH DIRECTIONS The focus of our research is to developed and tested throughout training of dietetics students, as well as Our research is linked to the improve outcomes for people 2009 –10. Two intervention manuals running a strong continuing professional multidisciplinary tumour stream teams affected by cancer by: (the Nurse Intervention Manual and the development program supporting we work closely with, and in 2010 our Peer Intervention Manual) were drafted dietitians outside • Actively engaging with people research directions included: based on identified unmet needs and of Peter Mac in nutritional management affected by cancer and clinicians best available evidence for self-care. in oncology. We prioritise maintaining • Permanent implementation of the involved in their care to identify gaps The Nurse Intervention Manual specified and improving the quality of our services Inpatient Strategy in supportive care service provision. the content of patient consultations to and play a significant role in clinical into usual care. • Developing and testing innovative provide tailored information, self-care research. • Ongoing development and completion and sustainable supportive care coaching and multidisciplinary team Current research projects underway of evidence-based care pathways interventions applicable across care-coordination. The Peer Intervention in our department include: for all tumour streams that map the illness trajectory. Manual described the content of phone evidence-based dietitian interventions • Supporting rigorous assessment calls to patients that provide psychosocial • Inpatient malnutrition strategy. and frequency of intervention. support and encourage adherence to Head: Prof. Sanchia Aranda of quality of life in cancer trials. Head: Janelle Loeliger • Development of an evidence-based the self-care plan. Intervention sessions • LMICS / WCMICS partnership project • Developing and testing innovative nutrition care pathways for ‘Improving care for regional cancer models of care focused on enhancing are delivered at critical time-points in The Department of Nursing and The Depaertment of Nutrition continues different tumour streams. patients through collaboration self-management capacity of people the illness trajectory: pre-, mid-, end- Supportive Care Research group to provide nutritional support and between Integrated Cancer Services affected by cancer. and post-treatment. Both intervention • An integrated cancer services develops, evaluates and disseminates manuals were refined by clinician and advice to patients in both the inpatient partnership project between to support and mentor regional health • Developing and validating new new knowledge about nursing and consumer review. Peers and nurses were and outpatient settings at East Loddon Mallee and Western professionals’, a funded mentoring supportive care research measures. supportive care for people affected rigorously trained and the intervention Melbourne, at Box Hill and Moorabbin Central Melbourne Integrated project for dietitians and speech by cancer. We are committed to the pre-tested with six patients who provided satellites and for up to 100 tube-fed Cancer Services. pathologists in head and neck application of evidence to practice, qualitative feedback. patients at home at any one time. Our and upper GI cancers. kEY 2010 RESEARCH ACHIEVEMENT • Development and implementation education and policy. Our team works team consists of dietitians, nutrition • Jenelle Loeliger’s and Nicole Kiss’ in collaboration with cancer clinicians, PENTAGON: Peer and Nurse This unique intervention was assistants and secretarial support. of guidelines for gastrostomy well-received by consumers and tube insertion in head and neck work as members of the dietitian managers, educators and researchers support Trial to Assist women We aim to be recognised as one of committee developing the National both within Peter Mac, nationally and in Gynaecological Oncology multidisciplinary clinicians, and found to Australia’s leading oncology nutrition cancer patients. be relevant, acceptable, feasible Evidence Based Guidelines for the internationally. These collaborations centres. • Malnutrition strategy for Radiotherapy for gynaecological and useful. The final package addresses Nutritional Management of Head ensure that our research program is cancer (GC) has numerous potentially Chemotherapy Day Unit patients. and Neck Cancer. relevant to patients, carers and health key physical, functional, psychological, distressing side effects which impact sexual, informational and social needs • After two years of research, professionals, is at the cutting edge on psychosocial functioning and intimate of international innovations in cancer of patients that arise at critical points publishing ‘Oncology nutrition: relationships. Distress associated in the illness trajectory. RESEARCH FOCUS the essential resource for the nutritional supportive care and is translated with diagnosis and treatment can • Striving for excellence and ensuring that management of cancer’, an into practice. be ameliorated by comprehensive In November 2010, we were awarded our clinical practice is evidence-based. educational manual targeting dietitians preparation for treatment and addressing $1.13m in NHMRC funding for a national, multi-site trial of PeNTAGOn • Provision and improvement of patient which aims to provide guidance for the informational, physical and psychosocial nutritional management of oncology needs during treatment. (2011–14). This randomised controlled care through innovation, collaboration study will test the effectiveness of and education. patients. The initial objective of PeNTAGOn the intervention to reduce psychological • Extensive audit of malnutrition (Principal Investigator: Assoc. Prof. distress, informational and psychosocial prevalence in Peter Mac’s Intensive Penelope Schofield) was to develop, needs, symptom distress, psychosexual Care Unit. refine and pre-test an innovative difficulties and vaginal atrophy; and • Participation in the inaugural intervention package combining tailored improve patient preparation for treatment Australasian Nutrition Care Day Survey specialist nursing consultations with a and quality of life. This novel and timely — providing malnutrition prevalence telephone-based peer support person research to meet patients’ psychological data in acute care settings across (a GC survivor), to ensure its relevance and supportive care needs could have Australia and New Zealand. and acceptability to patients and economic benefits, and is potentially clinicians. A three-stage process for transferable to a range of treatment Reference: The Nutrition Department Peter developing complex interventions, settings and types of diseases, such MacCallum Cancer Centre. Oncology Nutrition: based on UK Medical Research Council as diabetes or cardiovascular disease, an essential resource for the nutritional management of cancer. Peter MacCallum Cancer Centre: 2009. (MRC) Framework (2008), was used: across Australia. If this intervention (1) problem definition; (2) refining the is successful, the proposed research intervention: evidence-based content, program has the potential to transform complexity and tailoring, delivery and health care practices nationally and dose, and integrity; (3) pre-testing the internationally. intervention with qualitative interviews to finalize the intervention. Drawing on extensive literature reviews, consumer input, and the MRC

Peter MacCallum Cancer Centre – Research Report 2010 Enabling Technologies and Interdisciplinary Research Platforms 119 3.2.12 onTrac@Peter Mac 3.2.13 Pain and Palliative Care

The mandate of the onTrac@PeterMac • An exploratory study into oncology RESEARCH FOCUS Current clinical trials include: Service is to provide: specialists understanding of the Pain and Palliative Care is focused on • A randomised, double blind healthcare preferences of young • clinical care and support for young projects which directly improve patient control trial of megestrol acetate, people living with cancer. people undergoing cancer treatment care through better integration of dexamethasone and placebo in • The role of PET/CT in the staging, palliative care across all of cancer care, the management of anorexia in • secondary consultation service evaluation of response to treatment to ensure symptom control is optimised people with cancer. to healthcare professionals, young and surveillance of disease recurrence not only at the end of life but throughout people and the wider community • A randomised control trial of in bone and soft tissue sarcoma the cancer trajectory. oral , oral , • professional development, training of children and young adults. and oral placebo with rescue and education program • A patient management platform RESEARCH DIRECTIONS subcutaneous in the • medical and psychosocial translational for cancer care: eCanCare: management of delirium in palliative research and data management. A collaborative study with the Pain and Palliative Care aims to improve care inpatients. Department of Nursing and the evidence base for palliative care • A randomised double blind Supportive Care at Peter Mac. through the conduct of clinical trials, Acting Head: Dr Lisa Orme Head: Dr Odette Spruyt placebo controlled trial of infusional RESEARCH FOCUS pharmacovigilance monitoring, • Transitions: An exploratory Study development of validated assessment subcutaneous in the OnTrac@PeterMac is committed to into Survivorship of Adolescents management of malignant bowel OnTrac@PeterMac is Victoria’s first The Department of Pain and Palliative tools, participation in national quality undertaking internationally outstanding and Young Adults with Sarcoma. obstruction in people with advanced and leading Adolescent and Young Care conducts research aimed at improvement activities such as PCOC, clinically-focused research aimed at cancer. Adult (AYA) cancer service, bringing For more information on related improving quality of life, pain and reflective case reports, clinical audits influencing health care and health policy together research and clinical service research, see: symptom control and end of life care and evaluation of the impact of palliative • A two-stage trial of therapy in the field of adolescent and young development. Located at Peter Mac, for patients with cancer. care in cancer care. in patients with cancer and adult oncology. - Sarcome Genomics and Genetics not related to anti-cancer therapy. this specialist multidisciplinary team laboratory (pg 35) We have a current project implementing offers specialised, age appropriate end of life care pathways across four Study 1: A randomised open label - Medical Oncology and Early Phase care to AYAcancer patients treated WCMICS sites and a project conducted study of guideline-driven targeted RESEARCH DIRECTIONS Clinical Trials (pg 82) within adult hospitals. The team on behalf of the Department of Health antiemetic therapy versus single Cancer during adolescence and early includes a medical and paediatric - Sarcoma Service (pg 91) to conduct a literature review on palliative agent antiemetic therapy. adult life is one of the most under oncologist, psychologist, social worker, care pain indicators and develop an • A two-stage trial of antiemetic researched areas within oncology. education advisor, music therapist, implementation plan for these indicators therapy in patients with cancer and Assumptions about the best way to education and training officer and to be incorporated into quality assurance nausea not related to anti-cancer manage the care of the AYA patient are research officer. in cancer care and palliative care. therapy. Study 2: A randomised based on studies conducted with other We also aim to promote the development controlled double blind study of This unique service model is based age groups and are not appropriately of palliative care in oncology in the methotrimeprazine or on the integration of research and targeted towards the specific needs developing world and evaluate the versus placebo with rescue clinical service development offering of the AYA population. This practice is impact of clinical mentorships. (best supportive care) young people access to the most assumed to be contributing to the issues in patients with refractory nausea. current cancer therapies and clinical associated with this age group. trials whilst providing the most Addressing this practice is one of the • Multi-site cluster randomised comprehensive developmentally central goals of onTrac@PeterMac. controlled trial comparing the severity targeted psychological, social of constipation symptoms experienced Over the past five years, onTrac@ and emotional support. by palliative care patients receiving PeterMac has become a world leader usual care compared to those in AYA evidence-based cancer research. diagnosed and managed according The team has developed and to the usual pathophysiology. implemented a number of world-first studies both collaboratively and independently which will be able to inform both national and international AYA care. Below are some of the studies being lead by onTrac@PeterMac throughout 2010: • AYAPK Study: evaluating the effect of gender on the pharmacokinetics (PK) of in AYA’s newly diagnosed with osteosarcomas, Ewing sarcoma or Hodgkin lymphoma. • Patterns of care and experience of care for adolescents and young adults with cancer.

Peter MacCallum Cancer Centre – Research Report 2010 Enabling Technologies and Interdisciplinary Research Platforms 121 3.2.14 Pharmacy 3.2.15 Physical Sciences

RESEARCH FOCUS Current research projects include: RESEARCH FOCUS • Assessment of the benchmarking data for the ‘RAVES’ (Radiotherapy • The Pharmacy is actively involved • Pharmacogenomics Most of the Physical Sciences research Adjuvant Versus Early Salvage) clinical in a number of research activities (Personalised Medicine) projects are directly aimed at improving relating to drug therapy, many of these patient care in radiotherapy. However, trial for post-prostatectomy patients. - Identifying predictive and prognostic involve collaborations within Peter Mac there are also external collaborations • Investigation into ways to minimise biomarkers and the development of and with national collaborative groups. including both applied and basic out-of-field doses in radiotherapy genotyping assays. research. • Particular focus includes medication of brain lesions in children. - Preventing or overcoming safety, pharmacokinetics and In 2010, the research focus of the • Development of mathematical chemotherapy resistance with pharmacodynamics, drug stability, Physical Sciences team was on the models based on radiobiological posaconazole (p53 resistance) pharmacogenomics, adverse development of new techniques and models and functional imaging, with (Senthil). drug reactions and chemotherapy technologies for radiotherapy delivery. the objective of improved treatment drug dosing. • Pharmacotherapeutics A particular emphasis was the introduction of prostate cancer (Cancer Australia of these techniques into the clinic funded project). • Research experience includes - Preventing DVTs in cancer patients via clinical trials, both in-house and on Head: Sue Kirsa clinical and practice-based through effective thromboprophylaxis Head: Jim Cramb a national level through TROG. • Assessment of radiation dose research with self-initiated projects, strategies (Verna). outside of the treatment field with The Pharmacy at Peter Mac provides competitively funded initiatives the aim to determine and minimise - Using Azol antifungals in prophylaxis The Department of Physical Sciences medicines management support for and supervision of undergraduate RESEARCH DIRECTIONS risk of secondary cancer induction against systemic mould and fungal comprises medical physicists, who patients and staff, focusing on ensuring and postgraduate students. due to radiotherapy. This is part infections effectively in severely provide a range of services underpinning • Continuing research into and medicines use by Peter Mac patients of an NHMRC funded project. immunocompromised patients. the planning and delivery of radiotherapy development of imaging modalities, are safe, effective and efficient. treatments. These include equipment in particular to allow for or correct for • Development of a technique for The Pharmacy conducts high quality RESEARCH DIRECTIONS Other audits and roll out of clinical practice guidelines have similar aims commissioning and quality assurance, organ movement during radiotherapy extracranial stereotactic radiotherapy research that will contribute positively The key focus of the Pharmacy’s on a local scale — providing support development and enhancement of treatment. treatments for small lung cancers to the drug therapy outcomes of our research work is on improving the for clinicians to provide evidence treatment techniques, fundamental as part of a Cancer Australia funded patients. efficacy of medicines. Research has • Development of a protocol to use based care to our patients and providing and clinically oriented research, clinical trial (CHISEL). This involves mainly centred on formulating, rolling out a hand-held ultrasound scanner feedback to clinicians about how closely involvement in clinical trials and to confirm bladder volume prior also work on motion management. and then auditing medicine use following teaching. Medical physicists play our practice aligns with evidence. to radiotherapy treatment for • Development of a method for evidence-based guidelines. Through the a key role at our main campus at post-prostatectomy patients. credentialing of centres for participation robust methodology of literature review, For more information on related East Melbourne, and also at each in a clinical trial employing adaptive clinician practice survey and consensus research, see: of Peter Mac’s four satellite centres. • Development of a software tool meetings, we contribute to the radiotherapy for bladder cancer - Infectious Diseases (pg 115) to analyse data from clinical trial formulation of nationally consistent Our Biomedical Engineering section benchmarking exercises. This (BOLART — funded through NHMRC). approaches to medicine management: - Molecular Pathology laboratory is primarily responsible for the testing, application provides quantitative • Commencement of support for reducing practice variation, aligning (pg 117) maintenance and quality control of assessment of variations in contouring research activities in nuclear medicine practice with evidence and ultimately patient-related equipment. The team treatment volumes and organs at risk. and medical imaging as it pertains improving patient outcomes. also contributes to the to radiotherapy treatment planning. design and development of special- • Involvement in multiple clinical trials purpose radiotherapy equipment for including advice on QA activities both external beam radiotherapy and for trials using IMRT techniques, and the treatment with implanted radioactive participation in international discussion sources (brachytherapy). on global harmonisation of quality assurance standards in clinical trials.

