RESEARCH REPORT 2008 Peter MacCallum Cancer Centre

Peter MacCallum Cancer Centre RESEARCH Report 2008 People/Opportunities Discovery/Care As the largest cancer research site in Australia, Peter MacCallum Cancer Centre is a major contributor to advances in cancer diagnosis and treatment. The co-location of a sophisticated research facility and a world-class cancer hospital creates a highly synergistic combination. With researchers and clinicians working side-by-side, Peter Mac has made significant contributions to basic research, translational research and clinical trials. Our goal is to alleviate the burden associated with cancer through innovative research at Peter Mac, and through collaboration and contribution to international cancer research programs worldwide. Research Metrics TitleContents/

The Peter MacCallum Cancer Fellowships and Awards Research Metrics 02 Centre is Australia’s largest site – 8 NHMRC senior fellowships for cancer research Director’s Report 04 – 11 NHMRC career development and Fundamental to our excellence is postdoctoral awards Chief Executive Officer’s Overview 10 the fusion of an integrated research environment within a dedicated specialist – 5 clinical and research fellowship awards Cancer Immunology Program 12 cancer hospital. This integration provides (CCV, Pfizer, VCA) Cancer Genomics Program 22 unique opportunities for medical advances – 13 new scholarships awarded to to be developed and tested, and for clinical postgraduate students in 2008 Growth Control & Differentiation 36 questions to guide our research agenda. Cancer Cell Biology Program 44 Publications Cancer Therapeutics Program 62 Research Staff Total Peer-Reviewed Publications: 346 Translational Research Program 70 Research Division Ranked 3rd Australia-wide for overall – over 350 laboratory-based scientists and research impact, with average of 12.84 Clinical & Allied Health Research 82 support staff citations per paper * Tumour Streams & Clinical Trials 104 – including ~80 postgraduate and honours (*Thomas Scientific, 2007). students Core Technologies 132 Over 2000 refereed papers published – 25 research laboratories Education & Learning 144 since 2000. – 6 laboratory-based programs and Ethical Conduct of Research 154 translational research Funding Intellectual Property & • Cancer Cell Biology Total Grant Income: Commercialisation 158 • Cancer Genetics & Genomics – 2006/07: $24.31 million Publications & Patents 162 • Cancer Immunology Research – 2007/08: $27.53 million • Cancer Therapeutics – 2008/09: $33.35 million • Growth Control & Differentiation • In 2008-09, over $40 million supported • Molecular Imaging & Translational research programs and core facilities Medicine infrastructure. – Supported by 9 core technology NHMRC – In 2008 awarded 10 new project platforms grants totalling over $4.9 million Clinical Divisions – 1 new program grant jointly funded with – over 150 clinician researchers, the Ludwig Institute for Cancer Research. statisticians, research nurses involved in • Peer-reviewed funding for research has clinical trials and clinical research grown 50-fold since 1994. – over 100 clinical trials active at Peter Mac • More than double the national average for success in grants from the National Health & Medical Research Council (NHMRC) over the past five years.

Image Karen Chen, Research Assistant, Haematology Immunology Translational Research laboratory

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Director RESEARCH HIGHLIGHTS through deregulation of MAPK signalling. Professor David Bowtell The 2008 Annual Research Report Oncogene 27: 5988-6001. describes work associated with over 340 It is now recognized that regulation of publications. A few of these papers are cell shape is an important property of highlighted below to provide a snapshot normal cells and that this is controlled by of the scope and excellence of our a biochemical network of proteins called research program. the cell polarity complex. This complex includes Scribble, a protein first isolated Genomics Program in Drosophila melanogaster. Luke Dow, Qiu, W., M. Hu, A. Sridhar, K. Opeskin, a PhD student in Dr Patrick Humbert’s S. Fox, M. Shipitsin, M. Trivett, E. R. laboratory investigated the interaction of Thompson, M. Ramakrishna, K. L. Scribble and the human oncogene H-ras. Gorringe, K. Polyak, I. Haviv and I. G. Luke showed that loss of Scribble could Campbell (2008). “No evidence of clonal High resolution copy number analysis of cooperate with oncogenically mutated somatic genetic alterations in cancer- chromosome 8, showing data from an ovarian cancer case. The epithelial tumour component H-ras through de-regulation of the MAPK associated fibroblasts from human breast (bottom) has multiple amplifications and deletions, signalling pathway (see image below). The Cancer is a complex problem requiring Peter Mac’s ability to make internationally associated with the Peter MacCallum East and ovarian carcinomas.” Nature Genetics compared with data from the stroma (above) work increases our understanding of how an extraordinary effort if progress is significant contributions depends on Melbourne building would relocate to the 40(5): 650-5. which does not have any detectable copy to be made. As Australia’s largest bringing together talented researchers, new centre. Substantial expansion of the number alterations. signaling pathways influencing cellular research facilities is proposed to better There is an emerging literature suggesting architecture interact with those controlling site for cancer research, Peter Mac enabling them with advanced technology, Tumour Streams & Clinical Trials is a leader in the rapidly accelerating fuelling their research with funding, accommodate current research efforts and that fibroblasts surrounding epithelial cell proliferation. [See pg 60]. Karapetis CS, Khambata-Ford S, Jonker advances in understanding of cancer maintaining active communication between to allow the development of new streams malignancies may promote tumourigenicity DJ, O’Callaghan CJ, Tu D, Tebbutt NC, causation, diagnosis, treatment and scientists and clinicians, and ensuring that of research. On behalf of all researchers and that this attribute is acquired in part Simes RJ, Chalchal H, Shapiro JD, support. Fundamental to our excellence our findings are translated to the clinic. at Peter Mac, I’d like to express our through somatic mutation of genes in Robitaille S, Price TJ, Shepherd L, Au is the fusion of an integrated research On the following pages I highlight some appreciation for the efforts of the Victorian cancer associated cells (CAFs). Wen Qiu, HJ, Langer C, Moore MJ, Zalcberg JR environment within a dedicated specialist of our research achievements, Government and our partners – Walter a PhD student in Associate Professor (2008) K-ras mutations and benefit from cancer hospital, with over 500 scientists, development of our facilities, and and Eliza Hall Institute, Ludwig Institute for Ian Campbell’s laboratory, challenged cetuximab in advanced colorectal cancer. students, clinician-researchers, research recognition of our researchers. Cancer Research, University of Melbourne, previous studies that found that somatic N Engl J Med 359: 1757-65. nurses, support staff, and allied health and Melbourne Health – during the alterations were very common in CAFs. Work towards a new home for Peter professionals engaged in research. development of this exciting initiative. Wen’s definitive study used high-resolution This study reported the findings of Mac researchers DNA microarrays to provide a genome- evaluation of determinants of response to Our research program is therefore Our extraordinary success since moving wide assessment of DNA copy number an EGFR inhibitor (cetuximab) in over 570 underpinned at all levels by a belief in to East Melbourne in 1994 has meant change (see image right). Her analysis of patients with colorectal cancer. Conducted the importance of developing a deep that Peter Mac has outgrown its current CAFs and tumour epithelia from breast through the Australian Gastrointestinal understanding of the processes that home. Severe crowding of the research and ovarian cancers convincingly showed Trials Group and led by Professor John control cancer cells and employing this laboratories and clinical research facilities Professor David Bowtell that somatic alterations are extremely rare Zalcberg, the study demonstrated that Cancer Immunology Program knowledge in the clinic to develop rational, significantly limits our ability to develop Director in CAFs and strongly refute the theory patients with mutation in the k-ras gene Stagg J, Sharkey J, Pommey S, Young evidence-based protocols that improve new lines of research and capitalize on of stromal cell co-evolution. This study were unlikely to respond to cetuximab. R, Takeda K, Yagita H, Johnstone RW, cancer outcome. This evidence-based advances in technology. Over the last year indicates that therapies that target the The landmark study provided important Smyth MJ (2008) Antibodies targeted to approach is extended to areas of allied we have continued work with the Victorian tumour stroma are less likely to be negated information concerning response to this TRAIL receptor-2 and ErbB-2 synergize health and supportive care research, where Government Department of Human by the emergence of resistant fibroblasts costly but effective new drug and led in vivo and induce an antitumour immune we seek to develop the most innovative Services and the Department of Innovation, than those targeting the epithelial fraction to the inclusion of k-ras testing in new response. Proceedings of the National approaches to patient care. Industry and Regional Development, and of the tumour. [See pg 24]. colorectal cancer patients who were being Academy of Sciences USA 105: 16254-9. research and clinical partners in Parkville, considered for treatments with EGFR Anti-ErbB2 treatment is now a well- to develop a business case for a new inhibitors. [See pg 111]. established component of treatment comprehensive cancer centre located of many women with advanced breast adjacent to the Royal Melbourne Hospital Cell Biology Program cancer. This study by Dr John Stagg and University of Melbourne. It is intended Dow LE, Elsum IA, King CL, Kinross KM, in Professor Mark Smyth’s laboratory that the hospital and all research activities Richardson HE, Humbert PO (2008) investigated the effect of combined Loss of human Scribble cooperates treatment with monoclonal antibodies with H-Ras to promote cell invasion directed towards the ErbB2 cell surface receptor and tumour necrosis factor-

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related apoptosis-inducing ligand (TRAIL) inhibited c-Myc protein expression by and Grant McArthur. This program is Assoc. Professors Ricky Johnstone, clinical trials capabilities, and the research receptor-2 (DR5) (see image below). The decreasing c-Myc mRNA translation and designed to integrate various basic Grant McArthur, Ross Hannan and delivers new and improved treatment researchers found that the combination relieved the differentiation block induced research activities, platform technologies, Rick Pearson; outcomes for cancer patients. of therapies was remarkably synergistic by enforced c-Myc expression (see image and pre-clinical model systems available – Victorian Centre for Functional This program is closely affiliated with the in reducing tumour growth, and involved below). The work defines an important within Peter Mac to discover, develop, Genomics (VCFG), headed by manager Cancer Therapeutics and Translational induction of anti-tumour immunity through potential approach to targeted therapy characterise and refine novel cancer Dr Kaylene Simpson; Research programs, and the Early Phase CD8+ T cells. The work is provides in patients with activation of the c-Myc therapeutics for clinical use. [See pg 62]. – Peter Mac Early Phase Clinical Trials, Clinical Trials at Peter Mac. important pre-clinical data in the design of oncogene. [See pg 70]. The Cancer Therapeutics Program was headed by Assoc. Professors Grant novel clinical trials for women with ErbB2 established around the following research McArthur and Danny Rischin, and positive breast cancer. [See pg 16]. laboratories: Professor Miles Prince. Localization of the upstream binding factor (UBF) to nucleoli, the site of RNA polymerase I transcription – Gene Regulation, headed by Assoc. PETER MAC-PFIZER TRANSLATIONAL (A-C). UBF knockdown using short interfering RNA Professor Ricky Johnstone (previously ONCOLOGY RESEARCH oligonnucleotides (siRNAs) leads to a reduction based in the Cancer Immunology in UBF levels at the nucleoli (D-F). Arrows indicate COLLABORATIVE HUB (TORCH) Program, and still closely involved in UBF staining. In May 2008, the Peter Mac-Pfizer Immunology research). Cancer Therapeutics Program Translational Oncology Research – Molecular Oncology, headed by Collaborative Hub (TORCH) was Ellis L, Pan Y, Smyth GK, George DJ, Assoc. Professor Grant McArthur. launched by Senator Kim Carr, Federal McCormack C, Williams-Truax R, Mita Minister for Innovation, Industry, Science M, Beck J, Burris H, Ryan G, Atadja – Apoptosis and Natural Toxicity, and Research. P, Butterfoss D, Dugan M, Culver K, headed by Dr Nigel Waterhouse. Johnstone RW, Prince HM (2008) Histone – Translational Research Laboratory, Pfizer’s $15m commitment to cancer When mTORC1 is on, MYC is active and white cells headed by Dr Carleen Cullinane. Left to right: Assoc. Professor Danny Rischin, deacetylase inhibitor panobinostat are unable to mature. The drug rapamycin switches drug development at Peter Mac over Professor Rod Hicks, and Assoc. Professor Grant induces clinical responses with associated off mTORC1, reducing levels of MYC and allowing the next three years is one of its largest McArthur worked with Pfizer to establish TORCH at Anti-ErbB-2 and anti-DR5 monoclonal antibodies normal white cell development to occur. Peter Mac. (mAbs) synergize in vivo to induce tumour cell alterations in gene expression profiles collaborations currently within Australia. in cutaneous T-cell lymphoma. Clinical death. Clinical & Allied Health The collaborative research program aims Cancer Research 14: 4500-4510. VICTORIAN CENTRE FOR FUNCTIONAL Growth Control & Differentiation Jefford M, Baravelli C, Dudgeon P, to provide broad translational research GENOMICS Gene expression is controlled at several support to Pfizer’s oncology research and Program Dabscheck A, Evans M, Moloney M, The Victorian Centre for Functional levels, including protein acetylation. development programs, with a focus on Sanij E, Poortinga G, Sharkey K, Hung Schofield P (2008) Tailored chemotherapy Genomics (VCFG) was officially launched Recently a number of new therapeutics, personalising medicine through patients’ S, Holloway TP, Quin J, Robb E, Wong information faxed to general practitioners in May 2008 by the Hon Gavin Jennings including panobinostat, have been genetic information. LH, Thomas WG, Stefanovsky V, Moss T, improves confidence in managing adverse MLC, Victorian Minister for Innovation, developed that inhibit the deacetylation Rothblum L, Hannan KM, McArthur GA, effects and satisfaction with shared care: Pfizer senior clinical development executive Industry and Regional Development. of proteins and have shown activity in Pearson RB, Hannan RD (2008) UBF levels results from a randomized controlled trial. Briggs Morrison said it was conceivable The VCFG was funded by an innovative a range of different tumour types.This determine the number of active ribosomal Journal of Clinical Oncology 26: 2272-7. a treatment could be commercialised in partnership between the Victorian State study involved a collaboration between RNA genes in mammals. The Journal of General practitioners (GPs) are an about four years time. Speaking at the government and matching funding Assoc. Professor Ricky Johnstone’s Cell Biology 183: 1259-74. integral part of a multidisciplinary team launch of this collaborative project, Senator from Peter Mac, AMATA (Australasian laboratory and the Department of Medical in the management of cancer patient’s Carr praised the TORCH collaboration as Microarray and Associated Technologies Levels of the pool of ribosomes within Oncology led by Professor Miles Prince. treatment and well-being. The Supportive the type of “bench-to-bed” venture the Association) and Agilent Technologies. a cell is important in the control of A novel clinical trial showed impressive CMITR Centre for Molecular Imaging and Care Research Nursing Program has a Australian economy needs. protein translational capacity and therapeutic activity of panobinostat in Translational Research The first of its kind in Australia, the VCFG strong commitment to the development CRC-CT Cooperative Research Centre for Cancer cellular responses to growth stimuli. patients with cutaneous T cell lymphoma. The program brings together molecular provides Victorian researchers with the of innovative, evidence-based protocols Therapeutics Assoc. Professor Ross Hannan and his Translational studies by PhD student VCFG Victorian Centre for Functional Genomics imaging, cancer genomics and high quality opportunity to access a sophisticated RNA to improve patient management and collaborators have had a long-standing Leigh Ellis demonstrated that patient information. Dr Michael Jefford, Associate The program also integrates the following interest in the control of ribosomal rRNA samples showed distinct patterns of gene Professor Penny Schofield and colleagues research groups: transciption, in particular involving the expression change. [See pg 62]. upstream binding factor, UBF1, which is performed a randomized controlled trial to – Peter MacCallum-Pfizer Translational Translational Research Program a major controller of RNA Polymerase I assess the impact of sending information Oncology Research Collaborative transcription. In this study, Elaine Sanji and Wall M, Poortinga G, Hannan KM, tailored to the particular patient’s Hub (TORCH); colleagues showed that UBF1 controls Pearson RB, Hannan RD, McArthur GA chemotherapy regimen to GPs. The study – Centre for Molecular Imaging and the transcrtiptional state of rRNA genes by (2008) Translational control of c-MYC by found that the information communicated Translational Medicine headed by influencing histone-mediated chromatin rapamycin promotes terminal myeloid provided a simple, inexpensive intervention Professor Rod Hicks; remodeling (see image right). The work differentiation. Blood 112: 2305-17. that increased confidence managing chemotherapy adverse effects. [See pg 82]. – CRC for Cancer Therapeutics (CRC- provides important mechanistic insights c-Myc is one of the most commonly into the fundamental cellular processes CT) Peter Mac component, headed by over-expressed oncogenes in human NEW RESEARCH INITIATIVES project manager Dr Mark Devlin; that influence protein translation. cancer and has broad effects on cellular [See pg 40]. differentiation, proliferation and growth Establishement of a New Program in – Pfizer Genomics Program, headed control. In studies led by Assoc. Professor Cancer Therapeutics by Assoc. Professors Rick Pearson and Grant McArthur’s laboratory, Dr Megan The Cancer Therapeutics Program was Wayne Phillips; Left to right: Pictured at the Peter Mac-Pfizer TORCH launch are Dr Briggs Morrison (Senior Vice President Wall demonstrated that inhibition of the established in early 2008 and is headed – Cancer Council Victoria (CCV) and Head of Medicines Development for Primary Care, Pfizer), Professor David de Kretser (Governor of Victoria), Honourable Senator Kim Carr, Professor David Copolov (Chair, Research Advisory Committee), mTORC1 pathway using rapamycin by Assoc. Professors Ricky Johnstone Venture Grant Project, headed by Dr Joe Feczko (Chief Medical Officer, Pfizer).