Peter MacCallum Cancer Centre – Research Report 2010 Enabling Technologies and Interdisciplinary Research Platforms 123 3.2.16 Radiation Therapy 3.2.17 Social Work

RESEARCH FOCUS - Cancer Australia, DoHA & Prostate RESEARCH FOCUS Social Work as part of Allied Health at Radiation Therapy research crosses Cancer Foundation of Australia: Research activities focus on: Peter Mac, is also engaged in partnering ‘Translation of clinical and functional with Allied Health at St Vincent’s Health all types of cancer, with a focus on • Patient focused psychosocial priorities imaging data to brachytherapy in the Older Persons with Cancer Project. the appraisal and improvement of in treatment and survivorship radiotherapy techniques as a single treatment optimisation for prostate Supported by a grant from the Western • Social Networks, including caregivers and combined modality including: cancer’, 2010 –12. and Central Melbourne Integrated Cancer Service (WCMICS), the project, - Victorian Cancer Agency (VCA) • Workforce development and • 4D PET imaging is entitled ‘Can we improve the care of Supportive Care & Palliative Care sustainability. older people with cancer (OPWC) • 4DCT imaging Capacity Building Grant: ‘Evaluation through targeted supportive care of the psychosocial impact of a novel Current research projects focus on: • SBRT assessment, capacity building and intervention that aims to reduce anxiety • Family/caregivers partnerships with sub acute ambulatory • Gated Radiotherapy and aid coping in paediatric care service?’ • managing organ deformation radiotherapy patients by producing a • Gender short DVD about their treatment The general aim of this project is to • PET and tumour response • Multiculturalism Head: Aldo Rolfo experience’, 2010. Head: Alison Hocking improve the care of OPWC at St • Adaptive Radiotherapy. • Social Work interventions and Vincent’s and Peter Mac by testing the - Peter Mac Foundation Grant: ‘Bladder innovative service delivery methods feasibility of a geriatric screening volume surveillance using ultrasound The Department of Social Work assessment (GSA) with supportive care Significant change and increase volumetric imaging for the post- Department provides social work, • Vicarious trauma of practitioners. pathway and addressing the learning of complexity of radiotherapy RESEARCH DIRECTIONS prostatectomy patient undergoing music therapy and language services to needs of sub-acute ambulatory care treatment technology is enabling Many of the clinical trials being radiotherapy treatment’, 2010. patients and their families at Peter Mac. service staff to meet the needs of further refinement in our radiotherapy undertaken within the department RESEARCH DIRECTIONS - Cancer Australia Priority-driven Social workers are members of OPWC. The project will thus propose methods, the development of image are part of TROG. Clinical trials of Collaborative Cancer Research multidisciplinary teams across Following the commencement of the an improved supportive care pathway guided radiotherapy and patient motion innovative treatment strategies include: management; use of novel ‘diagnostic Scheme: ‘A randomised trial of all clinical services, providing research collaboration between Social for OPWC. imaging devices’ to assess the impact • NHMRC Project Grants: stereotactic versus conventional psychosocial assessment and Work and The University of Melbourne in radiotherapy for inoperable stage IA care planning. 2009, we have progressed research of organ motion on planning dosimetry; - ‘A multi-centre feasibility study non-small cell lung cancer’, 2009 –11. activities under the Collaboration and target volume assessments. of online adaptive radiotherapy Our Language Services staff arrange of Social Research in Cancer Care. Increased integration of imaging into for muscle invasive bladder cancer’, - VCA Platform Technology Grant: interpreting services for Peter Mac We are currently in discussions with the radiotherapy process is a key focus. 2010–12. A Victoria wide Web based electronic patients to ensure they are able to national and international partners to learning (eLearning) program for communicate with staff and receive The research efforts throughout - ‘Analysis of low radiation dose develop other joint research initiatives. Image Guided Radiotherapy’, the information they require in the Radiation Therapy continue to grow, outside of the treatment field delivered 2009 –10. The key research strategy language of their preference. particularly at the satellites, to cancer patients undergoing was based around the use of high with increasing emphasis on radiotherapy’, 2010 –12. multidisciplinary team programs. quality imaging available now on the - ‘RAVES - 2009 –13, with University of radiotherapy treatment machine. This Newcastle involved better targeting of the tumour - ‘Phase 3 trial comparing adjuvant and avoidance of normal health versus salvage radiotherapy for tissues. A specific example being the high risk patients post radical use of imaging for bladder cancer to prostatectomy 2008 –11. reduce the radiation dose to healthy tissues. This area of research - ‘Determination of unwanted radiation examined the dose reduction dose outside of the radiotherapy achievable to healthy tissues when treatment field’, 2008 –10. an image guided adaptive treatment - ‘A prospective single arm trial of plan is used. In a study of 27 patients, involved field radiotherapy alone 25 received significantly less dose to for stage I-II low grade non-gastric these tissues which correlated with marginal zone lymphoma’, 2007–11. reduced side effects. - ‘A randomised phase 3 study of - VCA Clinical Trial Funding (Tumour radiation doses and fractionation Stream): ‘A prospective study schedules in non-low risk ductal investigating the impact of serial PET/ (DCIS) of the breast’, CT scans on the radiation therapy 2007–11. treatment of patients with lung cancer’, 2008–10.

Peter MacCallum Cancer Centre – Research Report 2010 Enabling Technologies and Interdisciplinary Research Platforms 125 3.2 Interdisciplinary Research Platforms – personnel

Centre for Blood Centre for Cancer Imaging Research Officers Australian Leukaemia & Lymphoma Clinical Psychology Infectious Diseases Cell Therapies Group (ALLG) Operations Office Head Dr Delphine Denoyer Head Clinical Research Fellow Head Melissa Benedict Director Prof. Rod Hicks Dr Kathryn Kinross Annabel Pollard Assoc. Prof. Monica Slavin Cristina Conesa Prof. Miles Prince Research Assistants Research Officer Megan Ellis Clinical Staff Undertaking Research Senior Researcher Deputy Director Dr Annette Hogg Laura Kirby Megan Sanders Dr Ann Boonzaier Dr Karin Thursky Assoc. Prof. David Ritchie Richard Young Delaine Smith Dr Kate Neilsen Research Imaging Specialists Research Assistants Advanced Medical Science Janey Stone Operations Director Assoc. Prof. Eddie Lau Dr Iain Abbott (AMS) Student Dilu Uduwela Familial Cancer Centre Dr Dominic Wall Dr Kate Moodie Vivian Leung Ashray Gunjur (2009 – 10) Director Clinical Trials Unit Clinical Apheresis Director Research Coordinator Francis Wong (2010 – 11) Dr Gillian Mitchell Postgraduate Students Dr Simon Harrison and Clinical Trials Specialist Unit Manager Dr Michelle Anada-Rajah Geneticists David Binns Centre for Biostatistics Shannon Uren Senthil Lingaratnam Quality Manager and Clinical Trials Jason Callahan Assoc. Prof. Paul James Dr Leon Worth Martin Bleasdale Research Nurse Consultants Director Dr Alison Trainer Radiopharmaceutical Chemists (Team Leaders) Visiting Fellow Managing Director Assoc. Prof. Dina Neiger Clinical Research Coordinators Cell Therapies P/L Dr Oliver Neels Allison Lamb Dr James Koh Dr Peter Roselt Clinical Trials Program Manager Heike Raunow Kate Drew Ray Wood Rebecca Driessen Marianne Hundling Sam Ruell kConFab Follow-Up Project Radiopharmacist Joanne McKinley Business Manager Principal Investigator Peter Eu Development and Project Manager Research Nurses Sarah Sawyer Dr Wendy Chung Assoc. Prof. Kelly-Anne Phillips Paul Fahey Glenda Burke Research Coordinator Medical Oncologist Cryopreservation Duncan Colyer Project Coordinator Elizabeth Drummond Biostatisticians Dr Yoland Antill Peter Gambell Jill Davison Prue Weideman Ayse Mouminoglu Nuclear Medicine Technologists Marnie Collins Rebecca Doherty Assoc. Prof. Sue-Anne McLachlan Mathias Bressel Carrie Donohoe Research Fellow Cell Manipulation Silvana Breglevska Medical Oncologist and Geneticist Melanie Crowther Gaelle Dutu Karena Hanlon Dr Sandra Harvey Kerrie Stokes Dr Marion Harris Emily Hong Assoc. Prof. Richard Fisher Rosetta Hart Elise Butler Research Assistants Val Johnston Emma Link Jo Hawking Gastroenterologist Carmen Chong Kate Lucas Mick Thompson Alan Herschtal Kate Khamly Assoc. Prof. Alex Boussioutas Valerie Costa Lucy Stanhope IT Amanda Marshall Kate Dunster Nuclear Medicine Physician Psychiatrist Sharyn Meadows Molecular Pathology Alannah Evans Jenny Beresford Dr Daina Rumbergs Dr Michael Hofman Michele Mortos laboratory Javier Haurat Linas Silva Nuclear Medicine Specialist Carmela Rooney Genetic Counsellors Lucy Kravets Heads Trial Centre Data Managers Gillian Shilton Shauna Buscombe Maureen Loudovaris Dr Grace Kong Prof. Stephen Fox Ruth Columbus Linda Ciccarelli Nicole McCarthy Study Coordinators Assoc. Prof. Alex Dobrovic Nuclear Medicine Registrar Linda Cowan Lucinda Hossack Jude Moloney Fareda Fazli Tom Barber Juliana Di Iulio Alexandra Lewis Pathology Research Fellows Angela Morgan Sophie Katsabanis Kylie Gillberg Mary-Anne Young Tanya Pisanelli Analytical Chemist Katrina Parente Dr Peter Chan Bereha Khodr Dr Max Yan Gianna O’Donnell Dr Wayne Noonan Michael Kornhauser Anita Sridhar Genetics Nurses/Coordinators Diane Strong Gillian Treloar Visiting Scientist Narmatha Kuru Morgan Murphy Postdoctoral Scientists Dimitrios Tsiavos Vicki Walcher Mary Shanahan Nicolas Aide Poppy Kypreos Dr Chelsee Hewitt Lezly Penalver Ania Matera Clinical Trials Nurse Specialist Research Assistant Dr Thomas Mikeska Gabby Workman Radiologists Dr Renato Salemi Bev McClure Danielle Harvey Katrina Reeve Sichong Zhou Dr Robin Cassumbhoy Teresa Morgan Dr Angela Tan Apheresis Dr Churata Dagia Christina Phassouliotis Office Manager – Data Manager Dr Ee Ming Wong Administrative Team Leader Dr Nick Ferris Larissa Popowski Chris Michael-Lovatt Dr Stephen Wong Mel Darby Dr Catherine Mandel Christine Russell Tenille Gaylard Jack Parrington Postgraduate Students Research Officers Caroline Sardjono Honorary Nuclear Junior Study Coordinator Kathryn Alsop Heather Hondow Senior Scientist Janani Sivasuthan Medicine Physician Nicole Roylance Ashley Crook Elena Takano Dr. Paul Neeson Janey Stone Dr Rob Ware Lauren Plunkett Giada Zapparoli Marijana Vanevski Administrative Assistant Senior Research Associates Research Fellow Rachael Brooking Research Assistants Administration Prof. Rod Hicks Jean-Mathieu Beauregard David Byrne Robert Hannah Data Assistant Dr Kirsten Herbert Toni-Maree Rogers MRI Supervisor Ditas Sioco Gens George Noelene Bergen Julie Umek Ethics Submission Coordinators Research Project Leader Sarah Bascomb Dr Donna Dorow Hayley Pritchard

Peter MacCallum Cancer Centre – Research Report 2010 Enabling Technologies and Interdisciplinary Research Platforms 127 3.2 Interdisciplinary Research Platforms – personnel

Postgraduate Students Researchers Nutrition Pain and Palliative Care Charge Radiation Therapists Ida Candiloro Rachid Annab Head Head Brent Chesson Hongdo Do Carl Baravelli Jenelle Loeliger (Malnutrition Inpatient Dr Odette Spruyt Alison Cray Katie Huang Rebecca Bergin Strategy Project Manager) Katie Davidson Lara Dolling Consultant Dr Sarah Everitt Dan Mellor (part time) Matt Holmes Dietitians Dr. Natasha Michael Cathy Markham Dr Max Yan Dr Sarah Kofoed Gen Francis Karen McGoldrick Study Coordinator Summer/AMS Student (2010 – 11) Amanda Hill Andrea Paneghel Kerryann Lotfi-Jam Elaine Mills Belinda Hodgson (Malnutrition Inpatient Josh Rudolph Zi Rong Low (The University of Kerith Sharkey Strategy Project Co-Manager) Mike Sproston Melbourne) Anna Ugalde Research Nurse Amber Kelaart Ann Thompson Eva Yuen Indy Khera Nursing and Supportive Care Nicole Kiss David Tongs Project Co-ordinators Director of Cancer Nursing Research Postdoctoral Fellow Vivian Kong Sylvia Van Dyk Alex Brando (PCI) Prof. Sanchia Aranda Dr Carrie Lethborg Tracey Martin David Willis Sally Muir Di Saward (LCP) Postgraduate Students Head of Planning, Radiation Deputy Director of Cancer Fiona Rezannah Pharmacy Therapy Services Nursing Research Jenny Anderson Hannah Ray Assoc. Prof Meinir Krishnasamy Anna Boltong Director Julie Miller Mary Duffy Nutrition Assistants Director of Strategy (Malnutrition Inpatient Strategy) Sue Kirsa Head, Education and Development Priscilla Gates Unit, Radiation Therapy Services and Development Stephanie Acosta Deputy Director Miranda Goh Kate Wilkinson Assoc. Prof. Penelope Schofield Chi-Yin Kao Angela Harris Dan Mellor Kerryann Lotfi-Jam Chloe Schibeci Senior Clinician Researcher WCMICS Project Officer Social Work Anna Ugalde Pauline Tsang Dr Donna Milne Senthil Lingaratnam Head Senior Supportive Care Researcher AMS Students onTrac@Peter Mac Alison Hocking (The University of Melbourne) Postgraduate Student Dr Sibilah Breen Acting Director Senior Research Fellow Kelvin Koay (2009–10) Dan Mellor Dr Jessica Faggian Dr Lisa Orme Assoc. Prof. Lynette Joubert Simon Wu (2010–11) Physical Sciences Statistician Director Undergraduate Research Senior Social Workers Dr Karla Gough Director Opportunities Program Assoc. Prof. David Thomas Elizabeth Ballinger Jim Cramb Consultant Medical Oncologists (UROP) Student Manager Denise Beobich Assoc. Prof. Michael Jefford Desmond Chee (2010–11) Kate Thompson Principal Research Physicist Social Workers Dr Linda Mileshkin Prof. Tomas Kron Research Consumer Advisors Research Coordinator Annette Betheras Hamlata Bhana Research Operations Diana Black Lucy Holland Senior Research Physicist Fiona Hewitt Katie Emma Burrell Assoc. Prof. Annette Haworth Jennifer Burn Cherry Horan Annemarie Charles Research Assistant Catherine Coppolino Senior Physicists Wal Crellin Gavin Dyson Elizabeth Dillon Clinician Researchers Dorothy King Paul Roxby Tegan Murnane Senior Clinician Michaela Brindas Debbie Lee Chris Fox Lucy Pollerd Ilana Berger Lisa Demosthenous Dean Lynch Dr Jim Hagekyriakou Elena Schiena Tracey Dryden Helene O’Neill Adolescent and Young Adult Radiation Therapy Music Therapists Mary Duffy Sylvia Penberthy Research Fellow Dr Clare O’Callaghan Catherine Grima Vigneswara Rajah Dr Rachel Conyers Director Radiation Therapy Services Christine Mesarich Suzi Grogan Ian Roos Aldo Rolfo Adolescent Psychologist Allison Hatton Barbara Shaw Language Services Coordinator Dr Felicity Sleeman Radiation Therapists Lynette Joubert Beryl Shaw Kerrie Dunn Yolanda Aarons Trish Joyce Christine Thom Victorian and Tasmanian AYA Therese Chesson Nicole Kinnane David Wenzel Clinical Trials Officer Robyn French Mary Leahy Claire Wilkinson Deb Howell Brayden Geary Rebecca McMillan Leonie Young Andrew Murnane Education and Vocation Advisor Rebecca Height Cathie Pigott Support Volunteers Nicole Edwards Felicity Height Mary Shanahan Tamara Anghie Belinda McInnes VCA Fellow, onTrac@Peter Mac Kath Schubach Tia Field Richard Oates Lisa Sheeran Melinda Grant Assoc. Prof. Lynette Joubert Daniel Pham Kathy Watty Georgia Mills Maria Portillo Bernadette Kelly Cate Sproston Sue Rowsthorn Fiona Wightman

Peter MacCallum Cancer Centre – Research Report 2010 Enabling Technologies and Interdisciplinary Research Platforms 129 4 Education and Learning 4 Education and Learning

Ever since her first laboratory experience with the CSIRO at age 15, Katrina Falkenberg has wanted to work in medical research. Now a PhD student at Peter Mac, Katrina’s research is driven by an innate curiosity to understand cancer at a molecular level as well as a desire to improve treatment options for patients. Access to Peter Mac’s sophisticated equipment allows Katrina, with her team in the Gene 4 Regulation laboratory, to define the molecular and biological processes required for anti-cancer drug action and drug resistance.