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interference (RNAi) technology to perform within p53 itself or deregulation of other body for health and medical research, the Major Conferences Development) was the principal sponsor (Department of Anatomy and Cell Biology, comprehensive somatic cell genetic parts of the pathway. Ygal’s research NHMRC granted its Excellence Awards of the Symposium and the Public The University of Melbourne). The best 1st Peter Maccallum Cancer Centre screens. The VCFG uses technology achievements include the discovery of to the highest ranked recipients of grants Workshop Symposium on Cancer Lecture. The other principal sponsors of student presentation prize was awarded developed by Open BioSystems that mdm2, one of the major controllers of p53 and fellowships in 2008. Recipients Epigenetics the symposium were Sequenom, and to Dr Adam Parslow (Ludwig Institute, involves the use of a short hairpin protein abundance. His knowledge of this were assessed by a group of experts, Janssen-Cilag. Major sponsors were Melbourne). The meeting also provided The first Peter MacCallum Cancer Centre microRNA (shRNAmiR) delivered through important tumour suppressor pathway and through a comprehensive peer review Roche, Applied Biosystems, Human an important opportunity to establish Workshop Symposium on Cancer in a lentiviral delivery system. The ability to expertise in molecular and cellular biology, process. Professor Michael Good, Chair Genetic Signatures, Pfizer, and Illumina. close ties with Cell Cycle researchers in Epigenetics was held on 14th-17th knock down essentially any gene allows proteasomal degradation and imaging of the NHMRC, presented the awards at Singapore, and as a result the 2009 Cell October at the Wilson’s Promontory researchers to systematically search for techniques will provide invaluable expertise an invitation-only dinner in Canberra in Cycle Workshop will be held conjointly National Park, Victoria. protein signalling pathways that control the to the Division. December. Joe was among the first to with the IMCB Cell Cycle Regulation & growth of cancer cells and their response discover the toxic molecules associated The meeting was attended by 89 national Tumorigenesis Symposium, Sep 7th-8th, In addition to his studies with p53 Ygal’s to therapy. with the immune system’s so-called and international delegates, including the 2009 at the Institute of Molecular and Cell laboratory will investigate the regulation of killer cells. He and his team have since following international guest presenters: Biology, Singapore. Importantly, the VCFG has been PML, a protein that is frequently mutated devised new ways of activating the killer Jean-Pierre Issa (MD Anderson Cancer established as a resource for researchers in certain types leukaemia and aims to Inaugural Cell and Developmental cells as novel therapies for cancer, and Centre, Houston), Frank Lyko (Deutsche throughout Australia, not just at Peter Mac. translate findings in the laboratory to the Biology Meeting they have invented new drugs to block Krebsforshungszentrum, Heidelberg), The facility is supported by a Scientific clinic. His work is supported by grants certain other killer cells that can cause life- Toshikazu Ushijima (National Cancer In November, Peter Mac hosted Advisory Group comprised of renowned from the European Union and the National PHOTO: International speakers at Wilson’s threatening auto-immune diseases. This Centre Research Institute, Tokyo), John the Inaugural Melbourne Cell and researchers, many of whom external to Health and Medical Research Council Promontory (L-R): Kazu Ushijima, Jean-Pierre Issa, prestigious award is significant recognition Greally (Albert Einstein University, New Developmental Biology Meeting. Over Peter Mac, and provides advice about key of Australia, and the awarding of a 2009 Jeffrey Jeddeloh, Frank Lyko and John Greally. of the important contribution Joe and his York), Steven Jones (Michael Smith 90 attendees participated in the meeting directions for the facility. Located in the VESKI Innovation Fellowship. research team have made to Australian Genome Sciences Centre, Vancouver), 11th Annual Cell Cycle Workshop 2008 and witnessed presentations from PhD Research Division of Peter Mac, it will play medical research. John Edwards (Columbia University, New The 11th Annual Cell Cycle Workshop was students and postdoctoral research fellows a key role within the Cancer Therapeutics York), Nancy Kiviat (Fred Hutchinson held at the Department of Anatomy and from around Melbourne. The meeting was and Genomics Programs. External users Dr Kieran Harvey Cancer Research Institute, Seattle), Cell Biology at the University of Melbourne created to provide a forum for emerging in diverse fields such as neuroscience, Matthias Ehrich (Sequenom, San Diego), on November 21st-23rd, 2008, with the cell and developmental scientists to stem cell research, cardiovascular science, Philippe Collas (University of Oslo), and purpose of bringing together researchers present their research, and to raise the endocrinology, immunology, respiratory Jeffrey Jeddeloh (Roche Nimblegen). interested in cell growth, proliferation and profile of these disciplines in Melbourne. and reproductive biology are expected to mitogenic signalling pathways to exchange The meeting was organised by Dr. Kieran make heavy use of the facility. This meeting was a great success. The information and establish collaborations. Harvey (Peter Mac) and Dr. Ian Smyth science was of a high standard and the The workshop was organized by Dr Helena (Monash) on behalf of the Australian and size of the meeting and venue provided Richardson (Cell Cycle and Development New Zealand Society for Developmental the opportunity for attendees to interact Laboratory, Peter Mac), Dr Leonie Quinn Biology (ANZSCDB), and the Melbourne and discuss science informally. Many (Department of Anatomy and Cell Biology, Epithelial Group. young scientists from Australia had the The University of Melbourne – previously opportunity to present their recent work to Speakers represented Melbourne, a researcher at Peter Mac), Dr Boris Monash and Deakin Universities, as well national and international luminaries in the Sarcevic (St Vincent’s Institute) and Dr Pictured: Ygal and Sue Haupt cancer epigenetics field. The collegiate as several Research Institutes including Jorg Heierhorst (St Vincent’s Institute) with Peter Mac, Ludwig, WEHI, Howard atmosphere of the symposium was evident assistance from Sally Cane (Peter Mac). RECOGNITION OF LEADING Florey, and Murdoch Children’s. A broad in the willingness of experts to openly The meeting was supported by John RESEARCHERS range of cell and developmental biology Dr Kieran Harvey, Head of the Cell Growth provide constructive criticism to Morris Scientific, Applied Biosystems, topics were covered including oocyte Professor Joe Trapani and Proliferation laboratory in the Research junior scientists. Genesearch and CTx Research (Silver development, stem cells, cell polarity Division, was a 2008 recipient of one of Pictured at the Official launch of the VCFG in 2008: The keynote speaker, Professor Jean- sponsors) and GeneWorks, St. Vincent’s and control of organ size. The research the prestigious Young Tall Poppy Science Professor David Bowtell, Assoc. Professor David Pierre Issa, also presented a Public Lecture Institute, Olympus, Millennium Science presented was performed using an array of Thomas, Ibrahim Memet, Hon Gavin Jennings Awards, one of ten recipients selected at Peter Mac on Monday 13th October. In a and PMCC (Bronze sponsors) and by the experimental systems including flies, fish, – Minister for Innovation, Industry & Regional from a large national pool of nominees. Department of Anatomy and Cell Biology, Development, Victorian Government, Assoc. very engaging presentation, he addressed mice, marsupials, and cell culture. Dr Jane The awards recognize scientific excellence Professor Ricky Johnstone. issues related to “New horizons in cancer The University of Melbourne. International Visvader from WEHI gave an engaging and leadership of Australians who are at research and therapy”. invited speakers were Dr Wanjin Hong and plenary presentation on mammapoiesis Recruitment of a Leading p53 an early stage of their career. Kieran has Dr Philipp Kaldis, both from the Institute of and breast cancer. The PhD student and Researcher From Israel rapidly and effectively made the transition The Organising Committee at Peter Molecular and Cell Biology, Singapore. postdoctoral research fellow presentations I was delighted to announce the from postdoctoral fellow to Principal MacCallum Cancer Centre consisting of Over 50 scientists including group were of a very high standard with Dr Julian recruitment of Assoc. Professor Ygal Investigator of his own independent Alexander Dobrovic and Pritinder Kaur leaders, postdoctoral researchers, Heng (Howard Florey), and Kenneth Haupt from the Hebrew University in Israel research program. As a Tall Poppy, Kieran (convenors), Ricky Johnstone, Izi Haviv, students and research assistants from Walker (Monash) being awarded prizes for to establish the Tumour Suppression will be involved in communicating with David Thomas, Alex Boussiatas, Kieran around Australia and Singapore attended the best presentations. The meeting was Laboratory in the Research Division at students in secondary schools about his Harvey and Sally Cane (secretary) worked the highly successful meeting. The a great success and will become an Peter Mac [See pg 60]. Ygal is regarded work and the importance of science. with ASN Events to convene and oversee annual event. as one of the world’s leading experts in the this event. “Young Investigator Award for Best Oral Presentation” for postdoctoral researchers p53 tumour suppressor pathway, one of We would like to take this opportunity We would like to acknowledge the support Professor Joe Trapani was recognised by was awarded to Dr Nicola Grzeschik the most important pathways controlling to thank the sponsors of this event. The of Geneworks, Millipore and ANZSCDB for the National Health and Medical Research (Cell Cycle and Development laboratory, the cellular response to DNA damage. State Government of Victoria (Department their generous sponsorship of this event. Council (NHMRC) for his outstanding Peter Mac) and Dr Greg Somers The p53 pathway is defective in almost contribution to the success of research in of Industry, Innovation and Regional all cancer cells, either due to mutation this country. As Australia’s leading funding

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Chief Executive Officer Research at Peter Mac the major stakeholders’ ability to work I particularly appreciate the contributions Mr Craig Bennett Peter Mac aspires to be a leader in together to achieve our jointly-articulated made by those members of the Research cancer therapy, research, education and vision for the comprehensive cancer centre Advisory Committee who are external to training. We have more than 500 staff that will, in turn, shape and influence the Peter Mac. actively involved in laboratory, clinical and treatment of cancer patients in many Foundation support translational research into the causes, hospitals throughout Victoria and Australia. I am delighted that the vibrancy of the The Peter MacCallum Cancer Foundation consequences and treatment options for Research leadership Ltd, chaired by Professor Lester Peters cancer. No other organisation in Australia many research programs at Peter Mac AM, made over $470K available in 2008 has such a large-scale and dedicated Many thanks to the Director of Research: as peer-reviewed Foundation Grants to focus on cancer. Professor David Bowtell; the Deputy continued to be so evident throughout Director of Research: Professor Joe Trapani; support nine separate projects. In addition, Since 1949, we have continually refined the Assistant Director of Research: Assoc. as the sole fundraiser for Peter Mac, the 2008. We achieved much during the our model of care to increasingly focus Professor Ricky Johnstone; the Associate Foundation raised significant funds from on multi-disciplinary and evidence-based Director of Research and Director of both the community and corporate sectors year - we made solid progress in treatment protocols. In recent years, Commercialisation: Jerry de la Harpe; and to help fund research at Peter Mac. our aim to set national standards with the Chief Operating Officer (Research): The Foundation was also an important planning the new research facilities in our treatment protocols has become Mary Harney for their leadership of our source of funding support for key research increasingly evident in our integrated Research Division during the year. They technology platforms and items of the proposed comprehensive cancer approach to supportive care for various were well supported by all the Group equipment during the year. types of cancer. centre to be established at Parkville; Leaders and the other senior staff in the in Our researchers gratefully acknowledge Our co-ordinated treatment protocols the research and clinical divisions. the Foundation’s expertise in raising such our recent peer-reviewed grant benefit greatly from access to a broad Staff highlights monies, tapping into the broad support for range of vibrant clinical trials, which often our research activities across the Victorian Professor Joe Trapani was honoured by involve the use of new drugs, and from our community. successes continued; we finalised a the NHMRC with one of only seven peer- ability to translate our research findings reviewed Excellence Awards, granted to the into improved clinical practices. Strategic relationships number of commercial arrangements highest ranked recipients of their 2008 grants Peter Mac strives to work collaboratively At the laboratory, Peter Mac’s main and fellowships. Congratulations, Joe. with other cancer institutes and cancer- and we worked hard to enhance research themes include understanding Assoc. Professor Robin Anderson was related organisations, as well as with other the genetic basis of familial and sporadic awarded a prestigious National Breast medical research institutes and individual important strategic partnerships with cancers; identifying new bio-markers for Cancer Foundation Career Fellowship researchers. We have developed close early cancer diagnosis; advanced cancer in support of her research into breast relationships with the Victorian Cancer our peers, both in Australia and and molecular imaging; determining why cancer metastases. Agency and Cancer Australia and worked cancer cells resist certain drugs collaboratively during the year with the overseas, and with various branches and harnessing new immune-based Many of our other researchers also proponents of the New Sydney cancer therapies. distinguished themselves in 2008 and Cancer Centre. conveyed great credit on Peter Mac. of Government. I am very proud of our hard-working I congratulate them all. Thank You! researchers and their contributions, on Your interest in, and support of, research many fronts, to the fight against cancer. Our continued grant successes throughout at Peter Mac is much appreciated and 2008 are outlined throughout this report. Working towards a comprehensive continues to motivate and inspire our cancer centre in Parkville In addition, we welcomed Assoc. Professor researchers. Ygal Haupt from Israel to establish our Throughout 2008, a lot of very detailed I commend this report to you and hope Tumour Suppression Laboratory. work was undertaken on the Business that you will find it to be both interesting Case for the establishment of a world-class Research Advisory Committee and informative. comprehensive cancer centre at Parkville. The Research Advisory Committee, A key component of this centre would be chaired by Professor David Copolov: the re-located East Melbourne campus Deputy Chair of the Board of Directors, of Peter Mac. Discussions, negotiations provided rigorous oversight of our various and detailed analyses of various options Craig Bennett research activities during the year and were all undertaken in a positive and Chief Executive Officer advised the Board of Directors accordingly. constructive spirit, clearly demonstrating

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Harnessing the power of the Cancer Cell Death 14 Cellular Immunity 16 immune system to fight cancer. Immune Signalling 18 Immunotherapy Laboratory 20

For immunology research conducted within associated programs:

Gene Regulation, located in the Cancer Therapeutics Program 62 Haematology Immunology Translational Research, located in the Translational ‘Understanding the mechanisms behind the Research Program 70 eradication of viral infections and prevention of cancer by cytotoxic lymphocytes will improve the diagnostics of immune-mediated disease and allow the development of novel therapeutic strategies’.

Dr Ilia Voskoboinik Peter Mac Research Fellow Cancer Cell Death Laboratory

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Immunology Program/ 13 Cancer Immunology Program/ Cancer Cell Death

The Cancer Cell Death laboratory aims Research Overview Over the past decade or more, our up and scale up manufacture. Trials in an electrostatic (ionic) bond that stabilises – NHMRC Award for Excellence in Health to understand how the immune system Recent evidence has emerged that laboratory has also led the world in working experimental mouse models of disease the interaction. Katherine showed that and Medical Research. detects and kills cancerous and virus- the immune system plays a key role out the biochemical pathways activated will commence soon. In the context of perforin molecules that contained either – 3rd Annual HLH/CSL-Behring Lecturer of infected cells. We apply the knowledge in preventing or controlling cancer by by granzymes – showing that the principle cancer, perforin inhibitors may be useful two positive or two negative charges failed the Japan Hematology Society. to better understanding how cancer pro-apoptotic human granzyme (granzyme to block potentially life threatening graft- to polymerise, however reversal of the two detecting and destroying pre-malignant – Mentor, ASMR Professional Development drugs work, and how to optimise their B) powerfully activates a death pathway versus-host disease accompanying bone charges resulted in normal function. These or even malignant cells. Our laboratory is Program. use; developing new drugs to block the making headways in understanding how regulated by Bcl-2. The work is particularly marrow transplantation. In approximately studies form the basis of a collaboration Dr Nigel Waterhouse immune system in the case of graft- this cell death process works – which has important because many human cancers 30% of recipients, the replenished immune with Professor James Whisstock’s group versus-host disease (a common and major implications for the control of cancer. over-express Bcl-2 – and we are now system recognizes some of the recipient’s at Monash University, aimed at solving the – NHMRC RD Wright Fellowship 2005–09. serious complication of bone marrow determining how granzyme B and new tissue as foreign and attacks them. This crystal structure of the perforin monomer Dr Ilia Voskoboinik transplant); optimising immune-based We are particularly interested in the Bcl-2 inhibiting drugs can cooperate. can have severe consequences including and pore. [Reference: Baran K et al., – NHMRC RD Wright Career Development therapies of cancer and other diseases; molecular pathways used by certain cells skin reactions and bleeding from the Immunity 30: 684-95, 2009]. Award 2007–11. and understanding the basis of immune (CTL and NK cells) to induce death of 2008 Research Achievements gastrointestinal tract. Perforin elaborated affected cell. These cells synthesise and PRESENTATION HIGHLIGHTS deficiency related to perforin dysfunction. The First-Ever Small Molecule by activated immune cells is thought to GRANTS AND FUNDING store toxins – perforin and pro-apoptotic Inhibitors Of Perforin be responsible for some of this tissue Professor Joe Trapani RESEARCH FOCUS proteases known as granzymes – and – NHMRC Program Grant: $11.22 million, Perforin is critically important for damage. Additional benefits of developing – Keystone Symposia on Molecular release them when they make stable ‘Immune regulation, effector function and • Understanding the molecular basis of maintaining immune homeostasis and for perforin inhibitors may arise in other and Cellular Biology, Keystone, USA, contact with a target cell. Currently, we’re human therapy’, 2007–11. cancer cell death, which is brought on protection against intracellular pathogens, non-cancer-related diseases including February 2008 (Invited Plenary Lecture). working to determine how the protein – Juvenile Diabetes Research Foundation by cytotoxic lymphocytes and other particularly viruses. This is demonstrated juvenile onset diabetes and viral hepatitis. perforin forms pores in the target cell – Osaka Medical Institute for Maternal and Program Grant: $850,000, ‘Immune immune mediators. by the severe immune deficiency that [Reference: Lena G et al., (2009) Journal of membrane, allowing the passage of Child Health, Osaka, Japan, March 2008 mechanisms of beta-cell destruction’, occurs in children born with perforin Medicinal Chemistry 51: 7614-7624]. • Determining how a particular protein granzymes into the target cell, where cell (Invited Speaker). 2007–12. (perforin) exerts its cytotoxic effects, and deficiency, a rare condition known as death pathways are triggered. To date, – 3rd Annual HLH Lecture of the – Cancer Council Victoria Project Grant: relating its actions to specific domains hemophagocytic lymphohistiocytosis. we have developed a variety of ways to Japananese Hematology Society, Tokyo, $210,000, ‘Immunotherapy of Lewis Y+ and residues. Perforin can also cause tissue damage determine how perforin mutations are Japan, March 2008 (Keynote Speaker). malignancy using genetically engineered • Understanding the mechanisms (auto-immunity) if the immune response identified in children with the rare congenital – 8th EMBO Workshop on Cytotoxicity, T cells’, 2007–09. underpinning the mitochondrial pathway to viruses or self tissues is excessive or immune-deficiency HLH (hemophagocytic Cell Death and the Immune System, – NHMRC Fellowship (Senior Principal to apoptosis, particularly with respect inappropriate. To address some of the lymphohistiocytosis) – and how that results Zaragoza, Spain, September 2008; Research Fellow): $752,500, 2004–08. to Bcl-2-like pro-survival molecules deleterious effects of perforin, we screened in disordered cell function. (part of an international press briefing expressed by cancer cells. a library of 110,000 drug-like compounds – Leukemia and Lymphoma Foundation We are also working to treat/prevent life- held at The Walter and Eliza Hall Institute conducted by the Organising Committee). USA: USD600,000, ‘Redirected T cell • Developing small molecule perforin Figure 1: Intracellular localization of perforin in a rat threatening tissue damaged caused by to identify potent perforin inhibitors. basophilic leukemia (RBL) cell. The pore forming Dr Nigel Waterhouse therapy for multiple myeloma’, 2006–08. inhibitors to block CTL and NK function perforin by developing perforin inhibitors. protein perforin (red stain) is located in secretory A number of compounds have been – The European Workshop on Cell Death, – Cancer Research Institute USA: in various perforin mediated immune This development stands to save lives and developed through an iterative process lysosomes distinct from the endoplasmic reticulum (green stain) and golgi body (blue stain). Hauenstein, Germany, June 2008 (Invited USD450,000, 2007–10, (educational pathologies including severe graft- improve patient outcomes in cases such known as structure-activity relationships versus-host disease. Speaker/Session Chair). program for PhD and MD students). as kidneys undergoing graft rejection, (SAR) in collaboration with Professor Understanding the mechanism of – 7th International Cell Death Society pancreatic beta cells being killed in the Denny’s Medicinal Chemistry Group at pore-formation by perforin – NHMRC Project Grant: $450,000, Research Personnel Symposium, Shanghai, China, June 2008 course of type I diabetes, or where cells the Auckland Cancer Centre and ‘Mechanism and regulation of perforin Head The key molecular function of perforin (Invited Speaker). are being attacked by the immune system The University of Auckland. A number of function’, 2006–08. Professor Joseph Trapani is to permit pro-apoptotic granzymes during graft-versus-host disease – lead compounds that potently inhibit target passage into the cytosol of the target Dr Ilia Voskoboinik – NHMRC RD Wright Fellowship: $425,000, Senior Research Officers an often fatal complication of bone cell death mediated by CTL and NK cells cell, enabling them to access substrates – BIT’s World Cancer Congress, Shanghai, ‘Mechanisms and function of perforin, a Dr Vivien Sutton marrow transplantation. have been developed, some of which whose cleavage results in target cell China, June 2008 (Invited Speaker). key regulator of immune homoeostasis’, Dr Ilia Voskoboinik are under-going pharmacokinetic work death. Although the collaboration between – XXII International Congress of the 2007–11. Dr Nigel J. Waterhouse perforin and granzymes has long been Transplantation Society, Sydney, NSW, – NHMRC Project Grant: $323,000, ‘Project Research Officer recognised, the mechanism of synergy August 2008 (Invited Speaker). Grant Molecular mechanisms of death in Dr Sabine Hoves remains unclear. We have now taken a – 8th EMBO Workshop on Cytotoxicity, cells with defects’, 2007–09. major step in understanding this process, – NHMRC RD Wright Fellowship: $425,000, Research Assistants Cell Death and the Immune System, by determining the molecular basis for Zaragoza, Spain, September 2008 2005–09. Kylie Browne perforin pore formation. After its release, (Invited Speaker). – Peter Mac Foundation Project Grant: Jenny Chia perforin monomers bind to the target $12,500, ‘Bcl-2 inhibitors as modulators Annette Ciccone cell membrane in a calcium-dependent – Birkbeck College, University of London, of the anti-cancer immune response’, Karin Sedelies manner. Individual perforin molecules September 2008 (Invited Speaker). 2006–07. Kevin Thia then form ring structures (a pore) through Dr Katherine Baran Sandra Vershoor which granzymes enter the target cell. – PhD completion, The University of PUBLICATIONS AND PATENTS Postgraduate Students Katherine Baran performed a mutational Melbourne, 2008. Publications are listed at the end of the Desiree Anthony analysis of the perforin molecule and 150, 178, 190, 191, PRIZES AND AWARDS report and include references Katherine Baran identified two amino acids, Arg 213 and 255, 265, 292, 308, 322. Jenny Chia Glu 343 located on the front and back Professor Joe Trapani Olivia Susanto Left to right: Prof. Joe Trapani, Jamie Lopez, Daniella Brasacchio, Ilia Voskoboinik, Vivian Sutton, Diana of the perforin monomer, respectively. – National Health and Medical Research Motion, Olivia Susanto, Susie Roczo, Kylie Browne, Desiree Anthony, Wei Yeh, Amelia Brennan, Kevin Thia, When the monomers stack into a pore- PA to Professor Joseph Trapani Council (NHMRC) Senior Principal Sandra Verschoor. like structure, the positive and negative Diana Motion Research Fellowship 2004–08. charges on adjacent monomers provides

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Immunology Program/ Cancer Cell Death 15 Cancer Immunology Program/ Cellular Immunity