Peter MacCallum Cancer Centre – Research Report 2010 4 Education and Learning 4.1 Cancer Research Education program

Encouraging and training 4.1.1 Seminar programs Promoting recent advances in the rapidly changing technologies used in medical research is an important aspect medical researchers of the future of our development of the next generation of researchers. At Peter Mac, we host seminar activities designed to assist the professional development of scientists at all levels. In supporting Cancer Research at Peter 4.1 Cancer Research The weekly Research Seminar Series provides opportunities to hear about advances in cancer research at Peter Mac Education Program Mac, our Research Education program and external organisations. Staff and students also participate in weekly laboratory meetings and research hub seminars. provides excellence in scientific research • Seminar programs These seminars provide Peter Mac researchers with the opportunity to discuss their research with broader expert audiences training and support for all laboratory • Student training program while also assisting them in developing presentation and discussion skills to increase their breadth of science knowledge and researchers and students as they • Research awards build confidence. We also host seminars and workshops designed to broaden the professional development of our scientists develop expertise in new technologies, and students, and we organise an annual Topics in Cancer Seminar series to provide an opportunity for students and scientists • Peter Mac Postdoctoral program and help drive to expand their understanding of key aspects of cancer research. new discoveries that lead to changes • Community and school in research and clinical practice. outreach activities Our postgraduate PhD and DMedSc/MD 4.2 Clinical Research Education 2010 Postgraduate Seminar Series: Topics In Cancer students and our postdoctoral scientists and Training Programs contribute significantly to the success - Specialised Certificate in Date Presenters Topics in Cancer of Peter Mac, and we are proud of the Clinical Research (Oncology), 4-May Drs Amber Alsop, Kylie Gorringe, Mark Shackleton How do cancers progress? outstanding, motivated and enthusiastic The University of Melbourne Dr Caroline Owen, Education and staff and students who are an important 18-May Drs Trina Stewart, Michele Teng, Dan Andrews Cancer and immune regulation Communications Officer, Cancer Research - Clinical Research Methods part of our internationally recognised in Radiation Oncology 8-Jun Drs Trina Stewart, Linda Berry, Nicole Haynes Immunotherapy of cancer research team. Supporting the teaching 22-Jun Drs Kathy Jastrzebski, Kaylene Simpson, Megan Astle RNAi screening and cancer and learning needs of the next - Seminars in Oncology program Our Research Education program is 29-Jun Drs Petranel Ferrao, Mark Devlin, Amber Alsop Molecular targeted therapeutics/small molecule inhibitor drugs generation of research scientists underpinned at all levels by a belief in in cancer treatment and clinician-researchers at Peter Mac the importance of developing a deep 13-Jul Drs Kathryn Kinross, Nathan Godde, Geoff Matthews Mouse models in cancer research understanding of the processes that is a high priority, and we strive to foster control cancer cells, and employing this a collaborative and enabling environment 27-Jul Assoc Prof Grant McArthur Targeting oncogene addiction in clinical trials knowledge in the clinic to develop that encourages and supports our 10 Aug Prof Rod Hicks Imaging as a platform technology in translational research rational, evidence-based protocols that young researchers as they develop their improve cancer outcomes. Using potential for future leadership in health state-of-the-art facilities, we are focused and biomedical research. 2010 PROFESSIONAL DEVELOPMENT WORKSHOPS on supporting the next generations of The Cancer Research Education Date Presenters Topic basic translational researchers who will program is supported by full-time improve cancer diagnosis, treatment Education and Communications Officer, 30-Mar Peter Mac student participants and facilitators Prism and Endnote workshop and care. Dr Caroline Owen, who coordinates all 6-Apr Peter Mac student participants and facilitators Statistics workshop aspects of student and staff education 6-Jul Yovanna Adamis (The University of Melbourne), Student Careers Seminar and career activities across Cancer Dr Luke Lambeth and Dr Edwin Hawkins (Peter Mac). Research and affiliated clinical areas, and liaises with affiliated universities and research institutes. 2010 PETER MAC RESEARCH SEMINAR SERIES

Date Speaker Institute Topic 25-Feb Prof. Miles Prince Peter Mac Translational research in haematology at Peter Mac 4-Mar Assoc. Prof. Michael Ryan La Trobe University Assembly of mitochondria in health and disease 11-Mar Prof. John Hopper The University of Melbourne From tumour-type to phenotype: a new paradigm for breast and genetics services that will save lives 18-Mar Assoc. Prof. Kathy Belov University of Sydney, NSW The genetics of Devil Facial Tumour Disease (DFTD)” 25-Mar Assoc Prof. Burnet Institute HIV: from AIDS to chronic inflammatory disease Anthony Jaworowski 14-Apr Dr Axel Kallies The Walter & Eliza Hall Institute The transcription factors Blimp1 and IRF4 jointly regulate of Medical Research differentiation and function of effector regulatory T cells 21-Apr Prof. David Ashley Children’s Cancer Centre, the Epigenetics of childhood cancer Royal Children’s Hospital, Melbourne 28-Apr Assoc. Prof. Carola Vinussa The John Curtin School The Roquin pathway in RNA regulation and autoimmune disease of Medical Research, The Australian National University

Peter MacCallum Cancer Centre – Research Report 2010 Interdisciplinary Research Platforms 133 4.1 Cancer Research Education program 4.1 Cancer Research Education program

2010 PETER MAC RESEARCH SEMINAR SERIES (CONT.) 2010 SPECIAL SEMINARS AND TECHNICAL WORKSHOPS

Date Speaker Institute Topic Date Speaker Institute Topic 5-May Dr Matthew McCormack The Royal Melbourne Hospital Identification of Precancerous Stem Cells in a mouse model 27-Jan Dr Nikola Baschuk University Hospital of Cologne, Immune surveillance of cancer — molecular and translational aspects of T cell Leukemia Institute for Medical Microbiology, of Cytotoxi Effector: Target Cell Interactions Immunology & Hygiene, Germany 12-May Prof. Julian Rood Monash University Role of clostridial in human disease 9-Feb Amy Rappaport, Katie Cold Spring Harbor Laboratory, MLL/AF9 is required for the maintenance of aggressive acute myeloid 19-May Prof. Terry Speed The Walter & Eliza Hall Institute Combining matched gene expression and transcription factor binding McGukin New York, USA leukemia in mice(AR) of Medical Research sites: some lessons from an experiment with ERbeta Inducible, transgenic RNAi targeting essential genes in mice (KM) 27-May Prof. Wolfgang Weninger Centenary Institute for Cancer Visualising the orchestration of skin immune responses in real time 10-Feb Dr Jon Karpilow, Thermo Fisher Scientific Using RNAi screening to Identify host and pathogen genes Medicine and Cell Biology, NSW that are relevant to viral infection 3-Jun Prof. Peter Currie Australian Regenerative Medical Modelling muscle growth and disease in zebrafish 13-Apr Xose Fernandez European Bioinformatics Institute, Bioinformatics Services at EBI: An Introduction to EBI with a focus Institute, Monash University EMBL Outstation, Cambridge, UK on gene expression analysis 10-Jun Prof. Anne Kelso WHO Collaborating Centre Flu shifts backwards: the 2009 pandemic How the EBI is riding the tsunami: next generation sequencing for Reference and Research 25-May Assoc. Prof. Bill Matsui John Hopkins Sidney Kimmel Cancer stem cells in Multiple Myeloma: basic biology on Influenza, Melbourne Comprehensive Cancer Centre, and clinical translation 17-Jun Prof. Leann Tilley La Trobe Institute for Molecular Super-resolution optical microscopy and electron tomography Baltimore, USA Science of malaria parasites 25-May Dr Axel Kallies The Walter & Eliza Hall Institute The transcription factor Blimp1 Is a context specific B cell 24-Jun Dr Darren Saunders Garvan Institute of Medical Illuminating molecular pathways through integration of Medical Research tumor suppressor Research, NSW of functional genomics and proteomics 11-May Paul Ramadge Editor-in-Chief, The Age The media and science — a new relationship 8-Jul Prof. Ashley Bush Mental Health Research Institute Alzheimer’s disease and cancer 6-Sep Dr Stephen Laderman Agilent Laboratories Advanced measurement technologies for personalised 15-Jul Dr Jake Baum The Walter & Eliza Hall Institute The molecular mechanics of malaria parasite motility cancer medicine of Medical Research and host cell invasion 14-Sep Assoc. Prof. Han van der Cincinnati Children’s Research GMP manufacturing at the Cincinnati Children’s Hospital 22-Jul Prof. Richard Harvey Victor Chang Cardiac Research Cardiac-resident MSC-like stem cells: definition and origins Loo Foundation, USA translational cores Institute, NSW 14-Sep Dr Yuri Nikolsky GeneGo Inc Functional analysis of OMICs Data in breast cancer 29-Jul Prof. Levon Khachigian Centre for Vascular Research, Transcriptional control in vascular dysfunction 29-Sep Dr Gianfranco de Feo Sequenom Translating biomarker research to human health” University of NSW 1-Oct Dr Roderick Beigersbergen Netherlands Cancer Institute The powers of RNAi in cancer discoveries 5-Aug Prof. Alpha Yap Institute for Molecular Bioscience, Epithelial interactions: cadherins, signalling and the actin cytoskeleton University of Queensland, QLD 6-Oct Assoc. Prof. David Granville University of British Columbia, Granzyme B: A multi-functional protease in inflammation and disease Canada 12-Aug Prof. Melanie Wakefield Cancer Council Victoria Tobacco control in Australia: where have we come from and where are we going? 11-Oct Dr Grzegorz Popowicz Max Planck Institute for p53 interaction with Mdm2 and its implications for the activity Biochemistry Martinsried, Germany of the therapeutic drugs, the nutlins 19-Aug Prof. John Quackenbush Dana-Farber Cancer Institute Network and state space models: science and science fiction and the Harvard School of Public approaches to cell fate predictions 14-Oct Prof.John Scott University of Washington Cell signalling in space and time Health, Boston, USA School of Medicine, USA 26-Aug Dr Ben Solomon Peter Mac ALK gene rearrangements: A new target in non-small cell 8-Nov Prof. Ze’ev Ronai NCI Cancer Centre, Sanford- The ubiquitin ligase Siah2 in hypoxia and tumourigenesis lung cancer Burnham Medical Research Institute 2-Sep Dr Robert Vonderheide Abramson Family Cancer Research Cancer immune surveillance and immunotherapy in solid tumours: 7-Dec Dr Luke Dow Cold Spring Harbor Laboratory, Transgenic RNA interference defines new roles for the Adenomatous Institute, University of Pennsylvania strategies for stepping on the gas and cutting the brakes New York, USA Polyposis Coli tumour suppressor School of Medicine, USA 13-Dec Dr Laura Johnston Columbia Medical School, Homeostatic mechanisms during organ growth 9-Sep Prof. Peter Howley Harvard Medical School, USA HPV and cancer: regulation of viral oncogene expression New York, USA 16-Sep Prof. Peter Vischer Queensland Institute of Medical Genome-wide association studies and the problem of ‘missing Research, QLD heritability’ 23-Sep Prof. Christophe Marcelle Australian Regenerative Medicine Neural Crest regulates myogenesis through the transient Institute, Monash University activation of NOTCH’ 30-Sep Dr Stuart Tangye Garvan Institute of Medical Lessons for human knock-outs: what primary immunodeficiencies Research, NSW can tell is about immune regulation’ 7-Oct Assoc. Prof. Penny Schofield Peter Mac Sex, death and transformation: Improving outcomes for people affected by cancer 14-Oct Prof. Peter Gunning University of NSW Deconstructing the cytoskeleton and identification of the actin filaments which drive cell proliferation in normal and cancer cells 21-Oct Dr John Silke La Trobe University The TNF uncertainty principle — and lessons for other signalling pathways 4-Nov Assoc. Prof. Steven Stacker Peter Mac Lymph angiogenesis 11-Nov Prof. Sam Berkovic The University of Melbourne On the origin of epilepsies 18-Nov Prof. Jonathon Carapetis Menzies School of Health Priorities in Aboriginal health research Research, Northern Territory

Peter MacCallum Cancer Centre – Research Report 2010 Education and Learning 135 4.1 Cancer Research Education program 4.1 Cancer Research Education program