The Cellular Immunity laboratory RESEARCH OVERVIEW to mouse tumour necrosis factor-related safe and induces regression of established – Cancer Research Institute 16th Annual – National University of Singapore, undertakes basic and pre-clinical research While it is widely understood that the apoptosis-inducing ligand (TRAIL) tumours, while single agent treatment had Meeting, New York, USA, September Singapore (Invited Speaker). in cancer immunology, with a view to immune system has innate and adaptive receptor-2 (DR5) against ErbB2- little or no effect. These data demonstrate 2008 (Invited Plenary). GRANTS AND FUNDING combining new cancer immunotherapies driven breast cancer. Treatment with for the first time that combination therapies – 11th Meeting of the Society of Natural (memory) components that work together – Cancer Council Victoria: $300,000, with current first line cancer therapies. anti-DR5 or anti-ErbB2 mAb as single involving HDACi and activators of the Immunity, Fremantle, WA, October 2008 with cells that regulate these processes, it ‘Combined chemo-immunotherapies that is the coordination of these components agents significantly delayed tumour TRAIL pathway can be an effective cancer (Invited Symposium). RESEARCH FOCUS growth, although all tumours eventually treatment in experimental mouse models. eradicate established tumours’, 2008–10. and how they form an effective immune – 1st International Conference on Anti- progressed. Treatment with a combination – Association of International Cancer • Basic studies of the role of immunity in response to cancer that has remained Recognition of cancer by DNAM-1 cancer Chemo-immunotherapy, Paris, the tumour microenvironment. of anti-DR5 and anti-ErbB-2 mAbs induced Research (AICR 04–029): £183,000, ‘Can poorly understood – particularly at the DNAM-1, an adhesion molecule belonging France, October 2008 (Invited Plenary). level of the tumour microenvironment. complete response in a majority of mice. the immune system and tumour be in a • Immunosuppressive pathways that to the immunoglobulin (Ig) superfamily, – University of Adelaide Seminar Series, Our laboratory has made headway in In vivo blockade of CD11b+ cells, but not state of equilibrium’, 2008–10. prevent tumour regression. promotes many natural killer (NK) cells Adelaide, SA, November 2008 (Invited expanding knowledge in this field and in natural killer cell depletion, significantly – NHMRC Senior Principal Research • The biology of natural killer (NK) cells and CD8 T cell functions in vitro. To Speaker). uncovering new treatment modelling and abrogated the early anti-tumour response. Fellowship: $721,250, 2007–11. and NKT cells. Notably, depletion of CD8+ T cells address whether DNAM-1 has a unique – QIMR Seminar Series, Brisbane, unique therapy combinations. – NHMRC Program Grant: $2.162 million • Translational studies designing and provoked primary and secondary tumour function or is effectively redundant in vivo, November 2008 (Invited Speaker). With the wider goals of defining new and evaluated DNAM-1-deficient CD8 T cell per year ($10.81m over five years), testing new combination therapies pre- relapse, revealing the induction of anti- – 38th Annual Scientific Meeting of the more effective ways of harnessing immune and NK cell function in vitro and in vivo. ‘Immune regulation, effector function and clinically and clinically in cancer patients. tumour immunity by the combination Australasian Society for Immunology, system responses to kill cancer cells, Our results demonstrated that NK cells human therapy’, 2007–11. treatment. Combined therapy with anti-DR5 Canberra, ACT, December 2008 (Invited RESEARCH PERSONNEL we’re focusing our efforts on designing require DNAM-1 for elimination of tumour – Cancer Research Institute Post-doctoral and anti-ErbB-2 mAbs further significantly Plenary). Head and testing new combination therapies suppressed the growth of advanced cells that are comparatively resistant to Tumour Immunology Emphasis Program Professor Mark Smyth for cancer patients both in pre-clinical and spontaneous tumours in ErbB-2/neuT NK cell-mediated cytotoxicity due to the Dr Daniel Andrews (educational program for PhD and MD clinical environments. paucity of other NK cell activating ligands. – 11th Meeting of the Society of Natural students): $450,000, 2007–10. Postdoctoral Fellows transgenic mice, even when treatment was We conclude that DNAM-1 serves to Immunity, Fremantle, WA, October 2008 Dr Daniel Andrews Our approach includes novel combinations delayed until tumours were palpable. We – NHMRC Project Grant: $525,000, extend the range of cells that can activate (Invited Speaker). Dr Nicole Haynes of agents not being used elsewhere; thus demonstrated that the combination ‘Determining the mechanisms that of anti-DR5 and anti-ErbB2 mAbs might CD8 T cell and NK cells and hence may be – 38th Annual Scientific Meeting of the regulate long-term anti-viral immunity, Dr John Stagg state-of-the-art models of cancer and essential for immunosurveillance against Dr Trina Stewart immunodeficiency in mice for modelling be an effective new form of treatment for Australasian Society for Immunology, 2007–09. ErbB-2-overexpressing breast cancer tumours that evade recognition by other Canberra, ACT, December 2008 (Invited Dr Michele Woei Ling Teng treatment and toxicity and assessing activating or accessory molecules. – Susan G. Komen Breast Cancer Dr Adam Uldrich mechanism of action; state-of-the-art (see Fig 1). Speaker). Foundation Program Grant: $US250,000, monoclonal antibodies and access ‘Combination immunotherapy of Research Assistants Combination chemo-immunotherapy PRESENTATION HIGHLIGHTS Dr Nicole Haynes to humanised reagents; and rational of established cancer – 38th Annual Scientific Meeting of the established breast cancer’, 2006–08. Ming Li Professor Mark Smyth dissection of key genetic pathways. Although histone deacetylase inhibitors Australasian Society for Immunology, – Susan G. Komen Breast Cancer Nicole McLaughlin – Keystone Symposia on Molecular (HDACi) and activators of the TRAIL Canberra, ACT, December 2008 (Invited Foundation Program Grant: $US600,000, Suzanne Medwell 2008 RESEARCH ACHIEVEMENTS and Cellular Biology, Keystone, USA, pathway have different molecular targets Speaker). ‘Combination chemo-immunotherapy for Janelle Sharkey February 2008 (Invited Symposium). Sally Watt Dual antibody treatment of breast and mechanisms of action, they share Dr Trina Stewart established breast cancer’, 2008–11. cancer the ability to induce tumour cell-selective – National University of Singapore, PhD Students – 38th Annual Scientific Meeting of the – National Institutes of Health: $US800,000, Despite the development of human apoptosis. This year we demonstrated that Singapore, April 2008 (Invited Speaker). Desiree Anthony Australasian Society for Immunology, ‘The regulation of tumour immunity by epidermal growth factor receptor-2 the HDACi vorinostat synergises with a – WEHI Immunology Seminar Series, Paul Bolitho Canberra, ACT, December 2008 (Invited NKT cells’, 2004–08. (ErbB-2/HER2) targeted therapies, mouse DR5-specific monoclonal antibody Melbourne, Vic, May 2008 (Invited Ailsa Frew Speaker). – Novartis: $368,000, ‘Combination studies there remains an unmet medical need to induce rapid and robust tumour cell Speaker). -– Department of Immunology & with LBH589 and the XIAP inhibitor Honours Students for breast cancer patients with ErbB-2 apoptosis in vitro and in vivo. Importantly, – Hanson Institute Seminar Series, Microbiology Seminar Series, University LBW242 and the agonist anti-DR5 Chris Chan overexpression. We investigated the using a pre-clinical mouse breast cancer Adelaide, SA, May 2008 (Invited of Melbourne, November 2008 (Invited antibody MD5.1 with Novartis’, 2007–08. therapeutic activity of an agonist mAb model, we show that the combination is Speaker). Laboratory Manager Speaker). – Peter Mac Foundation: $300,000, Jason Brady – Immunology Victoria Master Class in Dr Michele Teng ‘Immunotherapy of kidney cancer’, Immunology, Melbourne, Vic, July 2008 Animal Technician – 38th Annual Scientific Meeting of the 2007–09. (Invited Symposium). Michelle Stirling Australasian Society of Immunology, – Canadian Institutes of Health Research – Latrobe University, Melbourne, Vic, Administrative Assistant Canberra, ACT, (Speaker). Fellowship: CAD$45,000 pa, 2007–09. August 2008 (Invited Speaker). Belinda Kelly – US Army Breast Cancer Concept Award: $US75,000, ‘Role of CD73 (ecto-5- nucleotidase) in breast cancer and characterization of anti-CD73 monoclonal antibody (mAb) therapy’, 2008. PUBLICATIONS AND PATENTS Publications are listed at the end of the report and include references 4, 5, 6, 43, 51, 52, 56, 100, 106, 130, 132, 133, 154, 160, 226, 268, 270, 273, 277, Left to right: Prof. Mark Smyth, Michelle Teng, Daniel Andrews, Nicole McLaughlin, Upulie Divisekera, Chris 278, 279, 286, 287, 288, 293, 294, 296, 299, 319, 322. Chan, Trina Stewart, Francisca Go, Melvyn Chow, Claire Cotterill, Belinda Kelly, Michelle Stirling, Jason Figure 1: Anti-ErbB-2 and anti-DR5 monoclonal antibodies (mAbs) Brady, Ming Li, Bianca Von Scheidt, Nicole Haynes, Shin Foong Ngiow, Jenna Langfield, John Stagg. synergize in vivo to induce tumour cell death.

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Immunology Program/ Cellular Immunity 17 Cancer Immunology Program/ Immune Signalling

Studying how the shape of immune cells RESEARCH OVERVIEW 2008 RESEARCH ACHIEVEMENTS efforts. Of particular excitement is a new PRESENTATION HIGHLIGHTS PRIZES AND AWARDS influences response to an environment, approach that can improve the resolution Our laboratory’s chief interest is how the Mouse models to elucidate how Dr Sarah Russell Dr Jane Oliaro the Immune Signalling laboratory recently of fluorescence approximately ten-fold. fate of lymphocytes is controlled by cell polarity affects immune function – 20th Lorne Cancer Conference, Lorne, – NHMRC Career Development Award I uncovered new ways that cell shape The power of this advance is such that shape (polarity). and cancer. Vic, February 2008 (Speaker). (CDA-1), 2008–11. influences immune function – with major the technique has been given the name We have spent considerable effort over potential for cancer treatment. During the past year, we discovered a ‘Super-Resolution Microscopy’ (see Fig 1). – Hunter Valley Cell Biology Conference, Dr Edwin Hawkins the last five years — in collaboration with novel means by which cell fate in immune NSW, April 2008 (Invited Speaker). – NHMRC Australian Biomedical the Cell Cycle and Cancer Genetics group To enable Peter Mac researchers to utilize RESEARCH FOCUS cells (lymphocytes) is controlled. Known – Gene Expression and Signalling in the Fellowship 2008–11. as asymmetric cell division, the process [see pg 50] — toward developing mouse this technology before it becomes widely • Basic research into the cell biology of models with which to understand how the available to biologists, we are working with Immune System, CSHL Meeting, New Faruk Sacirbegovic immune cell development, function and uses cell shape (polarity) to ensure the York, USA, April 2008 (Invited Speaker). two daughters of a dividing lymphocyte polarity proteins orchestrate development physicists at Swinburne to create a Super- – Harold Mitchell Travel Fellowship, 2008. cancer. – IgV (Immunology Group of Victoria) adopt different cell fates. This observation, and function of cells in vivo, and we Resolution Microscope. We were awarded – ASI Postgraduate Student Travel Annual Retreat, Yarra Valley, Vic, October • Developing new microscopic is considered a major breakthrough, and are now making some very interesting funding for this project from the NHMRC Fellowship, 2008. 2008 (Invited Speaker). technologies to study immune cell is now a significant focus for our Immune discoveries regarding their role in immune GRANTS AND FUNDING biology. Signalling laboratory. function. Generally, it seems that immune – Cell Shape and Polarity: Lymphocytes • Testing the role of tumour suppressor cells can develop in the absence of and Beyond, Chicago, USA, September – NHMRC Project Grant: $376,125, ‘A Another key discovery in the past year genes such as Scribble in immune cell immune proteins, but the behavior of the 2008 (Invited Participant). novel mechanism for the regulation of T stemmed from our work, and interest in biology. cells upon activation is altered. These – 11th Annual Australian Cell Cycle cell shape and function’, 2006–08. a group of proteins that regulate polarity findings are particularly exciting because • Identifying a role for asymmetric cell Workshop, Melbourne, Vic, November – NHMRC Project Grant: $481,500, in epithelial cells, and also act as tumour they show that these mouse models division in immune cell development, 2008 (Invited Speaker). ‘Competition for polarity influences suppressors in the vinegar fly (see Cell will make valuable tools with which to function and cancer. lymphocyte signalling and function’, Cycle and Development and Cell Cycle dissect the role of polarity in leukemia and Dr Jane Oliaro 2007–09. RESEARCH PERSONNEL and Cancer Genetics laboratories lymphoma. We are now working with other – Lymphocyte Activation and Signalling, pgs 48-51). researchers across Peter Mac to explore Keystone Symposia on Molecular – Cancer Council Victoria: $210,000, ‘A Head the impact of polarity disruption upon and Cellular Biology, Keystone, USA, new role for polarity proteins in leukemia/ Dr Sarah Russell Our recent discovery that this polarity February 2008 (Speaker). lymphoma’, 2007–09. network operates in T cells sparked new cancer progression using a number of Senior Research Officer research in our laboratory into whether different models of leukemia. in 2008. – Gene Expression and Signalling in the – ARC Project Grant: $263,000, ‘A Dr Jane Oliaro Immune System, CSHL Meeting, New novel role for Scribble and Dlg in cell these proteins control T cell fate, and also Illuminating T cell polarity and function Figure 1: These images show a T cell dividing Postdoctoral Fellows act as tumour suppressors in lymphocytes. while attached to an antigen presenting cell York, USA, April 2008 (Poster). protrusions’, 2007–09. As highlighted by a Nobel Prize to the demonstrating asymmetric distribution of the cell Dr Edwin Hawkins – Human Frontiers Research Program, in We’ve formed an active collaboration discoverers of Green Fluorescent Protein fate determinant, Numb. Asymmetric cell division – ComBio, Canberra, ACT, September Dr Betty Kouskousis is a potential means for generating the different collaboration with Swinburne University with researchers in the Centre for in 2008, time-lapse, fluorescent imaging 2008 (Speaker). Dr Kerrie-Ann McMahon types of T cells required for an effective immune of Technology and University of California MicroPhotonics at Swinburne University of living cells provides incredibly powerful Dr Edwin Hawkins response. Berkeley: US$1,050,000, ‘Testing the Visiting Scientist of Technology to develop new imaging opportunities to learn how cell behaviour – New Directions in Leukemia Research role of cell polarity during thymocyte Dr Ze’ev Bomzon technologies, such as multiphoton is controlled. Much of our efforts in the lab Conference, Sunshine Coast, Qld, April development’, 2007–10. Patrick Metz intravital microscopy, microfabrication involve using such approaches, facilitated 2008 (Speaker). for live imaging, and laser tweezers by the excellent infrastructure at Peter – NHMRC Project Grant: $528,750; Senior Research Assistant Kim Pham – for application in our studies of the Mac, to define the mechanisms by which Asymmetric cell division in T cells Mandy Ludford-Menting – Australasian Society for Immunology mechanisms of polarity and T cells. cell fate is controlled. However, there (508973)’, 2008–10. (ASI) 38th Annual Meeting, Canberra, Research Assistants continues to be a burning need to improve – Commercializing Emerging Technologies ACT, December 2008 (Poster). Olivia Cakebread these technologies, and we work with Grant: $70,400, 2008. Vanessa van Ham our colleagues at Swinburne University Faruk Sacirbegovic PUBLICATIONS AND PATENTS Postgraduate Students of Technology on a number of such – 4th International Conference on Gene Anupama Pasam Regulation in Lymphocyte Development, Publications are listed at the end of the 129, 261, 262, 311. Kim Pham Rhodes, Greece, October 2008 report and include references Faruk Sacirbegovic (Speaker). Raz Shimoni – Inaugural Melbourne Cell and Administrative Assistant Developmental Biology Meeting, Belinda Kelly Melbourne, Vic, November 2008 (Speaker). Laboratory Manager Jason Brady

Left to right: Dr Sarah Russell, Jane Oliaro, Stephen Ting, Kim Pham, Raz Shimoni, Mandy Ludford- Menting, Faruk Sacirbegovic, Kerrie-Ann McMahon, Edwin Hawkins, Vanessa van Ham.

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Immunology Program/ Immune Signalling 19 Cancer Immunology Program/ Immunotherapy Laboratory

The Immunotherapy laboratory focuses RESEARCH OVERVIEW CD137 injection led to activation of Adoptive transfer of gene-modified – Peter MacCallum Cancer Center Junior on preclinical development of novel Our ongoing research seeks to turn the dendritic cells and optimal expansion primary NK cells can specifically Investigator Award, $100,000 p.a, inhibit tumour progression in vivo immune therapies for cancer with the aim disease-fighting capacity of the immune of activated T cells in the blood. Gene 2006–09. of translating the most effective treatments system against cancer cells by using expression analysis revealed that CpG Natural Killer (NK) cells hold great potential Dr Maria Moeller into the clinic. upregulated a variety of genes, with those for improving the immunotherapy of anti-cancer genes to provide immune cells – ASI International Postdoctoral Travel associated with macrophage biology cancer. Nevertheless, tumour cells can with the ability to recognise and destroy Award. RESEARCH FOCUS being particularly well represented, but effectively escape NK cell mediated tumour cells. – CASS Foundation International Travel • Anti-cancer gene design. subsequent studies demonstrated that apoptosis through interaction of MHC Current studies in the lab include the depletion of macrophages in vivo led to molecules with NK cell inhibitory receptors. Award. • Testing various gene-modified immune following four areas: an enhancement of therapy, which has Thus, to harness NK cell effector function Hollie Pegram system cells to eradicate cancer in Figure 2: Micrograph of mouse brain. The brown not been previously reported. Long-term against tumours, we employed Amaxa preclinical animal models. (1) Anti-cancer gene design, where staining in this photo is due to the presence of – ASI International Postgraduate Travel molecular biology techniques are used surviving mice were resistant to tumour gene transfer technology to gene-modify the human growth factor receptor, Her-2, that is Award. • Development of novel combination rechallenge, demonstrating immunological primary mouse NK cells with a chimeric expressed on the surface of some cells in the to create the most potent cancer killing Sally Amos therapies against cancer. memory. In addition, we demonstrate, for single chain (scFv) receptor specific for the cerebellum of a transgenic strain of mouse. The molecules. growth receptor is also present on cells of the – Jomar Biosciences Award for • Translation of basic research discoveries the first time, that mice lacking B cells have human erbB2 tumour-associated antigen. mouse breast. This mouse was made by genetic into clinical practice. (2) Cell selection, where different immune a total loss of a recall response against The chimeric receptor was composed engineering to provide a good model to study Outstanding Presentation, IgV system cells are used including natural tumour, suggesting a role for B cells in the of the extracellular scFv anti-erbB2 breast cancer. conference, Beechworth, 2008. RESEARCH PERSONNEL killer cells, dendritic cells and several types induction of anti-tumour immunological antibody linked to the transmembrane and PRESENTATION HIGHLIGHTS GRANTS AND FUNDING Head of T cells. memory. This study provides support cytoplasmic CD28 and TCR-z signaling – Susan G. Komen Breast Cancer Dr Phillip Darcy (3) Combination therapies, where gene- for the use of combination treatments domains (scFv-CD28-z). In this study Dr Phillip Darcy Foundation Grant: ‘Combining vaccines Assoc. Professor Michael Kershaw modified immune cells are combined with stimulating multiple facets of immunity for we demonstrated that mouse NK cells – European Society of Gene and Cell and adoptive T cell transfer for breast Research Officer drugs or vaccines to produce the optimal the effective immunotherapy of cancer. gene-modified with this chimera could Therapy Congress, Brugge, Belgium, specifically mediate enhanced killing of cancer immunotherapy’, 2007–10. Dr Maria Moeller anti-tumour treatment. Particular cancers Combining adoptive immunotherapy November 2008 (Speaker). an erbB2+ MHC class I+ lymphoma in a –Bob Parker Memorial Foundation Grant: being addressed in this section are colon with Toll-like receptor (TLR) agonists – 2nd Australasian Vaccines and Research Assistants perforin-dependent manner. Expression $100,000 pa, ‘Developing improved cancer, kidney cancer, breast cancer and for the treatment of melanoma in mice Immunotherapeutic Development Dr Linda Berry of the chimera did not interfere with NK immunotherapies for kidney cancer’, multiple myeloma. Adoptive immunotherapy is showing great Meeting, Surfers Paradise, Qld, May Jenny Westwood cell-mediated cytotoxicity mediated by 2008–10. (4) Clinical translation, in which final promise for the treatment of melanoma 2008 (Speaker and Session Chair). Postgraduate Students endogenous NK receptors. Furthermore, – National Breast Cancer Foundation preparations of genes and cells are made although current treatment regimens are – Australasian Society for Immunology Sally Amos adoptive transfer of gene-modified NK (NBCF) and NHMRC Career ready for use in clinical trials. associated with significant side effects, and (ASI) Tumour Immunology Workshop, Hollie Pegram cells significantly enhanced the survival Development Award: $85,000 tumour regressions are not always long Canberra, ACT, December 2008 of RAG mice bearing established pa, ‘The development of effective 2008 RESEARCH ACHIEVEMENTS lasting. In attempts to enhance adoptive (Speaker). intraperitoneal RMA-erbB2+ lymphoma. immunotherapies for cancer’, 2004–08. immunotherapy, we have combined T Toll-like receptor triggering and T cell In summary, this data suggests that – ASI Tumour Immunology Workshop, cell transfer with intratumoural injection – NHMRC Career Development Award: costimulation induce potent anti- utilization of genetically modified NK Canberra, ACT, December 2008 (Session of TLR agonists that mimic infection. We $85,500 p.a., ‘Preclinical characterization tumour immunity in mice Chair). cells could broaden the scope of cancer of gene-engineered T cells for To simultaneously direct multiple immune have shown that approximately 20% of immunotherapy for patients. Assoc. Professor Michael Kershaw immunotherapy of cancer’, 2004–08. components against cancer we combined mice can achieve long-term regression of – Hunter Medical Research Institute, the Toll-like receptor agonist CpG 1826 established melanoma using this therapy. – NHMRC Project Grant: $92,250 p.a., Newcastle, NSW, September 2008 with a T cell costimulatory antibody In addition, we have demonstrated that ‘Generating tumour-specific dendritic (Invited Speaker). specific for CD137. This combination was interferon produced by the transferred cells for cancer therapy, 2007–09. demonstrated to eradicate established T cells plays a crucial role in the anti- Sally Amos – Cancer Council of Victoria Grant in malignancies in mice. Crucial roles for tumour effects. – Immunology Group of Victoria (IgV) Aid: $70,000 p.a., ’Immunotherapy of CD8+ T cells, NK cells and interferons Conference, Beechworth, Vic, October Lewis Y+ malignancy using genetically were demonstrated. CpG and anti- 2008 (Speaker). engineered T cells’ 2007–09. Hollie Pegram PUBLICATIONS AND PATENTS – IgV Conference, Beechworth, Vic, Publications are listed at the end of the Figure 1: Micrograph of mouse kidney cancer October 2008 (Speaker). 59, 161, 226, 279, showing cancer cells, blood vessels and white report and include references blood cells. This is an image of a section through – 20th Lorne Cancer Conference, Lorne, 322, 325. an established kidney cancer from a mouse. Many Vic, February 2008 (Poster). tumour cells can be seen with a characteristic punctate nucleus and some can be seen in mitosis. PRIZES AND AWARDS There are numerous leukocytes also present, which are evident from their darker and smaller nuclei. Dr Phil Darcy This picture shows that tumours can be a diverse – National Health and Medical Research mixture of different cell types including immune system cells, but that the presence of immune cells Council (NHMRC) Career Development is not enough to reject the tumour. Award (CDA2), 2004–08. Assoc. Professor Michael Kershaw – NHMRC Career Development Award (CDA2), 2004–08. Left to right: Dr Phil Darcy, Assoc. Prof. Michael Kershaw, Linda Berry, Leanne Wang, Sally Amos, Holie Pegram, Connie Duong, Jenny Westwood.