class of 2010 Devlin J, Investigating the role of AKT signalling Students in Progress Bywater M, Regulation of ribosome biogenesis Elsum I, The role of Scribble in oncogenic 4.1.2 Student in c-MYC driven tumorigenesis. Assoc. Prof. during lymphomagenesis. Assoc. Prof. G. signalling and tumourigenesis. Dr P. Humbert, Doctor of Philosophy (The University R. Pearson, Dr K. Hannan. Scholarships to support training McArthur, Assoc. Prof. R. Hannan, NHMRC. Assoc. Prof. H. Richardson, CCV. Training Program of Melbourne) Fund I, The role of signalling and polarity APA: Australian Postgraduate Award Candiloro I, Somatic DNA methylation and Falkenberg K, Targeting epigenetic enzymes Amos S, Enhancing lymphocyte trafficking Student teaching and learning are proteins in asymmetric cell division of T ASCC: ASCC Postgraduate Scholarship cancer predisposition. Assoc. Prof. A. Dobrovic, for the treatment of cancer. Assoc. Prof. R. for adoptive T-cell therapies. Dr M. Kershaw. lymphocytes. Dr J. Oliaro, Dr S. Russell. Dr T. Mikeska, MFS. Johnstone, Dr K. Simpson, APA. key activities in Cancer Research, and CASS: CASS Foundation Scholarship the attraction of high-quality students Everitt S, The utilisation of PET/CT for Halse H, Siah2 ubiquitin ligase dependent CCV: Cancer Council Victoria Postgraduate Cao Y, BMP4 — a metastasis suppressor Galea R, The role of the Scribble/Discs to undertake Doctor of Philosophy (PhD), assessing therapy naïve tumour growth, communication between breast cancer tumour Scholarship gene in breast cancer. Dr R. Anderson, Dr B. Lager polarity complex in development and medical doctorates (MD or DMedSc) radiation therapy target volumes and cellular cells and the immune system. Dr A. Moeller, CRIS: Cancer Research Institute Scholarship Eckhardt, MRS. tumourigenisis. Dr P. Humbert, Assoc. Prof. H. response in Non small Cell Lung Cancer. and honours programs in our laboratories Mr C. House. CSL: CSL Postgraduate Scholarship Richardson, APA. Assoc Prof M. MacManus, Prof T. Kron Carpenteri S, Pathways regulating continues as a priority. In 2010, we Kapadia N, Investigating receptor mediated EGIPS: Egyptian Government International asymmetric cell division and binary cell lineage Garsed D, Uncovering the molecular basis and Dr M. Schneider-Kolsky. Postgraduate Scholarship welcomed 12 new honours students, delivery of Iodine-125 labelled DNA ligand to fate in the intestine. Assoc. Prof. R. Ramsay, of well-differentiated liposarcoma. Assoc. Prof. EQUITY: Equity State Trustees 12 new PhD students and two DMedSc Grusche F, The regulation of tissue growth in the DNA of tumour cells. Dr P. Lobachevsky, Dr P. Darcy, LaTrobe. D. Thomas, Assoc. Prof. Y. Haupt, MRS. Drosophila melanogaster during development Assoc. Prof. R. Martin. FUSRS: Flinders University Student Research students to our team. and regeneration. Assoc. Prof. H. Richardson, Scholarship Carter R, Integrin ss3 as a therapeutic target George J, Integrated analysis of distinct Ko SY, Pathways that regulate intestinal crypt for breast cancer metastasis to bone. Dr R. molecular profiles of tumour data. Prof. Cancer Research is home to Dr K. Harvey, Dr T. Brumby. LaTrobe: La Trobe University Postgraduate cell fates and impinge upon cancer. Assoc. Prof. Scholarship Anderson, Dr N. Pouliot, NBCF. D. Bowtell, Assoc. Prof. G. Smyth, APA. approximately 100 students throughout Lin J, Effects of ribosomal protein hypomorphs R. Ramsay, Dr J. Malaterre. LF: Leukaemia Foundation Scholarship on cell growth and proliferation in Drosophila Chan AL, Regulation of Promyelocytic Hare L, Investigating the role of PIK3CA the year, including postgraduate, MFS: Melbourne Faculty Scholarship melangaster. Assoc. Prof. R. Hannan, Assoc. Lefebure M, Novel combination treatments Leukaemia (PML) by E6AP in human mutations in colorectal cancer. Assoc. Prof. honours and advanced medical science MGS: Monash Graduate Scholarship Prof. R. Pearson and Dr L. Quinn. against multiple myeloma. Assoc. Prof. R. cancers. Assoc. Prof. Y. Haupt, Assoc. Prof. W. Phillips, APA. students. In 2010 we also provided Johnstone, Dr G. Matthews. MIRS: Melbourne International Research D. Thomas, MRS. research placements for four international Pegram H, Gene modification of multiple Scholarship Huang K, Epigenetic mechanisms in benign Munforte L, In vitro evaluation of Chan C, NK cells in Tumour Immunosurveillance. and malignant breast cancer. Prof. S. Fox, Assoc. postgraduate students and for leukocytes for cancer immunotherapy. MRS: Melbourne Research Scholarship the combination of a new DNA-binding Prof. M. Smyth, Dr D. Andrews, LF. Prof. A. Dobrovic, MRS. Dr P. Darcy,Dr M. Kershaw. NBCF: National Breast Cancer Foundation undergraduate students associated radioprotector with a radical scavenger. Scholarship Cheasley D, Investigations of Myb target Huynh D, CSF-1/c-fms signalling in intestinal with our Summer Vacation Research Qiu, W, Cellular, molecular and genetic Dr P. Lobochevsky, Dr A. Smith. Program, undergraduate work characterisation of breast and ovarian cancer NHMRC: NHMRC Postgraduate Scholarship genes and regulation within stem/progenitor biology and cancer. Assoc. Prof. R. Ramsay, Woods S, A role for E6AP in the regulation cell populations of the intestine. Assoc. Prof. LaTrobe. experience and Biomedical Science associated fibroblasts (CAFS). Assoc. Prof. I. Peter Mac: Peter Mac Research Laboratory of p53 under stress conditions. Assoc. Prof. or Grant Funding R. Ramsay, APA. Campbell, Dr I. Haviv. Johnson C, Molecular profiling of breast (Pathology major) research projects Y. Haupt. RACS: Royal Australasian College undertaken in our laboratories. Wiegmans A, The biomolecular actions of of Surgeons Chee L, Differentiation therapy of acute myeloid ductal carcinoma in situ. Prof. I. Campbell, leukaemia: combining RARAgonists and G-CSF. Dr E. Thompson, APA. The Cancer Research team at Peter HDAC inhibitors. Assoc. Prof. R. Johnstone. SUT: Swinburne University Postgraduate Advanced Medical Science (AMS) Assoc. Prof. G. McArthur, Dr P. Humbert, CSL. Mac also offers opportunities to TAFE (The University of Melbourne) Scholarship Khoo P, Investigation of pathways that act and secondary school students to Bachelor of Science (Honours) Chia J, Investigating the molecular basis downstream of scribble and Rho GEF2 in Cordy R, Novel combination immunotherapies undertake short-term work placements (The University of Melbourne) of perforin dysfunction that leads to atypical cooperation with oncogenic RAS in a Drosophila induce immunogenic cell death in human PhD in Progress Haemophagocytic Lymphohistiocytosis (HLH) cancer model. Assoc. Prof. H. Richardson, in our laboratories. Barber F, Development of a functional genomic myeloma cells. Dr P. Neeson, Assoc. Prof. or other primary pathologies. Prof J Trapani, Dr P. Humbert, Dr T. Brumby, MRS. screen for novel modulators of drug resistance D. Ritchie. Ackora D, Pathways regulating asymmetric Dr I. Voskoboinik, CCV. Our comprehensive student program in ovarian cancer. Assoc. Prof. R. Pearson, cell division and binary cell lineage fate in Koh SY, Role of Proteases and PARs in includes mentor programs, dedicated Dr K. Sheppard. Gunjur A, The patterns of progression and the intestine. Dr J. Malaterre, Assoc. Prof. Chong L, Investigating Olt-4 in skin. Dr P. Kaur, Barrett’s Oesophagus and Oesophageal student scientific review committees, pseudo-progression for glioblastoma multiforme R. Ramsay, Ministry of National Education Dr H. Schluter, Peter Mac. Adenocarcinoma. Assoc. Prof. W. Phillips, Cameron D, Developing a screen for novel onsite workshops and seminars, patients treated with the ‘Stupp Protocol’. Assoc. Scholarship, Republic of Turkey. Dr N. Clemons, MIRS. regulators of RNA Polymerase I transcription. Prof. E. Lau, Prof. R. Hicks. Chow M, The role of inflammasome in cancer an annual retreat, and community Dr M. Astle, Assoc. Prof. R. Hannan. Alsop K, Genotypic and molecular analysis initiation and tumour immunogenicity. Prof. Kusuma N, Targeting of Laminin-10 in and outreach opportunities. Koay K, Understanding health information in of ovarian cancer. Prof. D. Bowtell, Dr G. Mitchell, M Smyth, Dr A. Moeller, CRIS. breast cancer metastasis. Dr R. Anderson, Cross R, Myb and its involvement in the oncology setting. Assoc. Prof. P. Schofield, CCV. Dr N. Pouliot, NHMRC. Our postgraduate, honours and development and tumorigenesis. Prof. R. Assoc. Prof. M. Jefford. Conyers R, Creation of an in vivo model AMS students contribute significantly Ramsay, Assoc. Prof. R. Anderson. Azad A, Enhancing the efficacy of ionising recapitulating amplification of MDM2 and CDK4 Lee R, Biochemical analysis of AKT3 specific Yeh WZ, Investigation of differential allelic radiation with the dual PI3K/mTOR inhibitor in human Liposarcoma. Assoc. Prof. D. Thomas, signal transduction. Dr R. Pearson, Assoc. Prof. to the success of Peter Mac. We warmly Dent L, Novel regulators of the Hippo tumour expression of the human PRF1 gene. BEZ235. Assoc. Prof. G. McArthur, Dr B. Dr M. Kansara, MRS. R. Hannan, APA. congratulate the following students suppressor. Dr K. Harvey, Dr C. Poon. Dr I. Voskoboinik, Prof. J. Trapani. Solomon, NHMRC. who successfully completed their Davis S, Integrated Genomic Analysis Leong G, Identification and characterisation studies at Peter Mac in 2010. Bearfoot J, Identification of microRNA genes and Functional Characterisation of Novel of novel tumour suppressor genes involved involved in breast and ovarian tumourigenesis. Oncogenes in Ovarian Cancer Prof. I. Campbell, in breast cancer. Assoc. Prof. R. Hannan, Assoc. Prof. I. Campbell, Assoc. Prof. W. Phillips, Dr K. Gorringe, Dr K. Simpson, APA. Assoc. Prof. R. Pearson, Assoc. Prof. R. Johnstone, NHMRC, NBCF. Assoc. Prof. A. Dobrovic, MRS. Do H, Genetic and epigenetic mechanisms Bishton M, Investigations into Histone determining responses to therapy in non-small Messina N, Role of STAT1 in Interferon Deacetylase Inhibitor induced Thrombocytopenia. cell lung cancer.Assoc. Prof. A. Dobrovic, signalling and immunity. Assoc. Prof. R. Prof. R. Johnstone, Prof. M. Prince, Peter Mac. Prof. S. Fox, Peter Mac. Johnstone, Dr C. Clarke, CRIS. Miao, YR, The role of Myb in mammogenesis and breast Duong C, Generating highly responsive Brown D, Regulation and function of mutant cancer. Assoc. Prof. R. Ramsay, Dr R. Anderson, T cells with tumour homing ability for use in the p53. Assoc. Prof. Y. Haupt, Dr P. Humbert, APA. MRS. adoptive immunotherapy of cancer. Assoc. Prof. Bruhn M, Role of SGK3 in tumourigenisis. Dr K. K. Kershaw, Dr P. Darcy, APA. Newbold A, Mechanisms of histone Sheppard, Assoc. Prof. R. Hannan, FUSRS. deacetylase inhibitors. Assoc. Prof. R. Ellis S, In situ protein and molecular Johnstone, NHMRC. Burrows A. The contribution of stromal characterisation of the hemopoietic stem cell caveolin-1 to breast cancer metastasis. Assoc. niche. Dr S. Nilsson, Dr I. Bertoncello, Peter Mac/ Prof. R. Anderson, NHMRC. ASCC/CASS.

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STUDENTS IN PROGRESS (CONT.) West A, The role of HDACi in anticancer Advanced Medical Science(AMS) We sincerely thank Jenni Metcalfe immunotherapy. Prof. R. Johnstone, Prof. M. 4.1.3 Peter Mac Ngiow SF, Immune suppressive pathways in progress (The University and Cathy Sage who ran the Smyth, NHMRC. in cancer: mechanisms and applications. of Melbourne) Research Postgraduate communications workshop, and the Withana N, Contribution of tumour derived Prof. M. Smyth, Dr M. Teng, Malaysian Georgiou C, Breast cancer brain metastasis: guest speakers who very generously cysteine cathepsins to breast cancer metastasis Student Society Government Scholarship. characterisation of a syngeneic mouse model gave their time to talk to the students, to bone. Assoc. Prof. R Anderson, Parker, NHMRC. including Dr Brett Kennedy (Illumina), Pasam A, Mechanisms and role of polarity for preclinical treatment evaluation of histone The Research Postgraduate Student proteins in T cells. Dr S. Russell, Dr P. Wong C, Inhibition of Siah ubiquitin ligase in deacetylase inhibitors. Dr N. Pouliot, Assoc. Dr Clara Gaff (VCCC), Dr Clarre Scott Society is a student-run organisation Humbert, MRS. breast cancer. Dr A. Moeller, Prof. D. Bowtell, CCV. |Prof R. Anderson. (WEHI), Dr Richard Hekker (CSIRO), that coordinates educational and social Ross Dickins (WEHI), and Dr Mark Pham K, Investigating polarity proteins in Wood P, Molecular analysis and therapeutic Lin D, Establishment and characterisation events for research students throughout of an immunocompetent mouse model for Devlin and Assoc. Prof. Rob Ramsay thymocytes — a potential role in asymetric cell targeting of the PI3K/AKT/mTOR pathway the year. The main goal of the student division? Dr S. Russell, Prof. M. Gu, NHMRC. in paediatric neuroblastoma. Assoc. Prof. osteosarcoma. Dr M. Kansara, Assoc. Prof. from Peter Mac. We would like to society is to provide a welcoming and G. McArthur, Assoc. Prof. D. Ashley, MRS. D. Thomas. acknowledge the sponsorship of Pilgrim C, Predicting chemotherapy induced supportive environment for students Loh J, Mechanisms of inducing immunogenic our industry supporters for the retreat hepatic injury on clinical, genetic and imaging Yassin M, Elucidating the molecular basis during their undergraduate and/or parameters following treatment of colorectal for hematopoietic cell fate determination cell. Dr P. Neeson, Assoc. Prof. D. Ritchie. in 2010: Miltenyi Biotec, Lonza postgraduate studies at Peter Mac. carcinoma. Assoc. Prof. W. Phillips, Dr C. Duong, by asymmetric cell division. Dr S. Russell, Australia, Quantum Scientific, Bio-Rad Low ZR, Analysis of gene methylation in CLL In this regard, the student society not only MRS/RACS. Dr P. Humbert, APA. Laboratories, Biocabinets Australia, for potential therapeutic targets. Assoc. Prof. supports scientific achievement at Peter Young S, Molecular analysis of myxoid A. Dobrovic, Dr T. Mikeska. Beckman Coulter Australia, Becton Quin J, Mechanisms regulating ribosomal gene Mac but also builds a strong social and transcription. Assoc. Prof. R. Hannan, liposarcoma. Assoc. Prof. D. Thomas, Dickinson and Company, GeneWorks, Wong F, The clinical impact of F-18 FDG PET/ interactive network. In 2010, students Dr E. Sanij, APA. Dr K. Kansara. Integrated Sciences, Jomar Bioscience, CT in the assessment of cutaneous malignant organised and facilitated several melanoma. Assoc. Prof. E. Lau, Prof. R. Hicks. Sigma-Aldrich, Stemcell Technologies Ramakrishna M, Identification of novel ovarian Yuqian Y, The role of sister chromatid cohesion professional development workshops cancer genes using a cross-platform, integrative in colon biology and carcinogenesis. Assoc. and Genesearch, Illumina, Interpath Wu S, Discussions of Chronic Myeloid to support graduate study. The 2010 genomics approach. Assoc. Prof. I. Campbell, Prof. R. Ramsay, Dr H. Xu, Dr J. Malaterre, MIRS. Services, Life Technologies, Qiagen, Leukaemia and Imatinib Adherence with committee was Nimali Withani, Alison Dr K. Gorringe, CCV. Patients and Health Professionals. Assoc. Prof. Thermo Fisher Scientific, DKSH West and Dan Brown, who we thank Ryland G, Next generation sequencing of Doctor of Medical Science/ P. Schofield, Assoc. Prof. J. Seymour. Australia, and MNX. for their hard work throughout the year. candidate ovarian tumour suppressor genes. Doctor of Medicine in progress Assoc. Prof. I. Campbell, Dr K. Gorringe, MGS. (The University of Melbourne) The Research Postgraduate Student Saad M, Biological characterisation of human Dickinson M, Biological and clinical effects of Society committee coordinates the phosphatidylinositide 3-kinase Mutations. Assoc. epigenetic agents for haematological disease. annual student retreat, which serves as Prof. W. Phillips, NHMRC. Assoc. Prof. D. Ritchie, Prof. M. Prince, Peter Mac. a forum for undergraduate and Sacirbegovic F, The role of polarity proteins in Handolias D, Molecular analysis of the PI3K postgraduate students to discuss T cell function. Dr S. Russell, Dr P. Humbert, MRS. pathway in epithelial ovarian cancer. Assoc. Prof. scientific ideas, career opportunities and G. McArthur, MRS. develop professional skills, as well as Sceneay J, The contribution of non-malignant cells to breast cancer progression. Dr A. Moeller, Kee D, Novel molecular and imaging allowing students to interact in a relaxed Prof. D. Bowtell, Prof. M. Smyth, Equity. characteristics of human skin cancers. Assoc. environment; the 2010 retreat was held Prof. G. McArthur, Prof. R. Hicks, MFS. in Torquay. Over two days, the students Shimoni R, The computational microbioreactor: Analysing asymmetric cell division in immune Khamly K, Tumour hypoxia and response participated in a communication cells. Dr S. Russell, Prof. Min Gu. SUT. to preoperative radiotherapy in soft-tissue workshop and seminar discussions sarcomas. Assoc. Prof. D. Thomas. on topics related to the research Shortt J, Therapeutic inhibition of the phosphatidylinositol-3 kinase/mammalian Yan M, The impact of the tumour process and career issues. A panel target of rapamycin pathway in Myc driven microenvironment on breast cancer prognosis of guest speakers provided excellent models of B-cell neoplasia. Assoc. Prof. Ricky and treatment. Assoc. Prof. A. Dobrovic, Prof. career advice and prompted very Johnstone, Assoc. Prof. Grant McArthur. LF. S. Fox, NHMRC. productive discussions. Our industry Sinha A, Control of organ size during supporters set up a tradeshow, to allow development and disease. Dr K. Harvey, MPhil in progress the students the opportunity to develop Dr C. Milton, MFS. (The University of Melbourne) their communication skills within Smith L, Characterisation of the signalling Arthur H, Molecular and biological a supportive environment. network through which Scribble exerts its tumour characterisation of interferon mediated signal suppressive function. Dr P. Humbert, transduction pathways and genes that respond Dr I. Haviv, APA. to interferon. Assoc. Prof. R Johnstone, MRS. Susanto O, Signalling pathways in To H, A genetic study of Barrett’s Oesophagus cytotoxic lymphocyte-induced cell death. and Oesophageal Adenocarcinoma using next Dr N. Waterhouse, Prof. J. Trapani, CRIS. generation sequencing. Assoc. Prof. W. Phillips, Mr C. Duong, RACS. Turkel N, Characterisation of a novel drosophila oncogene. Assoc. Prof. H. Tran T, PI3K pathway alterations in gastric Richardson, Dr T. Brumby, Peter Mac. cancer. Assoc. Prof. W. Phillips, Dr C. Duong, MRS Wang L, Gene-modified leukocytes for cancer therapy. Assoc. Prof. M. Kershaw, Dr P. Darcy, APA.

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4.1.4 Research Awards 2010 Nicole Lundie Undergraduate Student Prize The Nicole Lundie Undergraduate Student Prize is awarded It is a great reflection on research at Peter Mac that we have annually to the most outstanding honours student who has so many talented young research scientists and students undertaken their research project at Peter Mac. The award is at work in our laboratories, some of whom were recipients made in honour of Nicole Lundie, in memory of her exceptional of the following research awards. academic achievements, and her passion, drive and commitment to science. The 2010 award was a particularly competitive process, 2010 Peter Mac Postgraduate Research Medal with a very strong group of applicants. The 2010 prize was Peter Mac’s Postgraduate Research Medal aims to promote awarded to Marcus Lefebure who conducted his Honours excellence in cancer research by PhD and medical doctorate project in the Gene Regulation laboratory under the students at Peter Mac, and is judged in consideration of supervision of Assoc. Prof. Ricky Johnstone and Dr Geoff the international impact of the basic, translational or clinical Matthews. Marcus continued this research with a PhD project cancer research. Accompanying this prestigious medal to analyse the activities of histone deacetylase inhibitors is a plaque and a prize of $1,500. (HDAC) and other small molecule therapeutics to treat multiple myeloma, supported by a Leukaemia Foundation scholarship. The 2010 medal was awarded to Holly Pegram from the Immunotherapy laboratory, in recognition of her scientific The selection panel also highly commended Ivan Fung research into the utilisation of Natural Killer (NK) cells for cancer who undertook his Honours project in the Immune Signalling immunotherapy. Immunotherapy is a promising strategy for the laboratory, under the supervision of Dr Jane Oliaro, and Lucas treatment of cancer and Holly’s research findings have Dent who undertook his Honours project in the Cell Growth important implications for enhancing the use of NK cells in and Proliferation laboratory under the supervision of Drs Kieran adoptive cell transfer immunotherapy. In congratulating Holly Harvey and Carole Poon. on her research achievements, we also acknowledge the This award is sponsored by the Geelong Lions Club of achievements of the other applicants. The competitive nature Breakfast Group, the Lundie family, donations made in of the medal selection process reflects the high calibre of memory of Nicole Lundie, and Cancer Research at Peter Mac. research that continues to be undertaken at Peter Mac. We would like to thank the Lundie family and the Geelong Lions Club of Geelong Breakfast Group for their ongoing support of this award. 2010 Miller Family Travel Fellowships In 2010, the Miller family generously donated funding for international travel fellowships for three of our young 2010 Harold Mitchell Travel Fellowships researchers, designed to provide opportunities for them The Harold Mitchell Travel Fellowship program at Peter Mac to develop and build on their career pathways. The 2010 recognises two outstanding young researchers by awarding Miller Family Travel Fellowships were awarded to postgraduate them travel support to develop and build on their career students Jenny Chia from the Cancer Cell Death laboratory pathways. The 2010 Travel Fellowships were awarded to and Andrea Newbold from the Gene Regulation laboratory, postgraduate student Nimali Withani from the Metastasis and to postdoctoral scientist Dr Amelia Brennan from the Research laboratory, and to postdoctoral researcher Dr Helen Cancer Cell Death laboratory. These young scientists used Pearson in the Cell Cycle and Cancer Genetics laboratory. these awards to present their research at international These travel awards provide valuable career and collaboration conferences and to visit and speak at international research opportunities for the young scientists and Peter Mac. We thank laboratories. We sincerely thank the Miller family for its the Harold Mitchell Foundation for its generous ongoing generosity in providing support for these awards. support of this program.

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4.1.5 Peter Mac Postdoctoral scientists also lead Peter 4.1.6 Community of queries posed by an interested and (Biomedical and Biotechnology Mac outreach activities, participating in informed public. laboratories); and the Bionic Ear Institute. workshops and seminars to build new We would also like to thank Postdoctoral program and School Outreach Tours groups were shown examples research and education links with school the Inner Melbourne VET Cluster of our important research by our own Postdoctoral researchers undertaking and community groups. In 2010 many Activities (IMVC) for its generous support volunteers. The 20 tours that ran over research at Peter Mac have the of our postdoctoral scientists took in administering this program for us. a total of five hours were all at capacity, opportunity to work with Australia’s leadership roles in the development Annual Sir Peter MacCallum For further information about IMVC, demonstrating the enthusiastic support top cancer research scientists, in and presentation of seminars and Public Lecture visit: www.imvc.com.au. Cancer Research receives from the facilities designed to encourage workshops for our school outreach In October 2010, members of the public wider community. We would like to thank interaction and collaboration locally activities: Bringing Science to Life Science in Schools: Peter Mac and the Peter Mac community gathered the Peter Mac researchers who and overseas and to build successful program and the VCE Biology Lecture Cancer Essay Competition for the second annual Sir Peter generously donated their time to make research careers. The postdoctoral Series. Our early career scientists also With the view to reaching a wider MacCallum Public Lecture: Cracking the day such a smooth success. experience is a time when these assisted with presentations and visits the Cancer Code. Developed as an audience of schools and students, early-career scientists develop their by school and community groups. event to help celebrate the Science in Schools: in 2010 we launched the Peter Mac scientific and technical skills and gain achievements and vision of Sir Peter Cancer Essay Competition, open to all Cancer Research has an active VCE Biology Lecture Series experience in other skills needed for MacCallum, the public lecture provided Victorian secondary students in Years 10 postdoctoral society that coordinates This annual VCE Biology Lecture Series a professional career. The career a community education opportunity. and 11. Complementing the topic of the social and career development activities has been designed to complement the development of postdoctoral scientists On a warm spring evening, 3AW’s annual Public Lecture, the 2010 theme throughout the year. In 2010, the society VCE biology curriculum, and to provide is a key focus of Cancer Research. Dr Sally Cockburn welcomed the was ‘The human genome: cracking the was led by Drs Geoff Matthews, Linda an opportunity for students to revise enthusiastic audience — attendance cancer code’. Students were invited Our postdoctoral scientists play Howland and Jamie Lopez. This society and develop a better understanding was up by over 50 per cent on the to submit essays in scientific or creative a crucial role in facilitating the provides a nurturing environment for of the topics by placing them within inaugural 2009 event. categories. All entries were assessed Cancer Research Education program, postdoctoral scientists throughout the context of cancer research. Held at for their scientific and creative merit, undertaking roles as mentors and their time at Peter Mac, providing In the elegant Swanston Hall at Peter Mac, the lectures were attended and a shortlist of finalists was compiled. scientific committee members of opportunities to build an interactive Melbourne Town Hall, Professor by students from a range of Victorian All finalists were invited to attend the our Student Advisory Committees, network of science and industry links David Bowtell and Dr Gillian Mitchell public and private secondary schools. Annual Sir Peter MacCallum Public providing them with the opportunity that will benefit their future careers, gave informative, entertaining and - ‘Signalling molecules and drug design’ Lecture for the awarding of prizes. to support the next generation through the organisation of seminars, passionate presentations, updating (Prof. David Bowtell) We are grateful to the Geelong Lions of scientists while also furthering workshops and social activities. the community on the recent history Club Breakfast Group, who has been an their own supervising experience. and exciting future of cancer genetics - ‘Apoptosis and cell death’ ongoing sponsor of a student prize at and individualised patient care. (Dr Ilia Voskoboinik) Peter Mac and generously sponsored The two half-hour talks took the - ‘Differentiation and transcription’ a prize in this new essay competition. audience from the laboratory into (Assoc. Prof. Rob Ramsay). At the conclusion of the lecture, honorary the clinic, a structure that echoed Science in Schools: guest Dr Peter MacCallum joined Paul the on-site collaboration between Peter Mac Bringing Austin from the Geelong Lions Club basic and clinical research that defines Science to Life program Breakfast Group to award prizes for the Peter Mac as unique among Australian 2010 Peter Mac Cancer Essay public hospitals. Feedback from the In 2010 we continued our school Competition. First prizes were awarded event was overwhelmingly positive, science program, with 20 students to Anna Gruen from Melbourne Girls’ highlighting the value of the annual from a range of public and private Grammar School (creative essay) and Sir Peter MacCallum Public Lecture schools attending three days of science Zoe Calulo-Chan from MacRobertson as a key communications platform activities. Spread across three months, Girls High School (science essay). Five for Peter Mac Cancer Research. the program was open to science runners-up were awarded, reflecting We thank Dr Sally Cockburn and students in Years 10 to 12, and provided the depth and quality of the essay entries. the City of Melbourne for their a valuable opportunity for them to The runners up for the scientific essay support of this event. experience real science in action. The students attended an external were Yuan Mei Wan (Presbyterian Ladies Research laboratory tours: science or research site in the morning, College) and Katie Punshon (St Leonard’s Melbourne Open House before coming to Peter Mac for the College), and for the creative essay were Stephen Wong (Overnewton Anglican In 2010, Peter Mac again joined afternoon, during which they heard Community College), Nicole Da Cruz the Melbourne Open House program about our research activities in talks (MacRobertson Girls’ High School) by opening its doors to the public for provided by our young scientists. and Brooke Walter (Billanook College). tours of the research laboratories and The students then met with our young radiation therapy bunkers. Throughout researchers to participate in laboratory a very busy day, many curious science activities. Melburnians and visitors took the chance We thank the following groups who to glimpse the inner workings of our supported this program by opening their iconic research facility. Guides and laboratories to this group of students: demonstrators fielded a broad scope CSL Limited at Bio21 (Molecular Biology Research groups); Swinburne University

Peter MacCallum Cancer Centre – Research Report 2010 Education and Learning 143 4.2 Clinical Research Education 4.2 Clinical Research Education and Training Programs and Training Programs

The research strengths which underpin Peter Mac’s reputation as a national and international leader in clinical and basic Specialised Certificate Seminars in Oncology research also present a range of challenges related to the in Clinical Research (Oncology) In 2010, Cancer Surgery developed a new series of seminars, designed to provide opportunities for clinicians and scientists differing needs of researchers, and therefore their differing to expand their understanding of developments in clinical practice and clinical research. The Specialised Certificate in Clinical Research (Oncology), education and training requirements. The full schedule for 2010 is listed below. The University of Melbourne, was developed in partnership In 2010 a review of clinical research education and training with Peter Mac, and is coordinated by Assoc. Prof. Michael was undertaken by Dr Caroline Owen with the assistance of Jefford from Cancer Medicine. many of our busy clinician researchers and research managers. SEMINARS IN ONCOLOGY 2010 SCHEDULE This review provides the foundation for further development Designed to provide a better understanding of all types of of training opportunities for our clinical researchers as they research conducted in oncology as well as an understanding Date Presenters Topic all work to maximise the potential and translational impact of the essential components and features of successful 1-Mar Prof. David Ball, Dr Robin Cassumbhoy, Mr Gavin Wright of our cancer research. One thing that was strongly evident research activities and research careers, the course content Modern management of lung cancer (including new staging system) during this review process was the passion for excellence is largely delivered by Peter Mac clinicians and researchers. 15-Mar Assoc. Prof. Michael Henderson, Prof. Rod Hicks, Dr Damien Kee Multimodality management of stage IV melanoma in care, and passion for leading clinical research to translate It is designed for people currently working in oncology or other (including new staging system) to better treatment options and outcomes for our patients. health services — attendees include oncologists in training, 12-Apr Assoc. Prof. David Speakman, Dr Kate Moodie, Work up and management of breast lump clinical trials nurses, project coordinators, radiation therapists, Prof. Stephen Fox With our multidisciplinary team approach to clinical care, pharmaceutical personnel, sales specialists, registrars and teams of researchers are brought together with a common 24-May Dr Gavriel Haime, Dr Sian Fairbank, Assoc. Prof. June Corry Surgical management of SCC of head and neck, including allied health workers. Peter Mac’s involvement in the delivery of reconstructional options focus — to conduct significant research that leads to the this clinical research course is further evidence of our development of better models of care and improvements 16-Jun Mr John Spillane, Dr David Charlesworth, Management of neutropaenic patient leadership in supporting and educating the next generation of in treatment options and outcomes. These multidisciplinary Assoc. Prof. Monica Slavin researchers. teams make significant contributions to the welfare and 30-Jun Dr Trevor Leong, Mr Cuong Duong, Mr John Spillane Managing a patient with malignant dysphagia treatment outcomes of our patients, and the structure of the 14-Jul Dr Richard Sullivan, Dr Odette Spruyt Management of pain in a cancer patient and update team can also impact on the research conducted in that area. Clinical Research Methods on peri-operative care Multidisciplinary teams help drive research and build research in Radiation Oncology 28-Jul Dr Kate Moodie, Dr Nick Ferris, Assoc. Prof. Sam Ngan, Update on management of locally advanced rectal cancer momentum, utilising the expertise across the team to develop Assoc. Prof. Alexander Heriot a range of research directions related to clinical observations. The Clinical Research Methods in Radiation Oncology program 11-Aug Prof. Rod Hicks, Dr Charuta Dagia, Dr Ben Thomson, Dr Say Ng Pancreatic cancer management in 2010 Research naïve personnel within these teams are introduced was developed at Peter Mac to address the need for clinical 25-Aug Mr Simon Donahoe, Mr Felix Behan, Mr Miki Pohl, Reconstructional options for breast, abdominal and pelvic defects to research within a supportive team environment, which then research training for radiation therapists, but its audience has Mr Michael Findlay Versatility of local flap repair provides the opportunity for them to develop research interest broadened to also include allied health professionals, physicists, 8-Sep Assoc. Prof. Declan Murphy, Dr Farshad Foroudi, Dr Colin Styles Update on management of localised prostate cancer and skills by involvement in these activities. Such research nurses, study coordinators and radiation oncologists. 6-Oct Dr Adam Cichowitz, Miss Belinda Hodgson, Dr Adrian Hall Impact of nutrition and patient’s functional capacity momentum is reliant on leadership and mentoring within This program is in two modules — an introductory program on cancer outcomes the team, which is particularly strong in some clinical areas. delivered across two days, and an advanced program 3-Nov Ms Meg Rogers, Ms Carolyn Atkin, Ms Lucy Pollerd Importance of supportive care in the management The range of clinical expertise in the multidisciplinary teams delivered across three days. The program is delivered by of GI cancer patients can result in a breadth of skills, and in a great variety in the Peter Mac staff, with all discussions using an oncology context. 1-Dec Mr Damien Tange, Dr Catherine Mendel, Dr Claire Phillips Management of cerebral met research readiness in the clinical staff within the different These modules address key research topics including clinical disciplines, related to the amount of research incorporated into governance and ethics, statistics, research design and the training programs of the disciplines. Peter Mac strives to methodologies, project management and scientific writing. We thank Covidien Surgical Supply for its sponsorship of this seminar series in 2010. improve the research education of our clinicians and further More than 60 Peter Mac staff completed the course support them as they lead new research directions into clinical For full information about Peter Mac’s Cancer Research education and learning programs, in 2009 –10. In 2010, it also ran as an external program visit: www.petermac.org/Research/EducationandCareers practice, treatments and outcomes. with 56 attendees from across Australia and New Zealand. While much of the research training conducted at Peter Mac occurs within a largely informal structure including mentoring, seminars and workshops, and supervised research activities, there are several key areas where more structured programs have been developed for both internal and external audiences, and which form a basis for the development of further clinical education programs.