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Immunology Program/ Immunotherapy Laboratory 21 Cancer Genetics & Genomics Program/

Using sophisticated VBCRC Cancer Genetics 24 Cancer Genetics & Genomics 26 high-throughput genomic Surgical Oncology Laboratory 28 technologies to improve our Sarcoma Genomics & Genetics 30 understanding of cancer. kConFab 32 kConFab Follow-up Project 34

‘My key ambition is to prevent cancer from occurring by improving early detection through the identification of individuals at higher risk of developing the disease. It is an exciting time to do cancer research. We’re in an era where amazing technological advances are occurring as fast as in the computer industry. We are able to perform experiments in a week, that a year ago we did not think were even possible’.

Professor Ian Campbell Head, VBCRC Cancer Genetics

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Genetics & Genomics Program/ 23 Cancer Genetics & Genomics Program/ VBCRC Cancer Genetics

The major focus of the VBCRC (Victorian RESEARCH OVERVIEW We conducted a high-resolution LOH – American Association for Cancer Breast Cancer Research Consortium) Our strong recent studies put the VBCRC analysis using SNP arrays of 106 primary Research Annual Meeting, San Diego, Cancer Genetics Laboratory is the Cancer Genetics laboratory at the forefront ovarian tumours of various histological USA, April 2008 (Invited Speaker) identification of genes involved in the of identifying cancer-causing genes in breast subtypes together with matching normal – Queenstown Molecular Biology Meeting, predisposition, initiation and progression and ovarian cancers. DNA (see Fig 1). LOH was detected in at Queenstown, New Zealand, September of breast and ovarian cancer. least 35% of samples on chromosomes 2008 (Speaker). Using an integrative genomics approach to 17, 19p, 22q, Xp, 13q, 8p, 6q, 4q, 5q, – Marsha Rivkin Cancer Center Ovarian RESEARCH FOCUS investigate genes, we’re looking at data from 1p, 16q, and 9q with a median minimal Cancer Research Symposium, Seattle, several genome-wide array based platforms region of overlap of only 300 kb. We • Integrated genomic analysis to identify USA, September 2008 (Invited Speaker). genes involved in breast and ovarian in combination to more rapidly define the also identified 192 somatic homozygous – The Royal Women’s Hospital Research carcinogenesis. critical cancer-causing genes. The laboratory deletions (HDs). Recurrent HDs targeted has invested heavily in array based methods known TSGs such as CDKN2A (eight Symposium, Melbourne, Australia, • Genome-wide genome copy number of analysing gene copy number, loss of samples), RB1 (five samples), and PTEN August 2008 (Invited Speaker). analysis of breast ductal carcinoma heterozygosity (LOH), gene promoter hyper- (three samples). Additional recurrent HDs in situ to identify markers of disease Dr Kylie Gorringe methylation and microRNA expression. targeted 16 candidate TSGs near minimal progression. – 20th Lorne Cancer Conference, Lorne, In particular, we’ve been leading the regions of LOH on chromosomes 17, 13, Vic, February 2008 (Poster). • Identification of epigenetic and miRNA 8p, 5q, and X. Given the importance of application of ultra-high resolution SNP – Familial Cancer Research & Practice targets in primary ovarian cancer- HDs in inactivating known genes, these arrays containing over 1.8 million probes, for Combined Meeting, Couran Cove, Qld, associated fibroblasts. candidates are highly likely to be ovarian the purpose of identifying highly informative August 2008 (Poster). • Identification of genes involved in breast micro-deletions and amplifications in TSGs. Our data suggest that the poor cancer predisposition. primary cancer samples. The work has success of previous LOH studies was due PRIZES AND AWARDS to the inability of previous technology to RESEARCH PERSONNEL provided previously unobserved, and Assoc. Professor Ian Campbell surprising, insights into the somatic genetics resolve complex genomic alterations and – NHMRC Senior Research Fellowship, Head of cancer, which are expected to prove distinguish true LOH from allelic imbalance. 2008–12. Professor Ian Campbell particularly helpful in rapidly identifying novel This study shows that recurrent regions of alterations are extremely rare in CAFs and Figure 1: Prevalence of LOH and copy LOH and HD frequently align with known strongly refute the theory of stromal cell number loss in ovarian cancer. Frequency plot Research Fellow cancer-associated genes. Candidate genes of LOH (red) and copy number loss (blue) in GRANTS AND FUNDING TSGs suggesting that LOH analysis co-evolution. 106 cases of ovarian cancer analyzed by SNP Dr Kylie Gorringe are now under investigation for the presence – National Health and Medical Research of somatic alterations in primary breast and remains a valid approach to discovering arrays and compared with their matching normal Research Assistants Identification of BRCAX lymphocyte DNA. Council (NHMRC) Project Grant: ovarian cancers. new cancer biomarkers. Samantha Boyle Germline mutations in BRCA1 and BRCA2 $392,500, ‘Genome-wide SNP analysis Identification of genetic alterations in confer a high risk of breast cancer but Role of microRNAs in ovarian cancer David Choong 2008 RESEARCH ACHIEVEMENTS of fibroblasts juxtaposed or distant from cancer associated fibroblasts (CAFs) many high-risk breast cancer families There is accumulating evidence that epithelial breast and ovarian tumours’, Postgraduate Students Molecular Basis of Carcinoma There is an emerging literature suggesting (referred to as BRCAx families) do not microRNAs may function like classical 2006–08. Jennifer Bearfoot Promotion by Cancer Associated tumour suppressor genes but little that fibroblasts surrounding epithelial harbour mutations in either of these genes. – NHMRC Project Grant: $531,250, Joyce Lin Fibroblasts is known about their mechanism of malignancies may promote tumourigenicity This discrepancy indicates that at least one ‘Genome-wide study of loss of Wen Qiu inactivation in cancer cells. Ten cancer- Ovarian cancer is characterized by and that this attribute is acquired through more high penetrance breast cancer gene heterozygosity using high density Manasa Ramakrishna implicated microRNA genes were analysed complex genetic alterations, including somatic mutation of genes in stroma cells. remains to be identified. We have been SNP arrays to identify breast cancer Ella Thompson for somatic mutations in 93 ovarian copy number loss and copy number- Previous studies suggesting that somatic utilising ultra-high resolution LOH and copy predisposition genes’, 2006–08. neutral loss of heterozygosity (LOH). These alterations are very common in CAFs are number analysis of tumours from within epithelial cancers — matching normal – NHMRC Project Grant: $1,645,000, ‘A alterations are assumed to represent the potentially flawed, so we embarked on a BRCAx families to identify common regions DNA. High-resolution melt analysis and randomised Phase III study of radiation ‘‘second hit’’ of the underlying tumour definitive study using high resolution SNP of LOH. We have developed protocols to direct sequencing revealed numerous doses and fractionation schedules in suppressor gene (TSG), however, relative arrays. Our analysis of CAFs and tumour utilise DNA extracted from formalin-fixed germline base substitutions, deletions non-low risk ductal carcinoma in situ to the number of LOH hotspots reported, epithelia from breast and ovarian cancers paraffin-embedded tissues and have and insertions surrounding the mature (DCIS) of the breast’, 2007–11. few ovarian TSGs have been identified. has convincingly shown that somatic completed analysis of 65 BRCAx families. microRNA sequences. Novel germline Data analysis is correlating common variants were detected but these were – VBCRC Project Grant: $3 million, regions of loss within and between also found in the same proportion of ‘Identification of genes involved in families. Analysis of several candidate non-cancer control individuals, suggesting predisposition, initiation and progression genes has begun. they do not represent ovarian cancer of breast and ovarian cancer’, 2005–09. predisposing alleles. The absence of – NHMRC Project Grant: $523,500, ‘High somatic mutations in any of the ten resolution genome-wide genomic cancer-implicated microRNAs in our large analysis of DCIS to identify genes cohort of ovarian tumours suggests that involved in disease initiation and this may be an uncommon mechanism of progression’ 2008–10. inactivation of microRNAs. – NHMRC Senior Research Fellowship: PRESENTATION HIGHLIGHTS $595,000, 2008–12. Assoc. Professor Ian Campbell PUBLICATIONS AND PATENTS – Otago Genomics Facility Microarray Publications are listed at the end of the Meeting, Dunedin, New Zealand. report and include references 21, 38, 114, 115, Left to right: Prof. Ian Campbell, Ella Thompson, Kylie Gorringe, Sally Davis, David Choong, Georgina February 2008 (Invited Speaker). 116, 117, 244. Ryland, Manasa Ramakrishna, Samantha Boyle. Absent: Jennifer Bearfoot, Wen Qiu

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Genetics & Genomics Program/ VBCRC Cancer Genetics 25 Cancer Genetics & Genomics Program/ Cancer Genetics & Genomics

Our laboratory focuses on the molecular RESEARCH OVERVIEW Current studies focus on Siah’s role in laboratory. The assay development was Insights Into Cancer Using Genomic traits of ovarian and gastric cancer, and Our laboratory is discovering molecular tumour angiogenesis and inflammation. led by Dr Richard Tothill, in collaboration analysis of gastric cancer, Singapore, cancers of unknown primary site, as well subtypes of particular ovarian cancers in We are developing small molecule with Adam Kowalczyk (NICTA) and July 2008 (Invited Speaker). as understanding the role of the Siah E3 inhibitors in collaboration with the Centre Circadian Technologies. The partnership our efforts to understand the makeup of GRANTS AND FUNDING ligases in cancer progression. these cancers, and we are pursuing similar for Cancer Therapeutics (Institute of Cancer with Healthscope is expected to result in outcomes for gastric cancers. Research, UK). release of the diagnostic test in 2010. – DoD (US Department of Defense) RESEARCH FOCUS Translational Research Partnership: • Genomic characterisation of human We are particularly focused on the molecular 2008 RESEARCH ACHIEVEMENTS SIAH PROTEINS AS THERAPEUTIC US$750,000, ‘Genetic Profiling in the characterisation of key mutational events in TARGETS IN BREAST CANCER AND ovarian and gastric cancer. Molecular Analysis of Invasive and Australian Ovarian Cancer Study’, ovarian cancer where there are other clinical MELANOMA Borderline Malignant Serous Ovarian 2008–11. • Coordination of the Australian Ovarian conditions, such as women with primary or Cancer Tumour hypoxia induces the up-regulation – Cancer Australia: $600,000, ‘Germline Cancer Study cohort. acquired chemotherapy resistance. of Hif-1alpha, which in turn induces the BRCA1and BRCA2 Mutations in the • Development of a molecular diagnostic Ovarian cancer is the fifth most common Our work is based on an outstanding expression of genes including VEGF Australian Ovarian Cancer Study’, for cancers of unknown primary. cause of cancer deaths in women in resource – the Australian Ovarian Cancer Western countries. Of these, serous to recruit new blood vessel outgrowth, 2008–2010. • Biochemical and functional Study (AOCS) – which has enabled us to ovarian cancer accounts for approximately enabling tumour growth and metastasis. – NHMRC Project Grant: $545,500, characterisation of Siah E3 ligases in create the largest gene expression dataset 60—70% of all deaths and is an especially The hydroxylation of Hif-1alpha by PHD ‘Inhibitors of Siah Ubiquitin Ligase’, cancer models. for ovarian cancer to date. This research important histological subtype. Using proteins during normoxia serves as a 2008–10. • Development of novel small molecules has been supported by a DoD Translational Affymetrix microarrays, we generated recognition motif for its proteasomal – NHMRC Project Grant: $830,000, targeted to the Siah proteins. Research Partnership grant worth the largest gene expression dataset for degradation. Under hypoxic conditions, ‘Molecular Epidemiology of Ovarian US$750,000 between 2009 and 2011. serous cancers to date and linked this hydroxylation is inhibited and PHD proteins RESEARCH PERSONNEL Cancer: The Australian Ovarian Cancer to patient outcome, for the first time are themselves poly-ubiquitylated and We are working towards similar goals in Study National Clinical Follow-Up Core’, Head identifying novel molecular subtypes of targeted for degradation by Siah ubiqiuitin gastric cancer, which is one of the three 2006–10. Professor David Bowtell serous cancers. We identified a group of ligases. Led by Dr Andreas Moeller and most common causes of cancer death Colin House, we found that inhibition of the – NHMRC Enabling Grant: $1,000,000, Research Fellows serous invasive cancers that resembled in the world. The gastric cancer program interaction between Siah and PHD proteins ‘Australian Ovarian Cancer Study A Dr Michael Anglesio cancers of low malignant potential (LMP), is led by Associate Professor Alex interferes with the PHD degradation, Multi-disciplinary Ovarian Resource for Dr Rita Bustill and appear to have progressed from these Boussioutas, a specialist gastroenterologist the Genomics Area’, 2006–10. Dr Dariush Etemadmoghadam less malignant tumours. In subsequent decreased up-regulation of Hif-1alpha and clinician-researcher. Figure 1: Expression profiling of invasive serous Colin House experiments we characterized these LMP- target genes, and reduced tumour growth. – CASS Project Grant: $50,000, 2008–09. ovarian cancer (SOC) and serous borderline/low Reduced metastases were seen in Dr Andreas Möller Siah proteins function as ubiquitin E3 like invasive tumours and their precursors. malignant potential ovarian tumours (SBT/LMP): – NHMRC Project Grant: $535,500, melanoma in collaborative experiments Dr Richard Tothill ligases and have been shown to bind to In collaboration with the laboratories of (A) Unsupervised clustering using gene expression ‘Molecular markers of the progression of a wide range of potential substrates in in Assoc. Professor Georgia Chenevix-Trench data segregates LMP and SOC tumours while with Professor Ze’eve Ronai’s laboratory Senior Research Officers identifying a subset of histologically invasive SOC intestinal metaplasia to gastric cancer’, vitro assays. Research from our laboratory and Dr Anna DeFazio, we identified novel at the Burnham Institute for Medical Sian Fereday with an expression profile indistinguishable from 2007–09. and collaborative studies have identified mutations in ErbB2 in LMP tumours, further LMPs - highlighted in orange on the left side of the Research (USA). Nadia Traficante – NSW Cancer Council: $299,650 the mechanism of interaction of Siah with implicating ras-pathway mutations in the dendrogram. (B) The expression signature related ‘Chemo-sensitising pathways in ovarian Research Officer substrates; defined the 3D structure of the genesis of LMP and LMP-like invasive to MAP-kinase regulation is strongly evident within PRESENTATION HIGHLIGHTS the groups of co-regulated genes. [Reference: cancer’ 2007–09. Deborah Giles Siah substrate-binding domain; generated tumours. The preponderance of ras- Anglesio et al. 2008 Molecular Cancer Research]. Professor David Bowtell – Peter Mac Foundation Grant: $192,000, Research Assistants germline mutant mice and demonstrated a pathway mutations in LMP and some – 20th Lorne Cancer Conference, Lorne, ‘BRCA1 and BRCA2 genotyping of Leanne Bowes striking role for Siah proteins in regulating invasive serous cancer suggests that a DEVELOPMENT OF A DIAGNOSTIC Vic, February, 2008 (Invited Speaker). HIF1a-mediated responses in hypoxic subset of women with ovarian cancer may TEST FOR CANCERS OF the Australian Ovarian Cancer Study’, Laura Galetta – 29th Lorne Genome Conference, Lorne, Joy Hendley cells via targeting of PHD proteins for benefit from novel ras pathway inhibitors UNKNOWN PRIMARY 2007–09. Vic, February, 2008 (Invited Speaker). Reynolds Jeremy degradation. (see Fig 1). Cancers of unknown primary (CUP) – NHMRC Project Grant: $496,500, ‘Role – Ovarian Cancer Action International Mira Liu are cancers in patients with metastatic of Siah proteins in inflammation and Conference, London, UK, March, 2008 disease where the site of the primary or cancer’, 2006–08. Postgraduate Students (Invited Speaker & Moderator). Kathryn Alsop originating cancer is difficult to determine. – NHMRC Project Grant: $432,500, Joshy George Deaths from CUP in Western countries – 2nd International Ovarian Cancer ‘Combined Expression Analysis and Christina Wong are surprisingly common; in Australia Conference, Rhodes, Greece, June, SNP-based measurement of copy no 2008 (Invited Speaker). Research Associate CUP are the third most common cause variation in Ovarian Cancer’, 2006–08. of cancer deaths. In a large proportion Dr Andreas Möller Dr Alex Boussioustas PUBLICATIONS AND PATENTS of the patients, the site of origin of their – Keystone Conference Inflammation, Visiting Scientist cancer remains unknown despite intensive Microenvironment and Cancer, Salt Lake Publications are listed at the end of the Dr Åslaug Helland 7, 32, 33, 151, 152, investigation. Reliable identification of the City, USA, April 2008 (Poster). report and include references site of origin of the cancer is important to 158, 185, 203, 209, 217, 218, 222, 224, 243, 249, 307, 340. Executive Assistant to Professor Bowtell Dr Michael Anglesio Linda Stevens enable more directed therapy, understand Patent: Profiling of tumours potential initiators of the cancer, reduce – Combined Meeting of KConFab, patient morbidity associated with lengthy Australian Ovarian Cancer Study & Inventors: David Bowtell, Richard Tothill, diagnostic procedures, and to determine Family Cancer Clinics of Australia & New Andrew Holloway, Ryan van Laar, Adam whether CUP tumours have shared Zealand, Couran Cove, Qld, August Kowalcyk. 2008 (Invited Speaker). Left to right: Prof. David Bowtell, Laura Galetta, Linda Stevens, Prue Cowin, Christina Tucci, Michael biology. We have formed a partnership • Australian patent 2004219989. Anglesio, Joy Hendley, Sian Fereday, Kathryn Alsop, Elizabeth Loehrer, Dariush Etemadmoghadam, Alexandria McGeary, Joshy George, Christina, Wong, Mira Liu, Colin House, Jaclyn Sceneay, Rita Bustil, with Healthscope, a leading pathology Dr Alex Boussioutas Andreas Moeller, Alex Boussioustas, Leanne Bowes. provider in Australia, to make available a – 1st Annual Scientific Meeting of diagnostic test for CUP developed in our Singapore Gastric Cancer Consortium,

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Genetics & Genomics Program/ Cancer Genetics & Genomics 27 Cancer Genetics & Genomics Program/ Surgical Oncology Laboratory