Peter MacCallum Cancer Centre – Research Report 2010 Education and Learning 145 5 Leadership and Governance 5 Leadership and Governance

With 18 years experience in laboratory accreditation, Jane King understands the importance of research governance and accountability. As Research Governance Officer at Peter Mac, Jane works to ensure that good and sensible governance practices are woven through all aspects of our research, and that the community’s faith in Peter Mac’s research continues to be well deserved. 5 ‘Governance really does matter — to patients and their families, to research funders and taxpayers, research colleagues and the community as a whole.’

Peter MacCallum Cancer Centre – Research Report 2010 Leadership and Governance 147 5 Leadership and Governance 5.1 Research leadership

We are always striving for a more CANCER RESEARCH • Receiving and reviewing regular Peter Mac is committed to the development dynamic, efficient environment that MANAGEMENT TEAM (RMT) reports on all research activities fosters innovation and collaboration Prof. Joseph Trapani (Chair) at Peter Mac from the divisional of a research culture that reflects the core values among the hundreds of researchers executive directors and other who work at Peter Mac. At a time of rapid Assoc. Prof Ian Campbell senior clinicians/researchers. of excellence, innovation and compassion. advances in the understanding of cancer Assoc. Prof. Ross Hannan The Research Advisory Board reports biology and accelerated translation of Mary Harney to the Peter Mac Board of Directors. research findings to the clinic, Peter Mac provides an exciting and supportive Assoc. Prof. Ricky Johnstone environment for cancer research. Assoc. Prof. Grant McArthur RESEARCH ADVISORY Peter Mac’s excellence in research is Assoc. Prof. Rick Pearson BOARD MEMBERSHIP reflected in the strategic drive of our Prof. John Mattick AO (Chair) research leaders who help us keep our Assoc. Prof. Rob Ramsay Prof. David Copolov OAM (Deputy Chair) research at the forefront of discovery. Dr Helena Richardson Peter Acton Peter Mac is one of the few hospitals • Research leadership The committee structure now in place Dr Gian Sberna in the world with the benefit of having • Cancer Research management ensures that our laboratory and clinical Prof. Daine Alcorn its own integrated cancer research translational research is fully supported Mark Shannon • Governance Prof. Ashley Dunn programs and laboratories, providing by the strategic leadership of our senior Prof. Mark Smyth the opportunity to lead the way • Ethical Conduct of Research researchers, as outlined below and in Wayne McMaster Linda Stevens (Secretary) in translational research in cancer. • Commercialisation. the committee organisational chart. Prof. Christina Mitchell With a research program that continually Internal members: drives improvements in all aspects of Cancer Research Division RESEARCH ADVISORY BOARD (RAB) treatment and clinical care, our clinical Craig Bennett Executive and Management The Peter Mac Research Advisory and laboratory researchers are Dr Shari Lofthouse internationally renowned. The Cancer Research management team Board (RAB) provides advice on a meets regularly to advise the Executive range of issues, including oversight Prof. Joseph Trapani Our high quality, dedicated researchers Director of Cancer Research on key of research activities, to ensure that are supported by specialised equipment, Prof. John Zalcberg OAM strategic matters, to flag new issues and appropriate strategic planning processes technology and expertise that ensures assist Cancer Research in planning and are in place and implemented effectively. Les Manson (Secretariat) Peter Mac’s research program is focused implementing policy. The team receives on delivering the best outcomes for each The RAB is responsible for: reports from multidisciplinary groups as individual patient. required, and reports to the Cancer • Ensuring that research activities at DIVISIONAL RESEARCH EXECUTIVE Research Executive. Peter Mac are broadly consistent with Peter Mac’s overall strategic Prof. John Zalcberg OAM (Chair) directions and broader government Prof. Sanchia Aranda cancer research priorities. CANCER RESEARCH EXECUTIVE Jennifer Doubell • Providing advice and guidance Prof. Joseph Trapani for all research activities conducted Prof. Gillian Duchesne (Executive Director) at Peter Mac. Mary Harney Assoc. Prof. Ricky Johnstone • Monitoring compliance of research (Deputy Director) Assoc. Prof. Alexander Heriot activities with policies and procedures Assoc. Prof. Ricky Johnstone Assoc. Prof. Grant McArthur and legislative requirements, in (Deputy Director) conjunction with other Peter Mac Assoc. Prof. Danny Rischin Board committees. Ms Mary Harney Assoc. Prof. Penelope Schofield (Chief Operating Officer) • Conducting regular reviews of Deborah Sullivan research collaborations/partnerships, research commercialisation Prof. Joe Trapani opportunities, metrics of research Samantha Somers (Secretary) performance, and strategies to retain, as well as identify and attract, high-quality research staff.

Cancer Research Executive: Assoc. Prof. Ricky Johnstone (Deputy Director), Prof. Joseph Trapani (Executive Director), Ms Mary Harney (Chief Operation Officer), Assoc. Prof. Grant McArthur (Deputy Director).

Peter MacCallum Cancer Centre – Research Report 2010 Leadership and Governance 149 5.1 Research leadership 5.2 Cancer Research management

CLINICAL RESEARCH • Ensure that standards, guidelines and/ CLINICAL RESEARCH The important work of Cancer Research EXECUTIVE AND OHS Specialist GOVERNANCE COMMITTEE or policies for clinical research and for GOVERNANCE is led by the Research Executive, and OPERATIONS PERSONNEL Lisa Stevens continuously monitoring and improving COMMITTEE MEMBERSHIP underpinned by the activities of the As one of the core components of Peter RESEARCH EXECUTIVE Intellectual Property Mac’s business, clinical research must the quality of clinical research at Peter Prof. John Zalcberg oam (Chair) Research operations team, who provide Director and Development Manager be conducted within a robust and Mac are in place and are followed. support and resources for the essential Prof. Gillian Duchesne processes and procedures required Prof. Joseph A Trapani Mr Jerry de la Harpe (until June 2010) dynamic governance framework • Evaluate the clinical research by Peter Mac’s research efforts. Dr Shari Lofthouse to optimise outcomes and accord governance framework and oversee Mr Cuong Duong Assistant Directors with local, national and international and facilitate compliance with the Mary Harney The activities of the operations team Assoc. Prof. Ricky Johnstone Governance Officer standards of research conduct. pertinent standards, in particular, are driven by internal and external Assoc. Prof. Grant McArthur Jane King (from July 2010) Marianne Hundling the NHMRC documents National research management and reporting The Clinical Research Governance Chief Operating Officer AEEC Coordinator Statement on Ethical Conduct in Dan Mellor requirements. The scope of the Committee (CRGC) has been established Mary Harney Rosie Goldup (from July 2010) to develop and oversee the framework Human Research (National Statement) Dr Dina Neiger operations team includes: Reception and AEEC Assistant within which clinical research is conducted and the Code for the Responsible OPERATIONS & ADMINISTRATION Dr Jo Phipps-Nelson • Animal Ethics at Peter Mac. Conduct of Research (The Code) Kate McShane and other relevant guidelines and/or • Commercialisation Chief Operating Officer Assoc. Prof. Danny Rischin Personal Assistants The functions of the CRGC are to: policies. Mary Harney Assoc. Prof. John Seymour • Communications Diana Motion (Director) • Develop and maintain a framework • Make recommendations to the Deputy Chief Operating Officer Linda Stevens (Assistant Director) for clinical research governance Dr Dianne Snowden • Core Platform Technology Executive, Human Research Ethics Dr Gian Sberna Jacinta Arnup (Operations) at Peter Mac that ensures clinical Management Committee or other appropriate body Virginia Tuckwell Jade Tran (Cell Biology program research is properly conducted, Human Resources Officer in relation to matters under the scope • Education and Commercialisation) including adherence to accepted Shannon Uren Ms Sarah Dougas of this committee. • Grant administration Marianne Ciavarella (Cancer ethical principles, local, national and Jane King (Secretary) IT Manager (Research) Genomics program) international guidelines for clinical The CRGC receives reports from the • Human Resources Daniel Simpkins Belinda Kelly (Cancer research practice, relevant laws Human Research Ethics Committee and • Occupational Health and Safety Immunology program) and regulations and principles the Study Coordinators Group, and Application Specialist of risk management. reports to the Divisional Research • Physical Environment Zeus Villanueva Research Grants team Executive (DRE). and Infrastructure Dr Gian Sberna Education and Marianne Ciavarella • Research Education and Training Communications Officer Belinda Kelly Dr Caroline Owen • Research Governance. Katrina Wilson Communications Assistant Nick Sharp-Paul Physical Infrastructure and Environment Manager Mark Shannon Physical Infrastructure and Environment Officer Paul Dunne

Peter MacCallum Cancer Centre – Research Report 2010 Leadership and Governance 151 5.3 Governance Research organisation

In the words of Prof Joseph Trapani, Research, from students, early career During 2010, ties with Clinical Over 400 researchers are based in 27 sequencing technology, microarray from early phase clinical studies which Executive Director, Cancer Research, researchers through to long-standing Research Governance were further research laboratories within six key technology, molecular pathology, a allow our patients access to novel “it is of great importance that we get our researchers and operations staff. The strengthened with the development research programs: Cancer Cell Biology, tissue and tumour bank, and a anti-cancer drugs, through to research governance practices right.” program will define desired behaviour in of a research governance framework. Cancer Immunology, Cancer Genomics, transgenic and SPF facility. international randomised controlled trials the areas of conflict of interest, ethics, The framework summarises research Growth Control and Differentiation, designed to answer key clinical The Research Governance landscape is Our outstanding clinicians, nurses responsible publication practices and governance responsibilities and reflects Angiogenesis and Cancer Therapeutics. questions in cancer care. With extensive changing in Australia and internationally, and allied health professionals are data management. This program aims the close ties between basic, translational These are underpinned by an extensive cancer clinical trial activity, Peter Mac with research funding increasingly involved in a broad and diverse portfolio to raise awareness of what constitutes and clinical researchers at Peter Mac. infrastructure of core facilities and leads Australia in human and being tied to tangible demonstration of clinical studies to complement our research misconduct and to ensure Peter Mac’s Clinical Research services: advanced microscopy, infrastructure resources. of research integrity and responsible activities in the basic and translational that necessary subsequent procedures Governance Committee, chaired bioinformatics, flow cytometry and cell conduct of research. arenas. Their scope is wide-ranging, are in place. by Professor John Zalcberg OAM, sorting, functional genomics and Consistent with this increased emphasis has broad research representation, Cancer Research has had a wide on governance and our desire to lead oversees the research governance reaching set of operational procedures in all aspects of research, two major framework and has a strong role in in place for many years and these initiatives are being planned. driving clinical research governance Peter Mac research structure are being reviewed and refreshed to matters across the hospital. A Research Governance Program is in coincide with the roll out of the Research planning for delivery to all Cancer Governance Program in early 2011.

PETER MACCALLUM CHIEF EXECUTIVE OFFICER CANCER FOUNDATION LTD

Peter Mac Research Governance committee structure

PETER MAC BOARD CANCER CANCER CANCER RADIATION ONCOLOGY CLINICAL CANCER NURSING Strategic RESEARCH MEDICINE SURGERY AND CANCER IMAGING SERVICES Advisory Committee (SAC) Clinical Services HUMAN RESEARCH ETHICS COMMITTEE CHIEF EXECUTIVE OFFICER Cancer Cell Department of Department of Department of Nursing Services RESEARCH ADVISORY BOARD (RAB) Biology program Haematology Surgical Oncology Radiation Oncology (HREC) (CEO) Breast Service Executive Department of Nursing Performance Cancer Genetics and Department of Department of Surgical Radiation & Management Colorectal Service and Supportive Care Genomics program Medical Oncology Oncology Research Therapy Services Committee Research CLINICAL Expedited Probity Scientific (EP&MC) Gastrointestinal Service RESEARCH Review Advisory Advisory Cancer Immunology Pharmacy Academic Radiation Engineering COMMITTEE (CRC) Committee (ERC) Panel Committee program Robotic Surgery Gynae-oncology Familial Cancer Centre Physical Sciences Service Cancer Therapeutics Peri-operative Services Divisional Commercialisation Tissue Research EXECUTIVE DIRECTOR Research program Review Advisory Pathology Cancer Imaging Management CANCER RESEARCH Executive Haematology Service Committee Panels Panel Intensive Care Medicine (TRMC) Growth Control and Infectious Disease / Head and Neck Service Differentiation program Infection Control Department of Animal Office of Cancer Anaesthesia Experimentation Gene Lung Service Tumour Angiogenesis Pain and Palliative Care and Pain Medicine Ethics Technology program DIVISIONAL RESEARCH Committee (AEEC) Regulator EXECUTIVE (DRE) Melanoma and Psychiatry Platform Technologies Skin Service LABORATORY OFFICE OF CANCER RESEARCH RESEARCH Allied Health Bioinformatics Neuro-oncology Service (OCR) GOVERNANCE Cryopreservation Clinical Psychology CLINICAL RESEARCH GOVERNANCE Paediatrics Service (CRGC) Flow Cytometry Nutrition Functional Genomics Occupational Therapy Sarcoma Service

Media and Pastoral Care Laboratory Services Uro-oncology Functional Reporting Physiotherapy Microscopy Clinical Programs Direct Report Obligations Social Work Molecular Genomics Speech Pathology onTrac@PeterMac Transgenic Facility

Tissue Bank Centre for Blood Cell Therapies Research Operations Australian Cancer Survivorship Centre Office of Cancer Research Clinical Trials Research

Centre for Biostatistics and Clinical Trials

Ethics Secretariat

Peter MacCallum Cancer Centre – Research Report 2010 Leadership and Governance 153 5.4 Ethical Conduct of Research

is also responsible for monitoring the COMING IN 2011 Human Research Ethics Tissue Research Management Division of Radiation Oncology Peter Mac Human Committee (HREC) Committee (TRMC) & Cancer Imaging and Division ongoing conduct of all these projects. The Harmonisation of Multi-centre of Cancer Medicine Research Ethics Members of the HREC and associated Ethical Review (HoMER) system is a Board Member Assoc. Prof. Wayne Phillips (Chair) Assoc. Prof. Michael Mac Manus (Chair) committees are drawn from Peter Mac NHMRC initiative that aims to reduce Prof. Peter Sheldrake (Chair) Dr Alex Boussioutas Committee (HREC) Belinda Campbell staff and external community members. duplication of ethical and scientific Assoc. Prof. Ian Campbell Community Members Vanessa Estall and the Ethics All committee members kindly donate review of health and medical multi-centre Samantha Cauberg Dr Sarah Everitt the time required to attend monthly research. Under this system HRECs will Mary Rydberg (Deputy Chair) Marnie Collins Secretariat Dr Farshad Foroudi meetings and to review new projects, conduct single ethical review of multi- Anne Holmes Assoc. Prof. Alex Dobrovic Dr Kate Jones Dr Bronwyn King The major role of the Human amendments and other general matters. centre research in accordance with Prof. Stephen Fox agreed national criteria. Reviewing Catherine McKean Dr Simon Harrison Assoc. Prof. Trevor Leong Research Ethics Committee (HREC) The Ethics Secretariat coordinates HRECs under the HoMER system must Dr Grant Moss Dr Alan Herschtal Richard Oates and the associated committees and the Committee system and provides complete a rigorous certification process Tyson Wodak Colin House Dr Rebecca Owen review panels is the ethical review administrative support for the review, and maintain this certification for their Dr Andreas Moeller Dr Gail Ryan of human research. Human research approval and monitoring process. Staff Members ethical review processes. Institutions can Dr Normand Pouliot Dr Mark Shaw is research conducted with or about The Ethics Secretariat also provides Dr Lee-Anne Clavarino also join the system as a site that Dr Rick Redvers Dr Ben Solomon people, or their data or tissue. In making general advice to researchers. Jill Davison accepts single ethical review by HRECs Dr Rik Thompson (Cancer Medicine representative) decisions regarding the ethical conduct Tessa Jones Assoc. Prof. Scott Williams of human research the HREC relies NEW IN 2010 that have been certified under the Jeremy Kenner Heather Thorne HoMER system. Richard Young David Willis on the guidance provided in the In December 2009, as an initiative Helen McCallum Dr Andrew Wirth National Statement of the Ethical of the Victorian Government, the When fully implemented this system Assoc. Prof. Wayne Phillips Expedited Review Conduct in Human Research which was Single Ethical Review Process (SERP) will be an extension of the existing Assoc. Prof. David Ritchie Committee (ERC) Ethics Secretariat Staff developed by the NHMRC, Australian SERP system and apply to multi-site trials Sam Ruell for clinical trials undertaken in Victoria Dr Lee-Anne Clavarino (Chair: Jan – May) Jeremy Kenner (Ethics Coordinator) Research Council and Australian throughout Australia. Currently Victoria, Shane Ryan was introduced. This system is Jeremy Kenner (Chair: June – Sep) Dr Lee-Anne Clavarino Vice-Chancellors’ Committee. New South Wales and Queensland Dr Dianne Snowden coordinated by the Consultative Council Dr Dianne Snowden (Chair: Oct – Dec) (Assistant Ethics Coordinator Jan – May) are working towards implementing Dr Alison Trainer The Ethical Conduct of Human Research for Human Research Ethics and allows Dr Sibilah Breen Dr Dianne Snowden (Assistant requires that approval is obtained from multi-site clinical trials within Victoria to this system. Karen Wall Ethics Coordinator June – Dec) Assoc. Prof. Scott Williams Amrit Dhillon the HREC for new human research undergo a single ethical review by an During 2010 the following people Sharon Reid Assoc. Prof. Max Wolf Alison Hocking projects, taking into account scientific accredited HREC that is accepted by all served as members on the HREC Catherine Johnston Namita Mazzitelli advice from the Clinical Research participating sites. The aim of SERP is to or an associated committee or panel Clinical Research Lisa Macfarlane Committee (projects involving human provide a more efficient ethical review for all or part of the year: Committee (CRC) Megan Rogers participants), or the Tissue Research process for clinical trials to be conducted Stewart Sandon Management Committee (projects at multiple sites. Assoc. Prof. David Ritchie (Chair: Jan – July) Lisa Sheeran involving human tissue). Review of During the first 13 months of operation June Smith projects involving analysis of retrospective Assoc. Prof. Max Wolf until the end of 2010 the Peter Mac (Chair: Aug – Dec) Genevieve Story clinical data is delegated to the Ethics Committee reviewed 11 projects Divisional Review Panels and review of Dr Sibilah Breen Divisional Review Panels on behalf of all participating sites and Dr Jeremy Couper low risk projects is delegated to the accepted the external ethical review Division of Surgical Oncology Expedited Review Committee (ERC). Prof. Jim Cramb of eight projects as a participating site. Assoc. Prof. Michael Henderson (Chair) The HREC Dr Carlene Cullinane Jim Hagekyriakou Mr Cuong Duong Marianne Hundling Emma Link Assoc. Prof. Mei Krishnasamy Mr John Spillane Emma Link Tina Thorpe The number of new projects and amendments to ongoing projects reviewed Assoc. Prof. Michael MacManus by the committees in 2010 is presented in the following table: Dr Linda Mileshkin Dr Donna Milne Assoc. Prof. Dina Neiger Clinical and laboratory projects reviewed by the Ethics Committee after scientific review 80 Dr Jo Phipps Nelson by the Clinical Research Committee or Tissue Research Management Committee Carol Rice Low risk projects reviewed by the Expedited Review Committee 43 Caroline Sardjono Dr Ben Solomon Retrospective projects reviewed by a Divisional Review Panel 44 Shannon Uren Major amendments reviewed by the Committee 117 David Willis Administrative amendments reviewed by the Ethics Secretariat 37

Peter MacCallum Cancer Centre – Research Report 2010 Leadership and Governance 155 5.4 Ethical Conduct of Research (cont.) 5.5. Commercialisation

Ethical Conduct The Code requires that all proposals Peter Mac is uniquely placed to facilitate data derived from a large library of (Cancer Cell Death laboratory pg 26). to use live animals are assessed by rapid research translation through our tumour specimens and associated Establishment of this agreement of Animal Research a quorum of AEEC members; that is, governance structure and our many data to aid identification of the source included execution of a series of at least one committee member in each fostered relationships with industry. of origin of CUP tumours, thereby intellectual property licenses and The NHMRC has developed the of the following categories must be enhancing treatment selection and service contracts with our collaborative Our engagement with industry provides Australian Code for the Responsible present: (A) veterinarian, (B) scientific, patient outcomes. partners. benefits to our industry partners, to Conduct of Research, which is designed (C) animal welfare and (D) lay. industry via access to our new • Although the initial contract for the • The commercialisation office was to ensure that research is conducted For further information, technologies and intellectual property, Translational Oncology Research involved in a number of consortia ethically and with integrity. In accordance visit: http://www.nhmrc.gov.au/ and to our researchers through access Collaborative Hub (TORCH) with Pfizer negotiations, including the National with these guidelines, Peter Mac’s guidelines/animal_guidelines.htm. to alternative sources of funding and a has now expired, Pfizer has provided Breast Cancer Foundation Lifepool Animal Experimentation Ethics variety of research tools. The close an additional year of funding to collaborative grant, the Australian Committee (AEEC) takes an important AEEC AND APPLICATION interaction between our basic continue certain studies arising from Phenomics Network and the Victorian role in overseeing the ethical conduct PROCESSING IN 2010 researchers and our industry partners that collaboration. This program Cancer Biologics Consortium. of any work involving the use of animals All researchers at Peter Mac who wish enhances the understanding of the included studies directed towards for scientific purposes. • In addition, ten new invention to conduct research involving animals commercialisation process early on in molecular pathways in cancer and disclosures and continued As described by the NHMRC, the are required to submit a written proposal research planning stages, and ultimately development of associated imaging developments in our existing projects primary role of the AEEC is to ensure to the AEEC relating to their intended accelerates the flow of technologies into techniques. resulted in a number of new patent that the use of animals in experimental use of animals. AEEC approval is the clinic. • Prof. Joseph Trapani was successful in application filings, as detailed in the research is justified, provides for the required before the commencement Peter Mac Commercialisation highlights obtaining an interim Wellcome Trust table below. welfare of those animals, and of any project involving animals. in 2010: funding agreement in relation to the incorporates the principles of Similarly, any amendments to existing development of perforin inhibitors ‘replacement, reduction and refinement’: projects involving animals must first be • Continuation of the research and development agreement with Sirtex • Replacement of animals with reviewed and approved by the AEEC. Medical Ltd for development of other methods. Researchers are required to submit annual reports to the AEEC outlining radioprotectors in collaboration with • Reduction in the number of animals the work undertaken on their projects Prof. Roger Martin (Molecular used. and the progress that has been made. Radiation Biology laboratory pg 54). • Refinement of techniques used to In addition to this monitoring, the AEEC This project supports a number of reduce the adverse impact on animals. also conducts regular inspections patent applications, with a new US The AEEC conforms to the Australian of the facilities. provisional application being filed in 2010 for novel technologies arising Code of Practice for the Care and During 2010, the Peter Mac AEEC from the project. Use of Animals for Scientific Purposes. convened seven times and reviewed In conforming to the code, the AEEC 27 new project proposals (up 17 per • Further development of the diagnostic works to ensure the ethical and humane cent on the previous year), 221 minor assay for Cancers of Unknown care of any animals used for scientific amendment applications (up 307 per Primaries (CUP). Through our licensee purposes, and aims to promote the cent) and 54 annual and final reports Circadian Technology, this project is wellbeing of animals and minimise (down 22 per cent). The rigour of this developing the assay to a marketable their experience of pain and/or distress. review process ensures a high standard form in conjunction with Healthscope The responsibilities of the AEEC of animal welfare is practiced and further Ltd. The assay draws on molecular include the development of policies to ensure that the animal facilities are and standard operating procedures, maintained to the highest standard. Patent applications filed in 2010 education of members and users, dispute resolution, reporting and auditing. While scientific expertise is Title Type Date Filed Number derived primarily from the Peter Mac Cancer Diagnostic Australian Provisional 6 Sep 2010903995 research community, welfare and lay membership comprises independent Stimulating Immune Response Australian Provisional 21 Jun 2010902717 individuals who are not affiliated Methods of Treatment Complete applications filed in 26 Oct 2719442 with Peter Mac, in order to ensure Canada, Australia, US 2010236016 that committee decisions are impartial. 12/912,524 Method of Detecting Radiation PCT 16 Jul AU/2010/000913 Exposure and Adverse Toxicity Thereto

Recombinant Perforin, Expression Continuation 12 Feb 12/704715 and Uses Thereof New Perforin Compounds PCT 22 Dec PCT/AU2010/001731 Radioprotectors US Provisional 6 Apr 61/321288

Peter MacCallum Cancer Centre – Research Report 2010 Leadership and Governance 157 Title6 Publications 6 Publications

Anatomical Pathologist Dr Siddhartha (Sid) Deb is one of a growing number of clinicians undertaking postgraduate degrees to strengthen their clinical research focus. Sid’s PhD research proposes to be the largest study to molecularly characterise male breast cancer, establishing a cohort for extensive clinicopathological investigation and allowing valuable assessment of genotypic-phenotypic patterns to contribute to the 6 development of novel treatment strategies for breast cancers.

Peter MacCallum Cancer Centre – Research Report 2010 6 Publications 6 Publications