The Surgical Oncology laboratory uses RESEARCH OVERVIEW Oncology and Gastrointestinal Services. introduction of Cre replaces the wild-type of human oesophageal cells, enabling PRIZES AND AWARDS molecular and cellular approaches In collaboration with clinical colleagues, exon 20 with a duplicate exon encoding us to study the processes involved in the Our laboratory is leading research Dr Mirette Saad to understand the development and the laboratory is developing genomic the PIK3CAH1047R mutation. development of the normal oesophageal into particular signalling pathways in a – NHMRC Postgraduate Research progression of gastrointestinal cancers approaches to predict a patient’s clinical epithelium and the mechanisms underlying bid to better detect and treat cancers. We have prepared murine embryonic Scholarship, 2008. and to identify new treatments. response to chemo-radiotherapy in pathogenic processes such as Barrett’s Specifically, we’ve held a long- fibroblasts (MEFs) from these mice and order to help improve the management metaplasia or tumourigenesis (see Fig 2). standing interest in the role of the P13K confirmed that the introduction of Cre GRANTS AND FUNDING RESEARCH FOCUS of patients with advanced gastrointestinal (phosphoinositide 3-kinase) signalling results in the deletion of the wild-type exon – National Health and Medical cancers. • PI3-kinase signalling pathway. pathway in the development and 20 and insertion of the mutated exon in its Research Council (NHMRC) Project progression of human tumours. • Barrett’s Oesophagus. 2008 RESEARCH ACHIEVEMENTS place. The advantage of our ‘exon-switch’ Grant: $542,750, ‘Biological and We are interested in the biological and strategy is that the mutation is inserted clinical characterisation of human RESEARCH PERSONNEL A novel model of PIK3CA mutation clinical significance of somatic mutations into the endogenous gene and thus the phosphatidylinositide 3-kinase Head in cancer in the PI3K gene, PIK3CA, in human mutant allele will be expressed only in the mutations’, 2006–08. Assoc. Professor Wayne Phillips Phosphoinositide 3-kinases (PI3Ks) cancers. Current projects are aimed at same cells, and at the same levels, as the – NHMRC Project Grant: $277,500, ‘In vivo are a ubiquitous family of lipid kinases Research Officers understanding the significance of these wild-type gene. The ability to target the models for understanding the cellular that catalyse the phosphorylation of Dr Kate Brettingham-Moore mutations, which in turn will help us identify expression of the mutant to specific tissues and molecular pathogenesis of Barrett’s phosphatidylinositides at the 3 position of Dr Nicholas Clemons novel markers for diagnosis, prognosis and developmental stages makes this Oesophagus’, 2006–08. the inositol ring. The class 1a PI3Ks exist Dr Ivan Ivetac and early detection of cancer and enable mouse a powerful model for studying the as a heterodimer consisting of a 85 kDa – NHMRC Project Grant: $450,000, Dr Anjali Tikoo a rational approach to the design of new role of PIK3CA mutations in cancer regulatory sub-unit (p85) and a 110 kDa ‘Predicting response to anti-cancer therapies. (see Fig 1). Research Assistants catalytic sub-unit (p110) and are activated chemoradiotherapy in patients with Karen Montgomery Another of our laboratory’s interests is by receptor tyrosine kinases. The lipid Figure 2: In Barrett’s oesophagus (BO) the advanced rectal cancer’, 2008–10. Sarah Sawyer Barrett’s Oesophagus – a metaplastic, squamous epithelium of the normal oesophagus products of PI3Ks activate a variety of (yellow star, A) is replaced with an epithelium – ARC Discovery Grant: $400,000, ‘The Postgraduate Students premalignant abnormality that makes downstream targets that regulate a wide similar to that found in the intestine (red star, B). role of retinoic acid signaling in the Ms Lauren Hare patients 100 times more likely to develop range of important cellular processes, BO develops due to reflux induced changes to development of the oesophageal oesophageal adenocarcinoma. including cell proliferation, migration and stem cells that reside in either the basal layer of the epithelium’, 2008–10. Dr Mirette Saad squamous epithelium (black arrow, A) or the gland survival. We, and others, have previously duct (blue arrow, A inset), which connects to – Cancer Council NSW Strategic Research Advanced Medical Science Students Our laboratory has developed novel cell identified somatic mutations in PIK3CA, sub-mucosal glands (red arrows). Partnership Grant: $1,250,000, ‘PROBE- Jellyca Anton, Universitas Indonesia culture systems that allow the layered the gene coding for the p110α subunit of NET: Progression of Barrett’s Esophagus (2007–08) structure of the normal oesophageal PI3K, in a number of common human PRESENTATION HIGHLIGHTS to Cancer Network’, 2008–12. Lucia Cochrane-Davis, University of epithelium to be reproduced in the laboratory. We can use these models tumours, including breast and colorectal Assoc. Professor Wayne Phillips Melbourne (2008–09) cancers. These mutations are all single PUBLICATIONS AND PATENTS to better understand the molecular – 16th Seminars in Operative Surgery, amino acid substitutions, with over 85% and cellular processes involved in the Adelaide, SA, March 2008 (Invited Publications are listed at the end of the occurring in two ‘hot spots’ located in 57, 58. development of Barrett’s Oesophagus Speaker). report and include references and ultimately contribute to designing exons 9 and 20, and are assumed to have an important role in driving tumour – Royal Melbourne Hospital, Melbourne, For more information on related strategies for the management and Vic, April 2008 (Invited Speaker). research, see: treatment of Barrett’s Oesophagus development. To investigate this, we have – Queenstown Signal Transduction – Cancer Therapeutics Program [pg 62] and the prediction and/or prevention generated a novel mutant mouse with a Meeting, Queenstown, New Zealand, of the progression of this condition to Cre recombinase (Cre)-inducible ‘knock-in’ – Gastrointestinal [pg 110] of the most common tumour-associated September 2008 (Invited Speaker). oesophageal adenocarcinoma. Figure 1: Murine mammary epithelial cells grown PIK3CA mutation, PIK3CAH1047R. Prior to – Australian and New Zealand Hepatic, The Surgical Oncology laboratory has in 3D culture form spherical colonies of polarised Cre-mediated recombination the wild-type cells known as acini. Shown are acini formed by Pancreatic and Biliary Association Annual close links with the Division of Surgical exon 20 is normally expressed, while the mammary epithelial cells grown from (A) wildtype Meeting, Coolum, Qld, October 2008 H1047R and (B) PIK3CA mutant mice. (Invited Speaker). 3-D cultures of human oesophageal – 4th Australian Health and Medical epithelium Research Congress, Brisbane, Qld, (In collaboration with Dr Pritinder Kaur, November 2008 (Invited Speaker). Epithelial Stem Cell Biology Laboratory, Dr Nicholas Clemons see pg 56) – 20th Lorne Cancer Conference, Lorne, A novel three-dimensional in vivo transplant Vic, February 2008 (Poster). culture system has been developed for Dr Mirette Saad growing primary oesophageal epithelial – 20th Lorne Cancer Conference, Lorne, cells isolated from human tissue Vic, February 2008 (Poster). samples. Cells grown in this model form a multilayered, stratified epithelium which – Queenstown Signal Transduction recapitulates many of the structural Meeting, Queenstown, New Zealand, and histological features of the normal September 2008 (Invited Speaker). oesophageal epithelium. This unique Left to right: Assoc. Prof. Wayne Phillips, Shze Yung Koh, Vincent Roh, Thang Tran, Rachel Greaney, Kate culture system will allow us to model (and Brettingham-Moore, Lauren Hare, Karen Montgomery, Nick Clemons, Anjali Tikoo, Ivan Ivetac. Absent: Mirette Saad. manipulate) the growth and differentiation

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Genetics & Genomics Program/ Surgical Oncology Laboratory 29 Cancer Genetics & Genomics Program/ Sarcoma Genomics & Genetics

The Sarcoma Genomics and Genetics RESEARCH OVERVIEW underway to understand the mechanism identified in regions commonly amplified with vessel density, circulating markers Dr Andrew Holloway laboratory undertakes research into the The focus of our research is to understand by which this molecule works (see Fig 1). and over expressed in WDLPS. In the third of hypoxia and tumour growth. These – International Mesothelioma Interest inherited and somatic genetic causes the biology and genetics of sarcomas, project, we used the Victorian Centre for studies revealed a very high incidence Group Conference, Amsterdam, The of sarcoma. Our research program is with a focus on osteosarcoma and Functional Genomics (VCFG) genome- of PET-detectable hypoxia in primary Netherlands, October 2008 (Invited founded on the Australasian Sarcoma liposarcoma. We aim to translate these wide library of short-haipin RNAmirs to sarcomas (46%), which has adverse Speaker). Study Group (ASSG), a national screen for novel modulators of Nutlin-3a clinical significance. Patients with hypoxia observations into innovative clinical Dale Garsed cooperative research group which acts as sensitivity. Collectively this information will are more likely to demonstrate resistance research that will improve outcomes for – AMATA Meeting, Dunedin, New Zealand, a conduit for early phase clinical research patients with sarcomas. refine our understanding of liposarcoma to radiotherapy, or early relapse. arising from basic discoveries. development, and enhance the rational November 2008 (Speaker). We also have a strong interest in the design of therapies for this tumour (see PRESENTATION HIGHLIGHTS PRIZES AND AWARDS RESEARCH FOCUS broader area of adolescent and young Fig 2). Assoc. Professor David Thomas adult oncology, including public health Assoc. Professor David Thomas • High-throughput somatic and germline – 29th Lorne Genome Conference, Lorne, policy, health services research, and – Victorian Cancer Agency, Clinical screening for sarcoma genes. Vic, February, 2008 (Invited Speaker). cancer epidemiology. Researcher Fellowship, 2008–10. • In-depth biologic analyses on candidate – AMGEN Oncology Symposium, Sydney, – Associate Professor with title of genes. 2008 RESEARCH ACHIEVEMENTS NSW, February 2008 (Invited Speaker). Principal Research Fellow, University of • Translation of basic research discoveries WIF1 as a potential therapeutic in – European Society of Medical Oncology/ Melbourne. into clinical practice. osteosarcoma. CONTICANET Faculty Meeting Program, GRANTS AND FUNDING • Developing a collaborative research Previous studies in the laboratory Milan, Italy, May 2008 (Invited Speaker infrastructure nationally and identified the gene Wnt inhibitory factor and Session Chair). – Cancer Australia: $220,000, Australian internationally to undertake basic, 1 (WIF1), a secreted inhibitor of the Wnt – American Society of Clinical Oncology Sarcoma Study Group (ASSG), 2008. translational and clinical research into Pathway, to be silenced by promoter Annual Meeting, Chicago, USA, June – Cancer Council Victoria: $210,000, ‘The sarcomas. methylation in osteosarcoma. Silencing 2008 (Speaker). Role of WIF1 in osteosarcoma’, 2007–09. RESEARCH PERSONNEL of WIF1 was associated with loss of – RMIT University School of Medical – Department of Industry, Innovation, WIF1 protein expression, impaired Sciences Research Seminars, Head Figure 1: Osteosarcoma cell line B143 treated with Research and Development: $480,000, differentiation and increased proliferation. Wnt3A (right panels) and WIF1 (left panels). A and Melbourne, Vic, August 2008 (Invited ‘Functional Genomics: shRNA library’, Assoc. Professor David Thomas In osteosarcoma cell lines, we found that B are images taken by phase contrast microscopy. Figure 2: Metaphase fluorescence in situ hybridisation (M-FISH) analysis of well-differentiated Speaker). 2006–08. Research Fellows over expression of WIF1 or treatment with C & D shows b-catenin as fluorescence green staining. E & F show heat maps of high intensity liposarcoma cells. These tumours are characterised – Queensland Cancer Council Sam – NHMRC Project Grant: $340,500, recombinant WIF1 protein suppressed by the presence of giant marker chromosomes Dr Maya Kansara b-catenin staining red. Images are taken by Sciacca Lecture, Brisbane, Qld, August colony formation and cell growth in (mar 1 and 2), which are made up of interspersed ‘Identification of amplified oncogenes in Dr Andrew Holloway confocal microscopy. 2008 (Invited Speaker). osteosarcoma cell lines. Importantly, Wif1 regions of various chromosomes. liposarcoma’, 2008–10. Research Assistants Well-differentiated liposarcoma knockout mice were predisposed to the Denosumab in giant cell tumour – Molecular Biology and Therapeutics of – NHMRC Project Grant: $386,625, ‘In vivo Dale Garsed (WDLPS) genomics. development of both spontaneous and of bone. Musculoskeletal Oncology, September, modelling of WIF1 in bone development Sophie Young We have undertaken three projects using Salt Lake City, USA (Invited Speaker and radiation induced osteosarcoma. We This world-first study was led from our and tumourigenesis’, 2008–10. modern genomic technologies to uncover Session Moderator). Postgraduate Students now have data to suggest that systemic group in the Peter Mac, and demonstrated – Novartis: $100,000, ‘Development of in the molecular basis of WDLPS. In the first Nick Fleming administration of recombinant WIF1-Fc an 87% response rate in patients with – GEIS (Spanish Group for Research of vivo models for liposarcoma’, 2008. project, we are using a combination of Dr Ken Khamly protein in an orthotopic mouse model unresectable, advanced giant cell tumour Sarcomas) Annual Meeting, Madrid, chromosome flow sorting and massively – Peter MacCallum Cancer Centre Genni Newnham of human osteosarcoma dramatically of bone. The outcomes of the study were Spain, November 2008 (Invited Speaker). parallel sequencing to fine-map the Foundation, Edna and Murray Dunn suppresses primary osteosarcoma reported as an oral presentation at the – Annual Seminar Day, Israeli Society Honours Students architecture of WDLPS neochromsomes at Award: $35,000 per year, Fellowship growth and increases survival in a dose American Society of Clinical Oncology of Pediatric Hematology/Oncology, Aurelie Coppin the single nucleotide level. In the second 2006–11. dependent manner. This makes WIF1 a annual meeting in 2008. The Manuscript Jerusalem, Israel, November 2008 Hannah Wang project, we are using RNA interference to – Pfizer Investigator Initiated Grant clinically appealing drug candidate for has been submitted to the Journal of (Invited Speaker). functionally validate potential oncogenes scheme: $293,000 ‘Neoadjuvant sunitnib osteosarcoma and further studies are Clinical Oncology. – Connective Tissue Oncology Society and radiotherapy in resectable soft-tissue Hypoxic imaging of sarcomas. Annual Meeting, London, UK, November sarcoma’, 2007–09. This program is based upon the 2008 (Speaker). – Victorian Cancer Agency Clinician observation that many sarcomas are – Australian Health and Medical Research Scientist Fellowship, $150,000 per year, hypoxic, that radiotherapy is mitigated Conference, Brisbane, Qld, November 2008–10. in the presence of hypoxia and the 2008 (Invited Speaker). PUBLICATIONS AND PATENTS development of novel therapies targeting Dr Maya Kansara tumour vasculature. We have accrued – Models and Mechanisms of Cancer, Cold Publications are listed at the end of the 30, 67, 122, 162, 10 patients in a pilot study utilising Spring Harbor Laboratory, New York, report and include references 214, 344, 345. 18F-azamycin arabinoside and PET to USA, August 2008 (Poster). image hypoxia in patients with sarcoma

undergoing pre-operative radiotherapy. – Peter MacCallum Cancer Centre This study is designed to establish Workshop Symposium, Wilson’s the incidence of hypoxia, its relation to Promontory, Vic, October 2008 (Invited radiosensitivity of sarcomas, correlations Speaker).

Left to right: Assoc. Prof. David Thomas, Sally Whyte, Sophie Gatenby, Mandy Ballinger, Mohammed Sufian, Brianna Hay, Richard Tothill, Sophie Young, Dale Garsed, Andrew Holloway, Myrella Vlenterie, Maya Kansara.

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Genetics & Genomics Program/ Sarcoma Genomics & Genetics 31 Cancer Genetics & Genomics Program/ kConFab

The Kathleen Cuningham Foundation RESEARCH OVERVIEW 2008 RESEARCH ACHIEVEMENTS The option of surgery or radiotherapy did In the last two years, very rapid progress GRANTS AND FUNDING Consortium for Research into Familial not offer any significant advancement has been made by the international breast At present kConFab is supplying biological Loss of Heterozygosity at the BRCA2 – National Health and Medical Research Breast Cancer (kConFab) brings together specimens and data to more than 75 locus detected by MLPA is common in influencing survival. However, when cancer research community in identifying Council (NHMRC) Enabling Grant: geneticists, clinicians, surgeons, genetic research projects worldwide – and we in prostate cancers from men with a compared to non-curative options, patients additional genes that predispose to breast $500,000, ‘kConFab, the national counsellors, psychosocial researchers, continue to make data and biospecimens germline BRCA2 mutation. who chose surgery or radiotherapy had a cancer. kConFab has played an important consortium for research into familial pathologists and epidemiologists from better chance of survival. Regardless of part in this work by participating in two widely available for use in peer-reviewed, Our research work has found a new risk breast cancer’, 2008. all over Australia and New Zealand. They any treatment, BRCA2 mutation in prostate huge international consortia, the Breast ethically approved projects on familial factor in the development of prostate believe the causes and consequences cancer confers a mean survival of 4.8 Cancer Association Consortium (BCAC) – NBCF Enabling Grant: $243,000, aspects of breast cancer. cancer. Prostate cancer risk is increased of familial predisposition to breast and years only. Research publications of this and the Consortium of Investigators of ‘kConFab, the national consortium for for men carrying a pathogenic germline ovarian cancer can be understood only First established in 1997, working in data are under preparation. Modifiers of BRCA1/2 (CIMBA). In total, ten research into familial breast cancer’, mutation in BRCA2. Our primary aim was by a national effort at both the basic and conjunction with family cancer centres new breast cancer predisposition genes 2008. to test for loss of heterozygosity (LOH) Low risk genes and high risk genes clinical levels. across Australia and New Zealand, we have been identified by BCAC, and most at the locus of the mutation in prostate PUBLICATIONS AND PATENTS began enrolling families with a strong During the last 10-20 years, researchers of these have also been shown by CIMBA cancers from men who carry a pathogenic RESEARCH FOCUS history of breast and breast/ovarian cancer from all over the world have worked to influence the age of onset of breast Publications are listed at the end of the germline mutation in BRCA1 or BRCA2, 9, 36, 69, 75, 98, to capture genetic, epidemiological, together to identify those individuals at cancer in carriers of BRCA1 and BRCA2 report and include references • Germline screening for the known genes and to assess clinical and pathological 101, 152, 153, 185, 188, 280, 285, 304, 316, 324, 334. medical and psychosocial data – with greatest risk of developing life-threatening mutations. However, the effect of each such as BRCA1 and BRCA2 implicated features of these tumours. We examined information stored in a de-identified fashion diseases. We now know that, in most one of these newly-found genes on breast in the causation of breast and ovarian LOH at the BRCA1 and BRCA2 genes of in a central relational database. To date, we cases, the risk of developing a disease is cancer risk is very small, and it is likely cancer, and a gene discovery search for DNA from microdissected tumour. LOH at have accumulated data on more than 1400 determined by a combination of genetic that many more such genes remain to be new cancer susceptibility genes. BRCA2 was observed in 10/14 tumours multigenerational, multicase kindreds. susceptibility (‘nature‘) and environment found. For this reason, these new genes • To develop predictive risk models to from BRCA2 mutation carriers (71%), while (‘nurture‘). For some diseases, a single are not being used clinically in Australia to determine which mutation carriers are Biospecimens collected from family no LOH at BRCA1 was observed in four environmental factor – such as smoking in predict a woman’s breast cancer risk, at risk of developing breast or ovarian members are helping characterise tumours from BRCA1 mutation carriers lung cancer – is very strongly associated cancer and at what age. germline mutations in predisposing (p=0.02). with risk. In the case of breast and BCAC and CIMBA, along with consortia genes such as BRCA1 and BRCA2, and studying prostate and ovarian cancer, have • Delivery of clinically significant research This is the first study to demonstrate LOH ovarian cancer, environmental or lifestyle supporting the search for new genes that recently received a large grant from the mutation test results back to the clinic in prostate tumours of known BRCA2 risk factors turn out to be only weakly are involved in the development of breast European Commission to continue their and family. pathogenic mutation carriers at the related to the risk of developing disease. and ovarian cancer. work. The main aims of the project will be • Translation of basic research discoveries specific mutation locus. We have extended Instead, much of the risk of developing to identify more breast cancer susceptibility into clinical practice such as new this study to now include 36 men with a breast cancer seems to be genetic. In the genes, and to work out whether women targeted therapies like the PARPi pathogenic BRCA2 mutation and have last decade, several genes e.g (BRCA1 who carry particular versions of these new inhibitors. performed extensive clinical follow up by and BRCA2) have been identified that predispose strongly to breast cancer. ‘low risk’ genes are more liable to develop • To develop a resource to promote reviewing all treatment report for this group However, only about 30% of kConFab breast cancer if they are subjected to collaborative basic, translational and of men to determine the most effective families carry mutations in these genes. particular lifestyle or environmental risk clinical research into familial breast and type of treatment linked to survival. The So what genes are responsible for breast factors. ovarian cancer. clinical follow up data demonstrated that cancer in the rest of the families? the behaviour of carriers of a BRCA2 PRESENTATION HIGHLIGHTS RESEARCH PERSONNEL prostate cancer revealed a natural history Heather Thorne Head and progression which was quite different Professor Joe Sambrook from the general population. It affected – National Breast Cancer Foundation & younger men at diagnosis and has a 45% Prostate Cancer Foundation of Australia Research Manager mortality rate (16 of 35). What seemed to Annual General Meeting, Walter and Eliza Heather Thorne be important was the choice of treatment. Hall Institute, Melbourne, Vic, October Research Assistants 2008 (Key Speaker). Kirsty Baron – National Prostate Consortium Annual Lana Djandjgava Meeting November 2008 (Speaker). Danni Surace Dr Amber Willems Lynda Williams Data Manager Eveline Niedermayre

Left to right: Lynda Williams, Lana Djandjgava, Danni Surace, Kirsty Baron, Heather Thorne, Eveline Niedermayre, Amber Willems.

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Genetics & Genomics Program/ kCONFAB 33 Cancer Genetics & Genomics Program/ kConFab Follow-up Project

The kConFab Follow Up project RESEARCH OVERVIEW qualitative research with clinicians, which The Prognosis of kConFab Women PRESENTATION HIGHLIGHTS PUBLICATIONS AND PATENTS researches the clinical consequences of has shown that many do not discuss these With Breast Cancer Does Not Seem The kConFab Follow Up project continues Dr Katherine Field Publications are listed at the end of the having a hereditary predisposition to breast preventive medications with their patients. To Influence Their Decision To Have 45, 69, 181, 232. to collect data on participants, who took – American Society for Clinical Oncology report and include references cancer and the non-genetic factors that The research uncovered several modifiable Contralateral Prophylactic Mastectomy part in the original study, with funding from (ASCO) Annual Meeting, Chicago, USA, might modify cancer risk. Data on the risk barriers to discussing chemoprevention About 15% of women in kConFab have the National Health and Medical Research June 2008 (Speaker). management behaviours and outcomes Council (NHMRC), which has funded the in medical consultations and we are now contralateral prophylactic mastectomy after of kConFab participants is collected every work since 2001. working with groups nationally to try to lift their initial diagnosis of breast cancer. This PRIZES AND AWARDS three years. these barriers. This research was featured decision to have prophylactic contralateral Participants continue to be followed up in a broadcast of the Health Report on mastectomy does not seem to be Assoc. Professor Kelly-Anne Phillips RESEARCH FOCUS every three years, with data collected Radio National 4/8/2008, accessible influenced by the prognosis of their initial – Dr John Colebatch Clinical Research Fellowship, Cancer Council Victoria, • Prospective evaluation of the effect of using a self report questionnaire to on: [www.abc.net.au/rn/healthreport/ breast cancer or their BRCA1 or BRCA2 2006–10. non-genetic potential risk modifiers gather information on any new cancers stories/2008/2320385.htm]. mutation status. Younger women with such as risk-reducing surgery, that have occurred; any change to the breast cancer diagnosed in more recent Dr Katherine Field family history; uptake of risk reduction Overscreening with mammography is chemoprevention, reproductive years are the most likely to choose to have – American Society of Clinical Oncology surgery, chemopreventive agents and common in mutation negative women factors, exogenous hormones, alcohol, contralateral prophylactic mastectomy. Merit Award. cancer screening; use of exogenous from families that carry a BRCA1 or cigarettes, exercise. BRCA2 mutation Tamoxifen and Risk of Contralateral hormones, reproductive factors, exercise; GRANTS AND FUNDING • Prospective determination of penetrance use of cigarettes and alcohol; and use of Women from families with a mutation in Breast Cancer In BRCA1 and BRCA2 of BRCA1 and BRCA2. complementary and alternative therapies. BRCA1 or BRCA2 are considered at high Carriers – National Health and Medical Research • Evaluation of prevalence and Clinical details and pathology reports risk for the development of breast cancer This international study led from Peter Mac Council (NHMRC): Project Grant, predictors of use of various cancer risk are also sought for new cancers, and unless they themselves are found not to is using data from three major international $698,575, ‘kConFab Follow-Up Project: management strategies, including risk- pathology and operative reports are harbour the family mutation, in which case cohorts of BRCA mutation carriers to a prospective study of non-genetic risk reducing surgery, chemoprevention and collected for risk-reducing surgery. they are generally considered to be at only evaluate whether tamoxifen is an effective modifiers in women at high risk for breast cancer screening. average risk for breast cancer. We have secondary prevention strategy in BRCA cancer’, 2007–09. The Follow Up project works closely with shown that of these mutation negative carriers. RESEARCH PERSONNEL the kConFab core but is a separately women at average risk, approximately 50% For further breast cancer research see funded entity. overscreen with mammography up to three Head Breast Service [pg 108] and Familial Assoc. Professor Kelly-Anne Phillips years after learning their mutation negative 2008 RESEARCH ACHIEVEMENTS Cancer Centre [pg 92]. result. The reasons for this are uncertain Project Manager Breast Cancer Chemoprevention and are the subject of further research, but Prue Weideman Medication Is Infrequently Used by these results suggest that such women Research Assistants Australasian Women at High-Risk for may require an approach to mutation result Lucy Burnham Breast Cancer disclosure, counselling and follow-up that Kate Lucas The tablet medications, tamoxifen and is different from the one currently being used. Joanne McKinley raloxifene, taken daily for five years, Half Of Women At High Risk For Breast reduce the risk of breast cancer by up Student Cancer Use Complementary And to 50%. We have shown that only 1% of Dr Belinda Kiely (Breast Cancer Genetics Alternative Medicines women in kConFab who are at high risk and Survivorship Fellow) Our study has shown that 48% of for breast cancer use these preventive women at high risk for breast cancer use treatments. This is much lower than in complementary and alternative medicines most other countries. This finding in the (CAM). These treatments are unproven kConFab cohort led us to undertake further so it is reassuring that only 11% do so specifically in the belief that it will reduce their risk of breast cancer. This research highlights the need for doctors to enquire about CAM use when taking a medical history from high risk women, given the potential for drug interactions.

Assoc. Professor Kelly-Anne Phillips Left to right: Kate Lucas, Prue Weideman, Lucy Burnham, Joanne McKinley. Head, kConFab Follow-Up Project

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Genetics & Genomics Program/ kCONFAB Follow-up Project 35 Growth Control & Differentiation Program/

Understanding protein Protein Chemistry 38 Growth Control 40 chemistry, signal transduction, Molecular Oncology 42 cell biology and how these processes affect differentiation and cancer cell growth.

‘The motivation that comes from knowing that our work can have a major impact on the understanding and treatment of cancer, ultimately benefiting patients, makes being part of the Peter Mac research team a very rewarding experience’.

Dr Kathy Jastrzebski Growth Control & Differentiation Program, & Cancer Council Victoria Venture Project

Peter MacCallum Cancer Centre – Research Report 2008 Growth Control & Differentiation Program/ 37 Growth Control & Differentiation Program/ Protein Chemistry

The major focus of the Protein Chemistry RESEARCH OVERVIEW contribution made by the mTOR pathway cellular phenotypes including sensitivity Joanna Chan Dr Mirette Saad laboratory is to understand the molecular The availability of functional ribosomes and uncontrolled growth signalling. with pathway inhibitors, mutation status – 20th Lorne Cancer Conference, Lorne, – National Health and Medical Research basis of the regulation of the PI3K/Akt/ of candidate genes, global gene copy is a fundamental rate-limiting step for The Protein Chemistry laboratory and Vic, February 2008 (Poster). Council Biomedical Postgraduate mTOR/S6K signalling pathway and to number and mRNA expression patterns growth and proliferation in mammalian other groups have shown that the mTOR Sandy Hung Scholarship. use this knowledge to address how and metabolic activity (see Fig 1). cells. Seminal findings on the regulation of pathway is activated in >65 per cent of deregulation of this process may contribute – 20th Lorne Cancer Conference, Lorne, GRANTS AND FUNDING S6K during previous studies identified the ovarian cancers. Our research aims to Defining the role of the PI3K/AKT/ to cancer. Vic, February 2008 (Poster). mTOR/S6K pathway as a key regulator of take a range of complimentary cell biology, mTOR/S6K pathway in the regulation – NHMRC Project Grant: $511,500, Rachel Lee ribosome function. ‘Deregulation of ribosome signalling, RESEARCH FOCUS biochemical and genomic approaches to of ribosome synthesis and function characterize the role of activation of this in cancer – European Association of Cancer synthesis and function during malignant • Understanding the signal transduction The recent studies conducted in the Researchers-20th Conference, Lyon, transformation’, 2006–08. Protein Chemistry laboratory show that the pathway in tumourigenesis and to identify The PI3K/AKT/mTOR/S6K pathway is a pathways underpinning cell growth France, July 2008 (Poster). – NHMRC Project Grant: $542,750, mTOR pathway also regulates ribosome key pathways that also contribute to the key regulator of ribosome synthesis and control. ‘Biological and clinical characterisation biogenesis, thus acting as a hub for development of ovarian cancer. It is hoped function and hence protein synthesis and Jane Lin of human phosphatidylinositol 3-kinase • Biochemical and cell biology analysis coordinating nutrient and growth factor that these studies will provide a basis for cell growth. Our recent studies have shown – 20th Lorne Cancer Conference, Lorne, mutations’, 2006–08. of the role of deregulated cell growth in signalling to cell growth. generation of new therapeutics useful for that the oncogenic kinase AKT is sufficient Vic, February 2008 (Poster). cancer. second-line treatment of this cancer. to drive these processes in the absence of – The Beatson International Cancer – Cancer Council Victoria Venture A major focus of our laboratory research • Cell biology and genomic research into growth factors. Strikingly, this increased cell Conference, Glasgow, UK, June 2008 Grant: $1,200,000, ‘Identification of is working to understand the basic 2008 RESEARCH ACHIEVEMENTS the pathogenesis of ovarian cancer. growth is independent of its activation of (Poster). novel breast cancer suppressor and mechanisms by which mTOR regulates cell mTOR. Until now, the only factor identified chemotherapeutic drug sensitivity • High throughput functional screens to Systematic analysis of the – 11th Annual Australian Cell Cycle growth and how this couples to regulated to be sufficient to modulate all steps genes using shRNA-mediated functional identify novel genes important in breast transforming pathways in ovarian Workshop, Melbourne, Vic, November cell proliferation. Cells actively monitor their cancer required for the formation of functional genomics screens’, 2007–10. and ovarian cancer. ability to make ribosomes, rapidly arresting 2008 (Poster). The PI3K/AKT/mTOR pathway has been ribosomes is the proto-oncogene and in the cell cycle when ribosome biogenesis – NHMRC Project Grant: $562,750, RESEARCH PERSONNEL implicated as a major determinant of transcriptional regulator c-MYC. These PRIZES AND AWARDS is compromised but before the level of ‘Mechanisms of control of cell growth oncogenic transformation in ovarian studies place AKT alongside c-MYC as Head ribosomes is affected. Understanding the Assoc. Professor Rick Pearson and proliferation by the AKT kinase cancer. Recent studies have also a central, direct regulator of ribosome Assoc. Professor Rick Pearson mechanisms underlying this checkpoint – National Health and Medical Research family’, 2008–10. implicated the activation of RAS, over biogenesis and cellular growth/proliferation Senior Research Officer and linking cell growth and proliferation is Council (NHMRC) Senior Research – Cancer Council Victoria Project Grant: expression of MYC and the disruption and suggest that dysregulation of AKT Dr Kate Hannan a key issue in the field of protein chemistry Fellowship 2008–12. $300,000, ‘Mechanisms of AKT3 driven of Rb and p53 function as causative/ might pay an important role in growth and a critical aim of our studies. malignant transformation’, 2008–10. Research Officer contributing factors in tumourigenesis. control during malignancy. Our ongoing Dr Kathy Jastrzebski Dr Megan Astle The importance of deregulation of It is now evident that the pathways studies are focused on understanding the – PhD Completion, The University Of PUBLICATIONS AND PATENTS underlying mechanisms of this regulation Dr Kathy Jastrzebski mTOR/S6K signalling in cancer became involving these key oncogenes and Melbourne, 2008. Publications are listed at the end of the and examining its role in AKT-dependent Dr Robert Southgate clear when it was shown to be a major tumour suppressors form part of a “super- Jane Lin report and include references 265, 317. downstream mediator of signalling via network”, interacting with the central PI3K/ malignant transformation. We are using Research Assistants – Melbourne Abroad Travel Scholarship. the PI3K/AKT axis that is deregulated in a gain-of-function experiments in isogenic For more information on related Abigail Peck AKT/mTOR axis at multiple levels. It will high proportion of human tumours. Small fibroblasts and ovarian epithelial cells to research, see: Kim Riddell be critical to understand the relationships molecule PI3K and mTOR inhibitors are between these pathways in contributing examine the role of mutant forms of PI3K, – Cancer Therapeutics Program [pg 62] Postgraduate Students activated forms of the three AKT and SGK showing promise as anti-cancer agents to ovarian cancer in order to identify and Bradley Bidwell in clinical trials. Thus, the second major evaluate potential targets for therapeutic isoforms and S6K in conferring anchorage- Joanna Chan theme of our research is to understand the intervention. Thus we have assembled independent growth and transformation. Benjamin Green mechanisms by which PI3K/AKT signalling a panel of 40 ovarian cancer cell lines These studies will be complimented by Sandy Hung contributes to cancer and to gauge the and begun to integrate the expression shRNA and miRNA knockdown of specific Kathy Jastrzebski and activity of the critical pathways with kinases that we have already shown to Rachel Lee exhibit elevated signalling in transformed Jane Lin cells. An alternative approach will seek Dr Mirette Saad to define the roles of other oncogenic Nik Veldhuis pathways in contributing to the transformed phenotype. In preliminary studies we have Honours Student found that inactivation of the p53 tumour Elaine Chilcott suppressor protein is required for AKT Summer Scholarship Students driven cell proliferation and transformation. Fiona Bell Analia Lesmana pRESENTATION HIGHLIGHTS Assoc. Professor Rick Pearson – Hunter Medical Research Institute Conference on Translational Cancer Research, Newcastle, NSW, September, 2008 (Invited Speaker). – Cell Signalling Technologies November Left to right: Assoc. Prof. Rick Pearson, Rachel Lee, Abigail Peck, Kate Hannan, Katrina Wilson, Rob Figure 1: Immortalised human fibroblasts expressing constitutively active Akt (myr-Akt3) exhibit multiple Southgate, Joanna Chan, Megan Astle. 2008 (Invited Speaker). markers of cell senescence including an increase in size and enlarged nuclei (A), positivity for senescence- associated beta-galactosidase staining (blue precipitate) (B) and cell cycle arrest. Knockdown of p53 reduces senescence-like growth arrest in myr-Akt3 expressing cells (D/E/F).

Peter MacCallum Cancer Centre – Research Report 2008 Growth Control & Differentiation Program/ Protein Chemistry 39 Growth Control & Differentiation Program/ Growth Control

The focus of the Growth Control laboratory RESEARCH OVERVIEW acting forms and small interfering RNAs demonstrated that dMyc interacts strongly transcription and rRNA and exhibit elevated Joanna Chan is to understand the molecular basis of The major long-term interest of our (siRNA) to ribosomal gene transcription and synergistically with dS6K to modulate expression of key rDNA transcription factors – 20th Lorne Cancer Conference, Lorne, the regulation of the ribosomal gene by laboratory is to understand certain factors, including UBF and Rrn3. Our rDNA transcription by a mechanism that such as UBF. Current experiments are Vic, February 2008 (Poster). RNA Polymerase I and how deregulation of long-term goal is to determine if ribosome appears to involve initiation factor dTIF- examining the phenotypic consequence molecular processes and how these brake Rachel Lee this process contributes to the process of down during disease – and because biogenesis represents a rational target 1A. Finally, to complement our extensive of modulating ribosome biogenesis during malignant change. for a generation of new therapeutics to candidate biochemical approaches we are the development of B-cell lymphoma using – European Association of Cancer ribosomes are crucial to limiting growth and Researchers-20 Conference, Lyon, proliferation in cells, our particular focus treat cancer. using a shRNA-miRNA library delivered inducible expression of small interfering RESEARCH FOCUS France, July 2008 (Poster). remains the means by which ribosomal though lentiviruses to ‘functionally screen’ RNAs (siRNA) to rRNA gene transcription 2008 RESEARCH ACHIEVEMENTS Jane Lin • Epigenetic mechanisms regulating RNA (rRNA) gene transcription is regulated the entire human genome to identify novel factors including UBF and Rrn3. ribosomal gene transcription by RNA by RNA Polymerase I. Regulation of RNA Polymerase I signalling pathways and regulators of – 20th Lorne Cancer Conference, Lorne, PRESENTATION HIGHLIGHTS Polymerase I. Transcription rDNA transcription. Vic, February 2008 (Poster). Over the past 10 years we have made These projects centre on understanding – The Beatson International Cancer • Basic mechanisms underlying cell important contributions to this field – we the fundamental mechanisms regulating Conference, Glasgow, UK, June 2008 growth control. were the first to identify core components transcription of the 200 copies of the (Poster). • Dysregulation of ribosome biogenesis of Pol I that are regulated by growth factor ribosomal RNA genes by RNA Polymerase during cancer. signalling pathways. We found that despite – 11th Annual Cell Cycle Workshop, I in mammalian cells. We use inducible limiting growth, more than half of the 200 Melbourne, Vic, November 2008 (Poster). • Functional screens for novel tumour RNAi and conditional disruption of the rRNA genes were believed to be ‘silent’ at suppressors in breast cancer. gene encoding the cytoarchitectural PRIZES AND AWARDS any one time. RESEARCH PERSONNEL transcription factor UBF, combined with Assoc. Professor Ross Hannan For this reason, a major focus of our current functional rescue mutants of UBF, to define Head – National Health and Medical Research studies is to uncover the mechanisms its role in nucleolar function and rDNA Assoc. Professor Ross Hannan Council (NHMRC) Senior Research controlling the activity status of individual transcription. We have now shown that Fellowship 2006–10. Research Officers ribosomal genes, and determine why a one mechanism by which UBF regulates Dr Amee George majority are silenced. rDNA transcription is by modulating the Megan Bywater Dr Elaine Sanij – GSK Postgraduate Support Grant, A second major focus of our research is ratio of active to inactive genes rather 2008–09. Research Assistants to test the hypothesis that deregulation of than regulating the rate of transcription per gene (see Fig 1). This is shown to be Tim Holloway rDNA transcription contributes to malignant Figure 1: ChIP-sequening analysis of UBF Assoc. Professor Ross Hannan Jane Lin Abigail Peck transformation. This is based on the a physiologically relevant mechanism by binding across mouse ribosomal DNA. Total – 29th Lorne Genome Conference, Lorne, – Melbourne Abroad Travel Scholarship. fragmented genomic DNA as well as DNA Jaclyn Quin long held understanding that constitutive which Pol I transcription is down-regulated Vic, February 2008 (Invited Speaker). during terminal differentiation. These fragments crosslinked to UBF and isolated by activation of rRNA synthesis is an invariable immunoprecipitation were sequenced using the – The 6th International Conference on GRANTS AND FUNDING Postgraduate Students results represent a paradigm shift in our feature of malignant transformation – with Illumina Genome Analyzer system (GeneWorks, RNA Polymerases I and III, Québec City, – National Health and Medical Research Maressa Bruhn understanding of the regulation of Pol Australia). All sequences were mapped to the pathologists having used enlarged nucleoli Canada, June 2008 (Invited Speaker). Council (NHMRC) Project Grant: Megan Bywater I transcription. [Journal of Cell Biology published complete sequence of the mouse as an indicator of cell transformation. ribosomal DNA repeat (Gene bank accession $511,500, ‘Deregulation of ribosome Hsiu-wen Chan Dec 29 2008;183(7):1259-74; reviewed in – American Physiological Society number: BK000964). The graph represents the signalling, synthesis and function during Joanna Chan However, despite these observations, the Science (2009) 323 (5913) as the editor’s frequency of ribosomal sequences enriched in Intersociety Meeting, Hilton Head, malignant transformation’, 2006–08. Sandy Hung link between ribosome biogenesis and choice of recent literature highlights in UBF-immunoprecipitated DNA expressed as fold USA, September 2008 (Invited Plenary Rachel Lee cancer is correlative in most cases. As such molecular biology]. change over those of input genomic DNA. The Speaker). – NHMRC Project Grant: $609,000 ‘Grant: upper panel represents a schematic of a single Jane Lin our current approach is to examine the Regulation of cardiac hypertrophy at the In other experiments we are using genetic ribosomal DNA repeat. Scale bars in kb are shown – Department of Biochemistry, University phenotypic consequence of modulating below; the site of transcription initiation start is level of ribosome biogenesis’, 2008–10. Honours Student screens in Drosophila to identify novel of Alabama, Tuscaloosa, USA 2008 ribosome biogenesis in tumour cells, both indicated at 0kb. En: enhancer elements; ETS: (Speaker). – NHMRC Project Grant: $564,500 ‘EGFR Elaine Chilcott regulators of rRNA synthesis and to identify external transcribed spacer; IGS: intergenic spacer. in cell culture and in vivo. transactivation in cardiac hypertrophy’, Summer Scholarship Students the signalling pathways and effectors that – Department of Cell Biology, Oklahoma We are using inducible expression of connect established regulators of growth Is dysregulation of ribosome Medical School, Oklahoma City, USA 2008–10. Fiona Bell biogenesis a necessary step in constitutively active and dominant-negative to rDNA transcription. Importantly we have 2008 (Speaker). – NHMRC Project Grant: $562,750, Analia Lesmana malignant transformation? Dr Amee George ‘Mechanisms of control of cell growth One of the ways through which the Growth and proliferation by the AKT kinase – School of Biomedical Sciences, Control laboratory has been exploring family’, 2008–10. this hypothesis is by using a Myc driven Faculty of Science, The University of – Cancer Council Victoria Venture model of B-cell lymphoma (EµMyc). Queensland, Brisbane, Qld, November Grant: $1,200,000, ‘Identification of The transcription factor c-MYC plays a 2008 (Seminar). novel breast cancer suppressor and prominent role in cancer and, strikingly, Dr Elaine Sanij chemotherapeutic drug sensitivity our work has shown that the majority of – 11th Annual Australian Cell Cycle genes using shRNA-mediated functional genes regulated by c-MYC are associated Workshop, Melbourne, Vic, November genomics screens’, 2007–10. with various aspects of ribosome synthesis 2008 (Invited Speaker). and function. In collaboration with Grant – Department of Surgery, The University PUBLICATIONS AND PATENTS McArthur, we are currently testing the of Melbourne, Melbourne, Vic 2008 Publications are listed at the end of the intriguing hypothesis that many of the (Speaker). report and include references 124, 259, 260, 317. phenotypic effects of c-MYC — including its oncogenic potential — are related to its Megan Bywater For more information on related ability to modulate ribosome biogenesis. – Beatson International Cancer Conference, research, see: Left to right: Assoc. Prof. Ross Hannan, Analia Lesmana, Kylie Morgan, Maressa Bruhn, Jane LIn, Jaclyn Quin, Amee George, Katrina Wilson, Tim Holloway, Abigail Peck. Absent: Megan Bywater. As predicted, Eµ-MYC tumours are Glasgow, UK, June 2008 (Poster). – Cancer Therapeutics Program [pg 62] characterised by high rates of rDNA