Refereed Research Papers 17. Aymeric, L., et al., Tumor cell death and ATP 35. Bushnell, D.L., Jr., et al., 90Y-edotreotide for 56. Corcoran, N.M., et al., Open-label, phase I 72. Dickinson, M., et al., Improved survival for 87. Flaherty, K.T., et al., Inhibition of mutated, release prime dendritic cells and efficient metastatic carcinoid refractory to octreotide. dose-escalation study of sodium selenate, a relapsed diffuse large B cell lymphoma is activated BRAF in metastatic melanoma. New anticancer immunity. Cancer Research, 2010. Journal of Clinical Oncology, 2010. 28(10): p. novel activator of PP2A, in patients with predicted by a negative pre-transplant FDG-PET England Journal of Medicine, 2010. 363(9): p. 1. Ahmed, A.A., et al., Driver mutations in TP53 are 70(3): p. 855-58. 1652-9. castration-resistant prostate cancer. British scan following salvage chemotherapy. British 809-19. ubiquitous in high grade serous carcinoma of the Journal of Cancer, 2010. 103(4): p. 462-8. Journal of Haematology, 2010. 150(1): p. 39-45. ovary. Journal of Pathology, 2010. 221(1): p. 18. Azzato, E.M., et al., Association between a 36. Butow, P.N., et al., From inside the bubble: 88. Flanagan, J., et al., DNA methylome of familial 49-56. germline OCA2 polymorphism at chromosome migrants’ perceptions of communication with the 57. Couper, J.W., et al., Predictors of psychosocial 73. Doherty, J.A., et al., ESR1/SYNE1 polymorphism breast cancer identifies distinct profiles defined 15q13.1 and estrogen receptor-negative breast cancer team. Supportive care in cancer : official distress 12 months after diagnosis with early and and invasive epithelial ovarian cancer risk: an by mutation status. Breast Cancer Research, 2. Ahmed, A.A., et al., SIK2 is a centrosome kinase cancer survival. Journal of the National Cancer journal of the Multinational Association of advanced prostate cancer. Medical Journal of Ovarian Cancer Association Consortium study. 2010. 12 Suppl 1: p. O4. required for bipolar mitotic spindle formation that Institute, 2010. 102(9): p. 650-62. Supportive Care in Cancer, 2010. 19(2): p. Australia, 2010. 193(5): p. S58-S61. Cancer Epidemiology, Biomarkers and 89. Fletcher, O., et al., Missense variants in ATM in provides a potential target for therapy in ovarian 281-90. Prevention, 2010. 19(1): p. 245-50. cancer. Cancer Cell, 2010. 18(2): p. 109-21. 19. Bancroft, E.K., et al., The carrier clinic: an 58. Crosbie, J.C., et al., Tumor cell response to 26,101 breast cancer cases and 29,842 controls. evaluation of a novel clinic dedicated to the 40. Byron, S.A., et al., FGFR2 mutations are rare synchrotron microbeam radiation therapy differs 74. Dowsey, M.M., et al., The impact of obesity on Cancer Epidemiology, Biomarkers and 3. Aide, N., et al., High throughput static and follow-up of BRCA1 and BRCA2 carriers-- across histologic subtypes of ovarian cancer. markedly from cells in normal tissues. weight change and outcomes at 12 months in Prevention, 2010. 19(9): p. 2143-51. dynamic small animal imaging using clinical PET/ implications for oncogenetics practice. Journal of Gynecologic Oncology, 2010. 117(1): p. 125-9. International Journal of Radiation Oncology, patients undergoing total hip arthroplasty. Medical 90. Fogarty, G.B., et al., Unexpectedly severe acute CT: potential preclinical applications. European Medical Genetics, 2010. 47(7): p. 486-91. Biology, Physics, 2010. 77(3): p. 886-94. Journal of Australia, 2010. 193(1): p. 17-21. Journal of Nuclear Medicine and Molecular 41. Caddy, J., et al., Epidermal wound repair is radiotherapy side effects are associated with Imaging, 2010. 37(5): p. 991-1001. 20. Bao, H., et al., Second harmonic generation regulated by the planar cell polarity signaling 59. Cullinane, C., et al., Preclinical evaluation of 75. Dowsey, M.M., et al., The impact of pre-operative single nucleotide polymorphisms of the imaging via nonlinear endomicroscopy. Optics pathway. Developmental Cell, 2010. 19(1): p. nilotinib efficacy in an imatinib-resistant KIT-driven obesity on weight change and outcome in total melanocortin-1 receptor. International Journal of 4. Aide, N., et al., 18F-FLT PET as a surrogate Express, 2010. 18(2): p. 1255-60. 138-47. tumor model. Molecular Cancer Therapeutics, knee replacement: a prospective study of 529 Radiation Oncology Biology Physics, 2010. 77(5): marker of drug efficacy during mTOR inhibition by 21. Barber, T.W., M.S. Hofman, and R.J. Hicks, Breast 42. Campbell, B.A., et al., Long-term outcomes for 2010. 9(5): p. 1461-8. consecutive patients. Journal of Bone Joint p. 1486-92. everolimus in a preclinical cisplatin-resistant Surgery (British), 2010. 92(4): p. 513-20. ovarian tumor model. Journal of Nuclear lymphatic drainage via the pulmonary lymphatic patients with limited stage follicular lymphoma: 60. Currow, D.C., et al., Planning phase III multi-site 91. Fogg, P., et al., Thermoluminescence dosimetry Medicine, 2010. 51(10): p. 1559-64. system. European Journal of Nuclear Medicine involved regional radiotherapy versus involved clinical trials in palliative care: the role of 76. Drabsch, Y., R.G. Robert, and T.J. Gonda, MYB for skin dose assessment during intraoperative and Molecular Imaging, 2010. 37(11): p. 2203. node radiotherapy. Cancer, 2010. 116(16): p. consecutive cohort audits to identify potential suppresses differentiation and apoptosis of radiotherapy for early breast cancer. Australasian 5. Akiyama, T., P.F. Choong, and C.R. Dass, 22. Barry, P., et al., Music therapy CD creation for 3797-806. participant populations. Supportive Care in human breast cancer cells. Breast Cancer Physical & Engineering Sciences in Medicine, RANK-Fc inhibits malignancy via inhibiting ERK Cancer, 2010. 18(12): p. 1571-1579. Research, 2010. 12(4): p. R55. 2010. 33(2): p. 211-14. activation and evoking caspase-3-mediated initial pediatric radiation therapy: a mixed 43. Cappellini, M.D., et al., Tailoring iron chelation by anoikis in human osteosarcoma cells. Clinical methods analysis. Journal of Music Therapy, iron intake and serum ferritin: the prospective 61. Da Silva, L., et al., HER3 and downstream 77. Duchesne, G.M., et al., Tribulations of a prostate 95. Foroudi, F., et al., Development and evaluation of and Experimental Metastasis, 2010. 27(4): p. 2010. 47(3): p. 233-263. EPIC study of deferasirox in 1744 patients with pathways are involved in colonization of brain cancer trial - lessons learned from TOAD, a a training program for therapeutic radiographers 207-15. 23. Bayne, M., et al., Reproducibility of “intelligent” transfusion-dependent anemias. Haematologica, metastases from breast cancer. Breast Cancer Cancer Council Victoria and Transtasman as a basis for online adaptive radiation therapy for 2010. 95(4): p. 557-566. Research, 2010. 12(4): p. R46. Radiation Oncology Group trial. Journal of bladder carcinoma. Radiography, 2010. 16: p. 6. Akiyama, T., et al., The non-vascularised fibular contouring of gross tumor volume in non-small- cell lung cancer on PET/CT images using a 44. Carney, D.A. and J.F. Seymour, Therapy-related 62. D’Angelo, M.E., et al., Cathepsin H is an Medical Imaging and Radiation Oncology, 2010. 14-20. graft: a simple and successful method of 54(5): p. 508-11. reconstruction of the pelvic ring after internal standardized visual method. International Journal myelodysplasia and fludarabine combination additional convertase of pro-granzyme B. Journal 96. Fox, C., et al., Extraction of data for margin hemipelvectomy. Journal of Bone Joint Surgery of Radiation Oncology, Biology, Physics, 2010. therapy - do the benefits justify the risk? Leukemia of Biological Chemistry, 2010. 285(27): p. 78. Dunning, T.L., et al., Do High-risk Medicines Alerts calculations in prostate radiotherapy from a (British), 2010. 92(7): p. 999-1005. 77(4): p. 1151-7. & Lymphoma, 2010. 51(11): p. 1957-9. 20514-9. Influence Practice? Journal of Pharmacy Practice commercial record and verify system. Journal of 24. Beauregard, J.M., et al., Pilot comparison of 45. Carney, D.A., et al., Therapy-related 63. Dass, C.R. and P.F. Choong, Sequence-related and Research, 2010. 40(3): p. 203-206. Medical Imaging and Radiation Oncology, 2010. 7. Akiyama, T., et al., PEDF regulates osteoclasts via 54(2): p. 161-70. osteoprotegerin and RANKL. Biochemical and F-fluorocholine and F-fluorodeoxyglucose PET/CT myelodysplastic syndrome and acute myeloid off-target effect of Dz13 against human tumor 79. Etemadmoghadam, D., et al., Amplicon- Biophysical Research Communications, 2010. with conventional imaging in prostate cancer. leukemia following fludarabine combination cells and safety in adult and fetal mice following dependent CCNE1 expression is critical for 97. Friedlander, M., et al., A Phase II, open-label 391(1): p. 789-94. Journal of Medical Imaging and Radiation chemotherapy. Leukemia, 2010. 24(12): p. systemic administration. Oligonucleotides, 2010. clonogenic survival after cisplatin treatment and is study evaluating pazopanib in patients with Oncology, 2010. 54(4): p. 325-32. 2056-62. 20(2): p. 51-60. correlated with 20q11 gain in ovarian cancer. recurrent ovarian cancer. Gynecological 8. Akiyama, T., et al., Systemic RANK-Fc protein 25. Bollag, G., et al., Clinical efficacy of a RAF 46. Carrington, C., et al., The Clinical Oncological 64. Dass, C.R., S.J. Galloway, and P.F. Choong, Dz13, PLoS One, 2010. 5(11): p. doi:10.1371/journal. Oncology, 2010. 119(1): p. 32-7. therapy is efficacious against primary pone.0015498 (14 pages). osteosarcoma growth in a murine model via inhibitor needs broad target blockade in Society of Australia (COSA) guidelines for the a c-jun DNAzyme, is a potent inducer of 98. Froldi, F., et al., The lethal giant larvae tumour activity against osteoclasts. Journal Pharmacy BRAF-mutant melanoma. Nature, 2010. safe prescribing, dispensing and administration caspase-2 activation. Oligonucleotides, 2010. 80. Everitt, S., et al., High rates of tumor growth and suppressor mutation requires dMyc oncoprotein and Pharmacology, 2010. 62(4): p. 470-6. 467(7315): p. 596-9. of cancer chemotherapy. Asia-Pacific Journal of 20(3): p. 137-46. disease progression detected on serial to promote clonal malignancy. BMC Biology, Clinical Oncology, 2010. 6(3): p. 220-37. pretreatment fluorodeoxyglucose-positron 2010. 8: p. doi:10.1186/1741-7007-8-33 (16 9. Al-Badriyeh, D., et al., Pharmacoeconomic 26. Bolton, K.L., et al., Common variants at 19p13 are 65. Dass, C.R., et al., Dz13 induces a cytotoxic stress associated with susceptibility to ovarian cancer. 47. Chan, A.C., et al., Testing the NKT cell hypothesis response with upregulation of E2F1 in tumor cells emission tomography/computed tomography pages). evaluation of voriconazole versus posaconazole scans in radical radiotherapy candidates with for antifungal prophylaxis in acute myeloid Nature Genetics, 2010. 42(10): p. 880-4. in lenalidomide-treated myelodysplastic metastasizing to or from bone. Oligonucleotides, 99. Frowen, J., et al., Impact of demographics, tumor syndrome patients. Leukemia, 2010. 24(3): p. 2010. 20(2): p. 79-91. nonsmall cell lung cancer. Cancer, 2010. 116(21): characteristics, and treatment factors on leukaemia. Journal of Antimicrobial 27. Bonelli, M.A., et al., Synergistic activity of letrozole p. 5030-7. Chemotherapy, 2010. 65(5): p. 1052-61. and sorafenib on breast cancer cells. Breast 592-600. 66. de Azambuja, E., et al., The effect of body mass swallowing after (chemo)radiotherapy for head Cancer Research and Treatment, 2010. 124(1): p. 48. Chan, C.J., et al., DNAM-1/CD155 interactions index on overall and disease-free survival in 81. Fainsinger, R.L., et al., An international multicentre and neck cancer. Head & Neck, 2010. 32(4): p. 10. Andrews, D.M., et al., Innate immunity defines the validation study of a pain classification system for 513-28. capacity of antiviral T cells to limit persistent 79-88. promote cytokine and NK cell-mediated node-positive breast cancer patients treated with suppression of poorly immunogenic melanoma docetaxel and doxorubicin-containing adjuvant cancer patients. European Journal of Cancer, 100. Gaire, R.K., et al., MIRAGAA--a methodology for infection. Journal of Experimental Medicine, 2010. 28. 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Peter MacCallum Cancer Centre – Research Report 2010 Publicaions 161 6 Publications 6 Publications

106. Gordon, L.G., et al., Medical costs and outcomes 123. Hayden, A.J., et al., Australian & New Zealand 140. Jefford, M., et al., Use of chemotherapy and 159. Kron, T., et al., Adaptive radiotherapy for bladder 178. Mele, T., et al., Anti-angiogenic effect of tamoxifen 199. Oliaro, J., et al., Asymmetric cell division of T cells for Australian women with ovarian cancer: a Faculty of Radiation Oncology Genito-Urinary radiotherapy in patients with pancreatic cancer in cancer reduces integral dose despite daily combined with in breast cancer upon antigen presentation uses multiple patient-level analysis over 2.5 years. International Group: 2010 consensus guidelines for definitive Victoria (2002-2003): a retrospective cohort study. volumetric imaging. Radiotherapy and Oncology, patients. Breast Cancer Research and Treatment, conserved mechanisms. Journal of Immunology, Journal of Gynecologic Cancer, 2010. 20(5): p. external beam radiotherapy for prostate Medical Journal of Australia, 2010. 192(6): p. 2010. 97(3): p. 485-7. 2010. 123(3): p. 795-804. 2010. 185(1): p. 367-75. 323-7. 757-65. carcinoma. Journal of Medical Imaging and 160. Kwak, E.L., et al., Anaplastic lymphoma kinase 179. Michael, M., et al., Phase Ib study of CP-868,596, 200. Oliva, M., et al., EEG dipole source localization of 107. Gorringe, K.L., et al., Copy number analysis Radiation Oncology, 2010. 54(6): p. 513-25. 141. Johnatty, S.E., et al., Evaluation of candidate inhibition in non-small-cell lung cancer. New a PDGFR inhibitor, combined with docetaxel with interictal spikes in non-lesional TLE with and identifies novel interactions between genomic loci 124. Haynes, N.M., et al., CD11c(+) dendritic cells stromal epithelial cross-talk genes identifies England Journal of Medicine, 2010. 363(18): p. or without axitinib, a VEGFR inhibitor. British without hippocampal sclerosis. Epilepsy in ovarian cancer. PLoS One, 2010. 5(9): p. and B cells contribute to the tumoricidal activity of association between risk of serous ovarian cancer 1693-703. Journal of Cancer, 2010. 103(10): p. 1554-61. Research, 2010. 92(2-3): p. 183-90. and TERT, a cancer susceptibility “hot-spot”. doi:10.1371/journal.pone.0011408 (13 pages). anti-DR5 antibody therapy in established tumors. 161. Lasocki, A., et al., Hidradenitis suppurativa 180. Miki, Y., et al., The significance of size change of 201. Ou, S.H., et al., Rapid and dramatic radiographic PLoS Genetics, 2010. 6(7): p. e1001016. 108. Gough, D.J., et al., Functional crosstalk between Journal of Immunology, 2010. 185(1): p. 532-41. responding to treatment with infliximab. soft tissue sarcoma during preoperative and clinical response to an ALK inhibitor type I and II interferon through the regulated 125. Height, R., et al., The dosimetric consequences 142. Jones, D.N., et al., Establishing national medical Australasian Journal of Dermatology, 2010. 51(3): radiotherapy. European Journal of Surgical (crizotinib, PF02341066) in an ALK translocation- expression of STAT1. PLoS Biology, 2010. 8(4): p. of anatomic changes in head and neck imaging incident reporting systems: issues and p. 186-90. Oncology, 2010. 36(7): p. 678-83. positive patient with non-small cell lung cancer. challenges. Journal of the American College of e1000361 doi:10.1371/journal.pbio.1000361 (12 radiotherapy patients. Journal of Medical Imaging 162. Lau, E.W., et al., Comparative PET study using 181. Milne, R.L., et al., Assessing interactions between Journal of Thoracic Oncology, 2010. 5(12): p. Radiology, 2010. 7(8): p. 582-92. pages). and Radiation Oncology, 2010. 54(5): p. 497-504. F-18 FET and F-18 FDG for the evaluation of the associations of common genetic susceptibility 2044-6. 109. Gowans, E.J., et al., A phase I clinical trial of 126. 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International Journal of Radiation 110. Grainger, M.N., et al., Discussing the transition to Biological Therapy, 2010. 10(1): p. 113-25. 146. Jordan, S.J., et al., Pathways to the diagnosis of Castlemans disease with rituximab therapy in a R110. Oncology Biology Physics, 2010. 77(4): p. palliative care: evaluation of a brief 127. Herr, A., et al., Geminin and Brahma act epithelial ovarian cancer in Australia. Medical HHV8-positive, HIV-negative patient. International 182. Milton, C.C., et al., Differential requirement of 1248-56. communication skills training program for antagonistically to regulate EGFR-Ras-MAPK Journal of Australia, 2010. 193(6): p. 326-30. Journal of Hematology, 2010. 91(2): p. 347-8. Salvador-Warts-Hippo pathway members for 203. Pegram, H.J., et al., Characterizing the anti-tumor oncology clinicians. Palliative and Supportive signaling in Drosophila. Developmental Biology, 147. Kamel, S. and D. Ritchie, Intra-atrial thrombosis 164. 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Handolias, D., et al., Clinical responses observed study. British Journal of Anaesthesia, 2010. Cancer Research, 2010. 70(20): p. 7788-99. and Treatment Planning in Candidates for Radical 193. Nazarian, R., et al., Melanomas acquire prevalence and associated comorbidities. with imatinib or sorafenib in melanoma patients 105(2): p. 145-9. 155. Kolahdooz, F., et al., Meat, fish, and ovarian Radiation Therapy with Unresectable Non-small resistance to B-RAF(V600E) inhibition by RTK or Diseases of the Colon and Rectum, 2010. 53(1): expressing mutations in KIT. British Journal of 136. Ivanov, A.I., et al., Tumor suppressor scribble cancer risk: Results from 2 Australian case- Cell Lung Cancer. International Journal of N-RAS upregulation. Nature, 2010. 468(7326): p. p. 71-6. Cancer, 2010. 102(8): p. 1219-1223. regulates assembly of tight junctions in the control studies, a systematic review, and Radiation Oncology, Biology, Physics, 2010. 973-7. 212. 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215. Qi, J., et al., Siah2-dependent concerted activity .230. Schofield, P., et al., Effectively discussing 248. Tan, M.L., P.F. Choong, and C.R. Dass, Direct 265. van Oers, M.H., et al., BCL-2/IgH polymerase 282. Whiley, P.J., et al., Effect of BRCA2 sequence 10. Bruhn, M.A., et al., Second AKT: the rise of SGK of HIF and FoxA2 regulates formation of complementary and alternative medicine in a anti-metastatic efficacy by the DNA enzyme Dz13 chain reaction status at the end of induction variants predicted to disrupt exonic splice in cancer signalling. Growth Factors, 2010. 28(6): neuroendocrine phenotype and neuroendocrine conventional oncology setting: communication and downregulated MMP-2, MMP-9 and treatment is not predictive for progression-free enhancers on BRCA2 transcripts. BMC Medical p. 394-408. prostate tumors. Cancer Cell, 2010. 18(1): p. recommendations for clinicians. Patient MT1-MMP in tumours. 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