Peter MacCallum Cancer Centre – Research Report 2008 Growth Control & Differentiation Program/ Growth Control 41 Growth Control & Differentiation Program/ Molecular Oncology

The Molecular Oncology laboratory RESEARCH OVERVIEW damage and subsequent cell death. We cancer for treatment with PI3K/mTOR – Drug Discovery & Development Megan Bywater investigates new targets for cancer Our research program aims to link detailed are investigating a CHK1 inhibitor PF- pathway inhibitors. Conference, Couran Cove, Qld, July – GlaxoSmithKline Postgraduate Support treatment that control cell growth, division knowledge of the molecular processes 477736 alone or in combination with a 2008 (Speaker). Grant, 2008–209. and differentiation. commonly used chemotherapeutic agents – AMSA Convention, Melbourne, Vic, July that control cell growth, division and GRANTS AND FUNDING differentiation in the hope of developing including gemcitabine, in Phase 1 clinical 2008 (Speaker). RESEARCH FOCUS trials and in laboratory studies. Inhibition new cancer treatments. – Victorian Cancer Agency Career – NHMRC Project Grant: $166,708 pa, of CHK1 can have single agent activity in • The interaction between the MYC Development Seminar, Melbourne, Vic, ’Predicting Outcomes of Treatment in oncogene and the PI3K pathway in Our work focuses on three main lines of some malignant cells, where in other cells Head and Neck Cancer’, 2006–08. investigation, including: understanding the July 2008 (Speaker). regulating cancer progression and responses to DNA damaging agents is – NHMRC Project Grant: $143,250 pa, role of oncogenes MYC in cell growth and – Geelong Hospital, Geelong, Vic, August maintenance. enhanced. Inhibition of CHK1 increases ‘Imaging functional changes during developing new therapeutic strategies to 2008 (Invited Speaker). the DNA damage response in S-phase molecularly targeted therapy in a • Fundamental mechanisms of regulation treat MYC-driven cancer, understanding and during the G2 and mitotic phases – Diamantina Institute for Cancer new model of gastrointestinal stromal of cell growth by MYC. the mechanisms of response to novel Figure 1: PC3 prostate cancer cells following of the cell cycle resulting in abnormal treatment with either Gemcitabine alone (Gem) or in Immunology and Metabolism, Brisbane, tumour’, 2006–08. • Targeting CHK1 kinase for cancer cancer therapeutics by using candidate mitosis (see Fig 1) and premature entry combination with a CHK1 inhibitor (Gem + CHK), Qld, August 2008 (Speaker). treatment. gene approaches together with the stained for phosphorylated histone H3 (red), tubulin – NHMRC Project Grant: $93,750 into mitosis from earlier phases of the cell – Victorian Oncology Pharmacy Special • Targeting BRAF Kinase for cancer performance of genetic screens, and cycle. Our studies show substantial effects (green) and DNA (blue). The combination treatment pa, ‘Regulation of ribosomal gene results in cells displaying features of ‘mitotic Interest Group, Melbourne, Vic, transcription by c-MYC during treatment. investigating novel therapeutics in of CHK1-inhibition in both p53 wild type catastrophe’. September 2008 (Speaker). differentiation and lymphomagenesis’. • Targeting retinoic acid receptors for the regulating self-renewal and differentiation and mutant cells and in a variety of model Regulation of growth and ribosome – Melbourne Girls’ College, Burnley, Vic, 2006–08. treatment of AML. in models of cancer. systems including human tumour lines in biogenesis in myeloid cell September 2008 (Invited Speaker). We use a number of model systems to test vitro, in human xenografts in mice and in – Cancer Council Victoria (CCV): $140,000 RESEARCH PERSONNEL differentiation and lymphomagenesis – Royal Australasian College of Physicians, these processes, including: transgenic and syngeneic mouse models of malignancy. pa, Sir Edward Dunlop Clinical Research The c-MYC transcription factor is a global Sydney, NSW, September 2008 (Speaker). Head gene-targeted models of cancer in myeloid Fellowship, 2006–10. Gene expression profiling identifies regulator of ribosome biogenesis. We Assoc. Professor Grant McArthur cells, lymphoid cells and epithelial cells; – FRACP Exam preparatory Course, – National Institutes of Health (USA): feedback control of the PI3K/AKT/ have previously shown that MYC can human cancer cells, including the use of Melbourne, Vic, October 2008 (Speaker). US$702,400, ‘Defining Molecular Senior Research Fellow mTOR pathway in estrogen receptor regulate transcription of the 45S subunit of RNA-interference models of target and – Ludwig Institute of Medical Research, Markers of Hypoxia’, 2006–10. Dr Petranel Ferrao positive breast cancer rRNA a key rate-limiting step in ribosome gene modulation; and cellular models of In breast cancer the PI3K/AKT pathway Parkville, Vic, November 2008 (Invited – CCV: $1.2 million (over 3 years), Senior Research Officer biogenesis. We have now shown that myeloid differentiation. is commonly activated by genetic Speaker). “Identification of novel breast cancer Dr Gretchen Poortinga MYC can regulate the proportion of active aberrations. These genetic changes – Mutational Analysis in GIST, Novartis, suppressor and chemotherapeutic drug 2008 RESEARCH ACHIEVEMENTS rDNA genes. During terminal granulocytic Research Fellow are expected to render tumours highly differentiation there is a reduction in the Melbourne, Vic, November 2008 sensitivity genes using shRNA-mediated Dr Bianca Devitt Investigation of the cellular sensitive to therapeutic inhibition of the proportion of active rDNA genes from over (Speaker). functional genomics screens’, 2007–10. Research Officer responses to treatment of a selective PI3K/AKT/mTOR pathway. We have 50% to less than 10% that can be reversed – Australian Health Medical Research – NHMRC Project Grant: $128,125 pa, Dr Kathryn Kinross inhibitor of CHK1 analysed gene expression and protein by activation of MYC. Moreover in the Congress, Brisbane, Qld, November ’Inhibition of CHK1 Kinase for Cancer (P Ferrao, K Stanley in collaboration with data of ER+ breast cancer with PIK3CA Eµ-MYC mouse model of B-cell lymphoma 2008 (Organising Committee, Invited Therapy’, 2008–10. Research Assistants the Translational Research and Gene mutations, and found that mTORC1 there is an increase in the proportion of Speaker, Session Chairman). Daniel Brown – Victorian Cancer Agency: $339,000, ‘The Regulation Laboratories) signaling is down-regulated in tumours active rDNA genes from 10% to over 50% Melbourne Melanoma Project’, 2008–09. Jean Hendy with PIK3CA mutations, despite the ability PRIZES AND AWARDS Following DNA damage S-phase and as cells transform from a high growth of mutations to activate the pathway, – Novartis: $195,000, ‘Evaluation of Activity Technical Officer G2/M arrest is mediated by the protein premalignant state to a fully transformed Assoc. Professor Grant McArthur suggesting the presence of powerful of Nilotinib using PET Imaging’, 2006–08. Kym Stanley kinase CHK1. Selective inhibitors of CHK1 lymphoma. This body of work shows – Medical Media Award, “for his tireless feedback regulation. Our results suggest – Novartis: $429,875, ‘Mutation screening Postgraduate Students have been developed as potential cancer that the proportion of active rDNA commitment to the media to honour the a PIK3CA mutation-associated gene for Melanoma and other malignancies’, Megan Bywater therapeutics in an attempt to force cancer genes changes during differentiation dying wish of 26 year old Clare Oliver – signature may provide useful patient 2007–09. Dr Lynette Chee cells to prematurely progress though and with progression from premalignancy that the message about the danger of stratification in subsets of ER+ breast Dr Debbie Handolias the cell cycle resulting in extensive DNA to malignancy. sun bed tanning reach as many people – Pfizer: $14.99 million, ‘Peter MacCallum Dr Sherene Loi as possible”. Pfizer Translational Oncology Research PRESENTATION HIGHLIGHTS Collaborative Hub (TORCH)’, 2008–10. Dr Meaghan Wall – Sir Edward Dunlop Clinical Cancer Dr Paul Wood Assoc. Professor Grant McArthur Research Fellowship, Cancer Council PUBLICATIONS AND PATENTS – Children’s Cancer Institute of Australia, Assistant to Grant McArthur Victoria, 2006–10. Publications are listed at the end of the Sydney, NSW, May 2008 (Speaker). Anna Caldwell Dr Sherene Loi report and include references 2, 68, 94, 99, 123, – Royal Australian Chemical Institute – National Health and Medical Research 134, 162, 182, 184, 199, 208, 260, 265, 317, 341. Annual Meeting, Brisbane, Qld, June Council (NHMRC) Clinical Post Doc For more information on related 2008 (Plenary Lecture). Overseas Fellowship, 2008–12. research, see: – Lecture Series, The University of – Royal Australian College of Physicians – Cancer Therapeutics Program [pg 62] Melbourne, Parkville, Vic, May 2008 Bushell Travelling Fellowship. (Invited Speaker). – Translational Research [pg 70] – PhD Completion, The University of – Molecular Imaging Research [pg 74] – Centenary Institute for Medical Research, Melbourne 2008. Royal Prince Alfred Hospital, Sydney, – Centre of Molecular Imaging [pg 90] NSW, June 2008 (Invited Speaker). Dr Meaghan Wall – PhD Completion, The University of Left to right: Assoc. Prof. Grant McArthur, Anna Caldwell, Paul Wood, Bronwyn Neill, Daniel Brown, Megan Melbourne, 2008. Bywater, Kathryn Kinross, Debbie Handolias.

Peter MacCallum Cancer Centre – Research Report 2008 Growth Control & Differentiation Program/ Molecular Oncology 43 Cancer Cell Biology Program/

Utilising multidisciplined Metastasis Research 46 Cell Cycle Development 48 approaches to focus on the Cell Cycle & Cancer Genetics 50 cross-talk between cancer Cell Growth & Proliferation 52 and supporting cells, factors Differentiation & Transcription 54 Epithelial Stem Cell Biology 56 influencing cancer cell growth, Molecular Radiation Biology 58 and the genetic control of Tumour Suppression 60 cancer cell spread.

‘Improvements in early detection, community education about cancer and in cancer treatment have led to better outcomes for most cancer patients. Metastatic disease, in which the cancer spreads to other organs, is the main cause of cancer associated death and remains a challenge for us to find effective new treatments’.

Assoc. Professor Robin Anderson Head, Metastasis Research

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Cell Biology Program/ 45 Cancer Cell Biology Program/ Metastasis Research

Our laboratory aims to understand the RESEARCH OVERVIEW two breast cancer cohorts for which – DOD BCRP Era of Hope Meeting, GRANTS AND FUNDING molecular events underlying the spread The Metastasis Research laboratory outcome data was available. We found Baltimore, USA, June 2008 (Invited – NHMRC Project Grant: $444,750, ‘BMP4 of cancer throughout the body, focusing is leading important research into the no association between caveolin-1 Speaker). – a metastasis suppressor gene in breast primarily on breast and colon cancer. genetic causes of the spread (metastasis) expression in the epithelial compartment Bradley Bidwell cancer’, 2006–08. From this knowledge, new treatments can and clinical outcome. However, high of cancer, because it is metastasis that – AACR Annual Meeting, San Diego, USA, be developed for cancer that has spread levels of caveolin-1 in the stromal tissue – NHMRC Project Grant: $414,075, continues to be the main cause of death April 2008 (Selected Speaker). ‘Inhibition of breast cancer metastasis (metastasised). in cancer patients. Despite therapy for surrounding the tumour, rather than Rachel Carter through targeting of laminin-10 function’, primary tumours often being effective, there within tumour cells, was associated RESEARCH FOCUS – Cancer Therapeutics CRC Symposium, 2007–09. are few treatment options when cancer strongly with reduced metastasis and 2008 (Speaker). – AICR Project Grant: $270,000, • Development of mouse models of has spread. To meet this challenge, our improved survival (p<0.0001). The onset ‘Identification of cell surface proteins that metastatic disease, focusing on breast research is focused on uncovering the key of mammary tumours driven by Her2/neu Nimali Withana overexpression was accelerated in mice dictate site specific metastasis of breast and colon cancer. genes in the tumour cells or surrounding – Cancer Therapeutics CRC Symposium, lacking caveolin-1, thereby supporting the cancer’, 2007–10. • Identification of genes that regulate host cells that regulate metastasis. 2008 (Speaker). observation that the presence of caveolin-1 metastasis. – CASS Foundation Project Grant: From genomic profiling of the primary in the tumour microenvironment modulates PRIZES AND AWARDS $55,000, ‘Stimulation of critical immune • Examination of the molecular interactions tumours and their spread, we have tumour development. These studies defence pathways as a therapy to block between tumour cells and surrounding Assoc. Professor Robin Anderson identified genes critical to the process. suggest that stromal caveolin-1 expression Figure 1: Stromal expression of caveolin-1 the spread of breast cancer to bone’, host cells. – Appointment to Principal Fellow These genes offer potential for new may be a potential therapeutic target and correlates with improved survival. Kaplan-Meier 2008. • Development of compounds that inhibit molecular based therapies in advanced a valuable prognostic indicator of breast plots for caveolin-1 expression in the stroma in a (Honorary), Department of Pathology, consecutive series of breast cancer patients. The – NHMRC Project Grant: $428,950, genes that regulate metastasis. cancers and/or provide useful prognostic University of Melbourne. cancer progression. relationship between overall survival and caveolin-1 ‘Contribution of tumour and stroma markers for disease progression. Currently – Appointment to the Scientific Committee positive or negative tissue is shown over time derived cysteine cathepsins to breast RESEARCH PERSONNEL we’re looking to understand how these Basement membrane proteins and (years following diagnosis). Whilst the expression of the Victorian Breast Cancer Research their receptors in breast cancer cancer metastasis to bone’, 2008–10 Head genes regulate metastasis, with a focus of caveolin-1 in the tumour cells does not predict Consortium. metastasis. patient outcome, expression of this protein in host – Peter MacCallum Cancer Foundation: Assoc. Professor Robin L. Anderson on developing compounds to inhibit tissues surrounding the tumour is highly predictive. – Appointment to the Board of Directors, Two research projects investigate the role $24,942, ‘Evading immune recognition: a their advance. Metastasis Research Society 2008–12. Research Fellows of basement membrane proteins and We are testing the efficacy of these requirement for breast cancer metastasis Dr Bedrich Eckhardt To advance these studies, we have integrin adhesion receptors in the spread integrin inhibitors and specific inhibitors of Dr Bedrich Eckhardt to bone?’, 2007–08. Dr Belinda Parker developed clinically relevant models of of breast tumours to distant organs. signalling pathways triggered by integrin – Susan G Komen Breast Cancer – Peter MacCallum Cancer Foundation: Dr Normand Pouliot metastatic disease in mice, primarily for Our focus has been primarily on receptors against breast cancer metastasis Foundation Postdoctoral Fellowship, $82,000, ‘Development of a clinically Dr Richard Redvers breast cancer, but also for colon cancer. laminin-511 (LM-511), a basement to bone and other organs. 2006–09. We are further refining these models to relevant model to study breast cancer Senior Research Officer membrane protein produced abundantly – GlaxoSmithKline Postdoctoral Award, study spread to specific sites such as metastasis to brain’, 2007–08. Dr Izhak Haviv by aggressive breast tumours. LM-511 PRESENTATION HIGHLIGHTS 2007–08. – NHMRC Project Grant: $414,250, bone, liver or brain. contributes to the escape of tumour cells Research Assistants Assoc. Professor Robin Anderson – AACR-Aflac Inc. Travel Award for the ‘Integrin beta3 as a therapeutic target from the breast and assists them in going Bradley Bidwell 2008 RESEARCH ACHIEVEMENTS – Department of Defense (DOD) Breast Joint MRS-AACR Conference on for breast cancer metastasis to bone’, to bone and other organs by promoting Judy Doherty Cancer Research Program (BCRP) Era Metastasis, Canada. 2008–2010. Stromal cell expression of caveolin-1 their attachment, migration and invasion. Christina Restall of Hope Meeting, Baltimore, USA, June predicts outcome in breast cancer We have been testing novel inhibitors Dr Izhak Haviv – CCV and NBCF Project Grant: $434,375, Kathryn Visser 2008 (Invited Speaker). Caveolin-1 has been linked to tumour for their ability to interfere with integrin- – Keystone Symposia Inflammation, ‘Functional genomic screen for Postgraduate Students progression and clinical outcome dependent adhesion, including integrin – International Congress of the Metastasis Microenvironment and Cancer, Snowbird, metastasis suppressor genes controlling Bradley Bidwell in breast cancer, but without a clear receptors mediating LM-511 activity. Two Research Society, Vancouver, Canada, USA, March 2008 (Poster Award). breast cancer metastasis to bone and August 2008 (Invited Speaker). lung’, 2008–10. Allan Burrows resolution of its role as a prognostic compounds derived from snake venom Dr Belinda Parker Yuan Cao marker. We have assessed caveolin-1 are potent inhibitors of breast cancer cell Dr Bedrich Eckhardt – Peter MacCallum Cancer Foundation – ARC Discovery Grant: $255,000, Rachel Carter levels in normal breast tissue and adhesion, migration and invasion. – 20th Lorne Cancer Conference, Lorne, New Investigator Award, 2007–08. ‘Tumour localisation and enhancement Nicole Kusuma Vic, February 2008 (Invited Speaker). of anthracycline anticancer activity’, Rebecca Miao Dr Richard Redvers Dr. Izhak Haviv 2008–10. Nimali Withana – National Breast Cancer Foundation – DOD BCRP Era of Hope Meeting, – Ramaciotti Foundation Establishment (NBCF) Postdoctoral Fellowship, Grant: $30,000, ‘The role of the Baltimore, USA, June 2008 (Invited 2008–11. Speaker). extracellular matrix protein POEM in Nicole Kusuma breast cancer metastasis’, 2008. – Annual AHMR Conference, Brisbane, – NCI Scholar-in-Training Award for Joint October 2008 (Invited Speaker), – US DoD BCRP Idea Award: US$400,000 Metastasis Research Society, AACR ‘Functional genomics and epithelial to Dr Belinda Parker Conference on Metastasis, Canada. mesenchymal transition to manipulate – Mon-Man Workshop on Genetically Nimali Withana breast cancer metastasis and Modified Models of Human Disease, – Cancer Therapeutics CRC (CTx) Travel dormancy’, 2008–11. Melbourne, Vic, 2008 (Invited Speaker). Scholarship. PUBLICATIONS AND PATENTS Dr Normand Pouliot Allan Burrows – Gordon Research Conference on Publications are listed at the end of the – NHMRC Predoctoral Scholarship, 103, 222. Basement Membranes, Biddeford, USA, report and include references Left to right: Assoc. Prof. Robin Anderson, Nicole Kusuma, Rebecca Pelzer, Judy Doherty, Rachel Carter, 2008–11. Rick Redvers, Christina Restall, Normand Pouliot, Belinda Parker, Yuan Cao, Kathryn Visser, Cameron June 2008 (Invited Speaker). Johnstone, Nimali Withana, Allan Burrows, Erin Lucas.

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Cell Biology Program/ Metastasis Research 47 Cancer Cell Biology Program/ Cell Cycle & Development

We use a model organism, the vinegar fly RESEARCH OVERVIEW and Cancer Genetics, see pg 50, Immune the effect of Scrib on signalling pathways Dr Linda Parsons pathway important in cell division (Cdk Drosophila, to investigate the action of the The Cell Cycle and Development laboratory Signalling, see pg 18) we are translating in Drosophila and in mammalian MCF10A – Hunter Valley Cell Biology Conference, regulation of Brm complex)’, 2007–09. junctional neoplastic tumour suppressors uses the genetically amenable model, this work into mammalian epithelial or T epithelial cell models. In human epithelial NSW, April 2008 (Poster). – CCV: $35,000 pa, ‘A new role for and ECM proteins in tumourigenesis, cells and mouse models. We are also cells and in Drosophila over-expression the vinegar fly Drosophila, to study Dr Nathalie Martinek polarity proteins in leukemia/lymphoma’ how these cooperate with oncogenes mechanisms controlling cell proliferation investigating the role of extracellular of Scrib can act to block the Ras-MAPK 2007–09. in tumourigenesis and to identify small matrix proteins, in particular Sparc, in signalling pathway. – American Society for Matrix Biology and tumourigenesis within the context of a – NHMRC Project Grant: $167,750 pa, ‘The molecule inhibitors of tumour growth in tumourigenesis in collaboration with (ASMB), San Diego, USA, December whole animal. tumour suppressor, Lgl in the regulation vivo. Professor David Bowtell (Cancer Genetics PRESENTATION HIGHLIGHTS 2008 (Speaker). Our major focus is on the neoplastic tumour of cell signaling, proliferation and and Genomics laboratory, see pg 26). Dr Helena Richardson Felix Grusche RESEARCH FOCUS suppressors scrib, dlg and lgl, which affect apoptosis’, 2008–09. – Model Organisms and Stem Cells in – 20th Lorne Cancer Conference, Lorne, cell shape (polarity), proliferation and 2008 RESEARCH ACHIEVEMENTS – NHMRC Project Grant: $176,830 pa, • Modelling cancer in Drosophila. Development, Regeneration and Disease Vic, February 2008 (Poster). migration. We have shown that lgl mutant ‘Using Drosophila to define an epithelial Regulation of cell proliferation, cell International Symposium, Bangalore, – 20th International Congress of Genetics, • Mechanism of action of junctional clones show upregulation of the key cell cancer stem cell’, 2008–10. death and signalling pathways by India, February 2008 (Invited Speaker). Berlin, Germany, August 2008 (Poster). neoplastic tumour suppressor genes, lgl/ cycle gene, cyclin E, and ectopic cell apico-basal cell polarity regulators GRANTS AND FUNDING scrib/dlg. proliferation, independent of cell polarity – Queenstown Signal Transduction – COMBIO conference, Canberra, ACT, Loss of function of the neoplastic tumour • Role of the extracellular matrix protein defects, showing that lgl directly affects Meeting (QueST), Queenstown, New September 2008 (Speaker). – NHMRC Senior Research Fellowship B, suppressor genes, lgl, scrib and dlg, Sparc in tumourigenesis. proliferation independent of cell architectural Zealand, September 2008 (Invited $115,500 pa, 2007–11. leads to upregulation of the key cell Peytee Khoo defects. Speaker). • Screening for anti-cancer drugs using cycle regulator, Cyclin E, and ectopic cell – 20th Annual Lorne Cancer Conference, – NHMRC Project Grant: $99,167 pa, Drosophila cancer models. To identify the pathways misregulated in proliferation. In the analysis of lgl mutant – Children’s Medical Research Institute Lorne, Vic, February 2008 (Poster). ‘Modelling cooperative tumourigenesis in (CMRI), Sydney, NSW, May 2008 (Invited Drosophila’, 2006–08. RESEARCH PERSONNEL scrib/dlg/lgl mutants, we have carried out clones in the developing eye, we have Nezaket Turkel genetic screens and microarray expression shown that Lgl’s role in cell proliferation Speaker). – NHMRC Project Grant: $160,000 pa, Head – 20th Annual Lorne Cancer Conference, profiling, which has revealed that several regulation can be separated from its role in – Hunter Valley Cell Biology Conference, Lorne, Vic, February 2008 (Poster). ‘Sparc and Sparc cluster genes in Dr Helena Richardson signalling pathways are misregulated. apico-basal cell polarity. We also discovered NSW, April 2008 (Co-organiser, Co-chair tumourigenesis’, 2007–09. – Peter MacCallum Cancer Centre Senior Research Officer Despite the ectopic cell proliferation that that lgl mutant clones show upregulation and Session Organizer). Workshop Symposium, Wilson’s – Cancer Council Victoria (CCV) Venture: Dr Anthony Brumby occurs in scrib/dlg/lgl mutant clones, the of the inhibitor of cell death, Diap1, and – ComBio, Canberra, ACT, September Promontory, Vic, October 2008 (Poster). $193,750 pa, ‘Drosophila as a novel tool mutant tissue does not overgrow due to cell reduced developmental cell death. Research Officers 2008 (Plenary Chair, Co-chair and for anti-cancer drug discovery’, 2007–08. death or differentiation. Dr Nicola Grzeschik We have been investigating the signalling Session Organiser). GRANTS AND FUNDING – Australian Research Council (ARC): Dr Nathalie Martinek We have developed a two-hit cancer model pathways that mediate Lgl’s control on the – 11th Annual Australian Cell Cycle – National Health and Medical Research $70,000 pa to our lab, ‘Unveiling and Dr Linda Parsons in flies, where co-expression of oncogenic Cyclin E and Diap1, and from this analysis Workshop, Melbourne, November 2008 Council (NHMRC) Senior Research characterisation of a fundamental Dr Vin Sahota Ras or Notch in scrib/dlg/lgl mutant clones we have made the exciting discovery (Co-Organiser and Session Chair). Fellowship B, $115,500 pa, 2007–11. pathway important in cell division (Cdk overcomes the restraining forces of cell Research Assistants that Lgl acts antagonistically to the apical Dr Nicola Grzeschik – NHMRC Project Grant: $99,167 pa, regulation of Brm complex)’, 2007–09. death and differentiation to result in the Melinda Allott polarity regulatory complexes, aPKC and – Inaugural Melbourne Cell and ‘Modelling cooperative tumourigenesis in – CCV: $35,000 pa to our lab, ‘A new generation of invasive tumours. By genetic Karen Goulding Crumbs, to regulate the Salvador-Warts- Developmental Biology Meeting, Drosophila’, 2006–08. role for polarity proteins in leukemia/ screens we have identified other genes Hippo tumour suppressor pathway — we Lisa Mckenzie Melbourne, Vic, November 2008 – NHMRC Project Grant: $160,000 pa, lymphoma’ 2007–09. that can cooperate with scrib mutants or are continuing to investigate the precise Zalina Osman (Speaker). ‘Sparc and Sparc cluster genes in – NHMRC Project Grant: $167,750 pa, ‘The with oncogenic Ras in tumourigenesis and mechanism. We have also found that Rebecca Parsons tumourigenesis’, 2007–09. tumour suppressor, Lgl in the regulation are analyzing their mechanism of action. other signalling pathways are affected in – 11th Annual Australian Cell Cycle Lee Willoughby of cell signaling, proliferation and In addition, we are using our Drosophila lgl mutant clones and are determining the Workshop, Melbourne, November 2008 – Cancer Council Victoria (CCV) Venture: apoptosis’, 2008–09. Postgraduate Students cancer models to screen for small molecule importance of these in the deregulation (Speaker). $193,750 pa, ‘Drosophila as a novel tool Felix Grusche inhibitors that specifically target the tumours. of cell proliferation, apoptosis and other for anti-cancer drug discovery’, 2007–08. – NHMRC Project Grant: $176,830 pa, Peytee Khoo lgl mutant phenotypes. We have also Figure 1: Screening for drugs to cure flies of cancer: – Australian Research Council ‘Using Drosophila to define an epithelial Through collaboration with Drs Patrick Carole Poon collaborated with Dr Patrick Humbert’s Cell Drosophila tumour bearing larvae (scrib- + RasV12) (ARC): $70,000 pa, ‘Unveiling and cancer stem cell’, 2008–10. Nezaket Turkel Humbert and Sarah Russell (Cell Cycle in a 96 well plate. Tumours are labelled with GFP Cycle and Cancer Genetics laboratory on and exposed to different drugs. characterisation of a fundamental PUBLICATIONS AND PATENTS Technical Officer Publications are listed at the end of the Peter Burke report and include references 37, 70, 74, 145, Technical Officer (part-time) 198, 204, 211. Claire Bowtell

Left to right: Dr Helena Richardson, Karen Doggett, Linda Parsons, Tony Brumby, Alexandra Casson, Peter Burke, Nezaket Turkel, Nathalie Martinek, Lee Willoughby, Fleix Grusche, Peytee Khoo.

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Cell Biology Program/ Cell Cycle & Development 49 Cancer Cell Biology Program/ Cell Cycle & Cancer Genetics

Our laboratory investigates the RESEARCH OVERVIEW Demonstration that loss of human fundamental role of tissue organisation We have developed a program of Scribble cooperates with H-Ras to promote cell invasion through and asymmetry on cancer progression research focused on understanding how deregulation of MAPK signalling with the aim of identifying novel therapeutic the maintenance of tissue architecture strategies. and the shape (polarity) of cells within a Activating mutations in genes of the Ras- tissue regulates cell number and behavior MAPK pathway occur in approximately RESEARCH FOCUS – a better understanding of how these 30% of all human cancers. However, • Cell biology and genetic analysis of cell are disrupted in cancer could deliver mutation of Ras alone is rarely sufficient polarity protein function in 3D epithelial developments in new treatment therapies. to induce tumour development. Scribble cell culture models. is a polarity regulator recently isolated As a joint venture, together with Drs from a Drosophila screen for events that • Generation and analysis of Genetically Helena Richardson and Sarah Russell cooperate with Ras mutation to promote PRESENTATION HIGHLIGHTS suppressive properties of mammalian Engineered Mouse Models (GEMMs) (Cell Cycle and Development, see pg tumour progression and cell invasion. In Scribble’, 2007–09. to investigate role of polarity proteins Dr Patrick Humbert 48, Immune Signalling, see pg 18), we mammals, Scribble regulates directed cell – Prostate Cancer Foundation of Australia: in cancer progression and organ – Prostate Cancer Foundation of Australia applied information from Drosophila migration and wound healing in vivo, but $200,000, ‘The role of polarity regulators development in vivo. (PCFA) National Annual Conference, genetic screens and mammalian functional no role has been identified for mammalian Gold Coast, Qld, November 2008 (Invited in prostate cancer’, 2008–09. • Analysis of cell polarity proteins and screens to mammalian epithelial and Scribble in oncogenic transformation. We Speaker). – NHMRC Project Grant: $550,500, ‘The gene alterations in human cancers. T cell biology – and to the study of have now shown that in human epithelial – Australian Society for Medical Research role of scribble in mammalian tumour • Large Scale RNAi functional screens to human cancer. cells expressing oncogenic Ras or Raf, (ASMR) National Scientific Conference development’, 2008–10. identify effectors of Scribble function. loss of Scribble promotes invasion of Our laboratory’s initial studies have on Epithelial Biology, Brisbane, Qld, – NHMRC Project Grant: $513,250, ‘The cells through extracellular matrix in an • Collaborative analysis of tissue polarity in determined that human homologues November 2008 (Invited Speaker). tumour suppressor Lgl in the regulation cancer and development with the Russell of Drosophila polarity genes, such as organotypic culture system. Further, – 48th Annual Meeting of American Society of cell signaling, proliferation and and Richardson laboratories. Scribble, operate similarly in mammalian the mechanism by which this occurs is for Cell Biology, San Francisco, USA, apoptosis’, 2008–10. epithelial systems to prevent tumour through the regulation of MAPK signalling RESEARCH PERSONNEL December 2008 (Invited Speaker). formation. We are also looking at how by Scribble. The suppression of MAPK PUBLICATIONS AND PATENTS signalling is a highly conserved function of Head polarity proteins, such as Scribble, regulate Figures 1 and 2: Scribble loss promotes Ras- PRIZES AND AWARDS Publications are listed at the end of the Scribble as it also prevents Raf-mediated dependent invasion in MCF10A human mammary Dr Patrick Humbert tumourigenesis, and how their disruption in report and include references 18, 74, 145. defects in Drosophila wing development. epithelial cells. When grown in a 3D culture Dr Patrick Humbert human cancer relates to patient prognosis. system these cells normally form well organized, Research Fellows Our data have identified Scribble as an – National Health and Medical Research Dr Luke Dow hollow, growth arrested acini structures. In these In addition, we are using information important mediator of MAPK signalling experiments Scribble loss co-operates with a Council (NHMRC): RD Wright Career Dr Nathan Godde gleaned from Drosophila studies as well and provide a molecular basis for the RasV12 mutant to form increased protrusions that Development Fellowship, 2005–09. Dr Brad McColl as our biochemical, genetic and cellular invade into the surrounding extracellular matrix. observation that Scribble expression Susie Roczo Dr Helen Pearson analyses to understand how polarity is decreased in many invasive human – Department of Pathology Deans Prize, proteins interact in cellular signalling and cancers. [Reference: Dow LE et al., (2008) Research Assistants The University Of Melbourne, Top tumour progression. Oncogene 26:2272–82.] Allison Clarke Honours Student Pathology in 2008. Lorey Smith GRANTS AND FUNDING Technical Officer Olivia Cakebread – NHMRC Career Development Award: $437,500, ‘The Role of the RB/E2F Postgraduate Students pathway in Cell Cycle Control and Imogen Elsum Erythropoiesis’, 2005–09. Ryan Galea – NHMRC Project Grant: $495,650, Honours Students ‘Regulation of epithelial migration by Susie Roczo Scribble in development and wound Tanja Schlosser repair’, 2007–09. – NHMRC Project Grant: $376,125, ‘A novel mechanism for the regulation of T cell shape and function’, 2006–08. – Cancer Council Victoria (CCV): $205,956, ‘The role of Dlg1 in mammalian tumour development’, 2006–08. – CCV: $146,750, ‘Drosophila as a novel tool for anti-cancer drug discovery’, 2007–08. – Association for International Cancer Research UK: UK£133,640, ‘Molecular Left to right: Alison Clarke, Imogen Elsum, Nathan Goode, Lorey Smith, Dr Patrick Humbert, Susie Roczo, characterisation of the tumour Helen Pearson, Ryan Galea, Tanja Schlosser, Olivia Cakebread.

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Cell Biology Program/ Cell Cycle & Cancer Genetics 51 Cancer Cell Biology Program/ Cell Growth & Proliferation

Our laboratory studies mechanisms that RESEARCH OVERVIEW 2008 RESEARCH ACHIEVEMENTS TOR- and FOXO-dependent feedback PRESENTATION HIGHLIGHTS GRANTS AND FUNDING control organ size during development, inhibition contributes to the benign nature Our laboratory has played a major role in FOXO-mediated transcription restricts Dr Kieran Harvey – Leukemia Lymphoma Society Career and how break down of these processes of Tsc1 and Tsc2 human tumours. We understanding a newly identified signalling growth of tissues with excessive Tor – Hunter Valley Cell Biology Conference, Development Award: 2005–08. contributes to human cancer. speculate that inactivating mutations in pathway that helps regulate the size pathway activity NSW, April 2008 (Speaker). FOXO family transcription factors, and/or – International Human Frontier Science of organs by triggering a programmed The size of developing organs is tightly RESEARCH FOCUS FOXO-target genes that possess growth- – Institute of Molecular and Cell Biology, Program Career Development Award: limit to their growth. Our aim is to gain a controlled in order to generate the inhibitory properties, could promote Proteos, Biopolis, Singapore, May 2008 2006–09. • Developmental organ size control in the more complete understanding of organ- characteristic size and shape of different malignancy in normally benign Tsc1 and (Speaker). – National Health and Medical Research vinegar fly, Drosophila melanogaster. size control, and to understand how the animals. Multiple signalling pathways Tsc2 tumours. [Harvey et al. (2008). J Cell Council (NHMRC) Project Grant: • Functional characterisation of the breakdown of size control mechanisms control organ size including the target of – Department of Anatomy and Biol. 180, 691-696.] 2006–08. Salvador-Warts-Hippo tumour contributes to human cancers. With this rapamycin (TOR) and insulin pathways. Developmental Biology, Monash suppressor pathway in Drosophila. as our chief focus, we’ve continued to use The TOR pathway is an ancient signalling University, Clayton, Vic, October 2008 – NHMRC of Australia Career Development (Speaker). Award Fellowship Level 1: 2008–12. • Investigation of the Salvador-Warts-Hippo the model organism vinegar fly (Drosophila network conserved from yeast to humans tumour suppressor pathway in human melanogaster). that responds to environmental stimuli, Dr Claire Milton PUBLICATIONS AND PATENTS cancer. Our work has uncovered that the size of such as nutrient and oxygen availability, as – Inaugural Melbourne Cell and well as growth factor signalling. The insulin Publications are listed at the end of the different organs and animals is controlled Developmental Biology Meeting, 128. RESEARCH PERSONNEL report and include references both by nutrition and by signalling pathway evolved in metazoans to enable Melbourne, Vic, November 2008 Head pathways such as the Wnt/Wg, TGF-b/ dynamic control of cell growth, proliferation (Speaker). and metabolism in a systemic fashion. Dr Kieran Harvey Dpp and Notch pathways, and the newly Felix Grusche Multiple points of crosstalk exist between defined Salvador-Warts-Hippo (Hippo) – ‘Signalling and Growth Control’ Senior Research Officers these pathways, ensuring optimal control pathway – which we played a key role in Symposium, ComBio, Canberra, ACT, Dr Joffrey Degoutin of tissue growth. Dr Claire Milton identifying along with several aspects of its September 2008 (Speaker). Dr Xiaomeng Zhang function and regulation. In a collaborative effort between four labs across three continents, we recently PRIZES AND AWARDS Postgraduate Students The Hippo pathway restricts organ size by discovered that the FOXO transcription Felix Grusche stimulating programmed cell death and by Figure 1: (A–B) FOXO transcription factor is Dr Kieran Harvey factor (a downstream component of elevated and more nuclear in cells lacking Tsc1. Laila Ritsma restricting cells from growing and dividing – Leukemia Lymphoma Society Special the insulin pathway) is activated under Expression of FOXO (red in A and B) is elevated Ashesha Sinha excessively – properties central to the and nuclear in tissue lacking Tsc1 (GFP negative Fellowship, 2005–08. conditions of increased TOR activity formation of human cancer (Fig 1). in B), compared to wild-type tissue (GFP positive – Peter MacCallum Cancer Centre Junior Research Assistant (caused by mutation of the tuberous in B) where FOXO is cytoplasmic and expressed Investigator Award, 2006–09. Nathaniel Albanese The Hippo pathway controls these sclerosis complex1 (Tsc1) gene, which at lower levels. (C–E) FOXO represses overgrowth processes by limiting expression of cyclin normally restricts TOR). We found that Tsc1 of tissue lacking Tsc1. (D-G) Scanning electron – International Human Frontier Science Technical Officer micrographs of adult Drosophila melanogaster E (which stimulates cell cycle progression), Program Career Development Award, Lauren Hicks mutations cause FOXO protein expression eyes for the following genotypes: (C) wildtype, (D) and DIAP1 (which promotes cell survival). to increase and become nuclear, resulting Tsc1, (E) Tsc1-FOXO. Eyes lacking both Tsc1 and 2006–09. Most recently, we discovered that the Fat in elevated expression of FOXO-regulated FOXO are larger than Tsc1, which is already larger – NHMRC of Australia Career Development than wild-type. cadherin is a candidate transmembrane genes, some of which are known to Award Fellowship Level 1, 2008–12. receptor protein for the Hippo pathway. antagonize growth-promoting pathways. – Australian Institute of Policy and Science The Hippo pathway is functionally In addition we found that analogous Victorian Young Tall Poppy Award, 2008. conserved in mammals, and the human transcriptional changes were observed counterparts of several Hippo pathway in mammalian cells implying that FOXO components have been implicated in the attenuates TOR-driven growth in genesis of mammalian cancers. diverse species.

Left to right: Dr Kieran Harvey, Felix Grusche, Ashesha Sinha, Xiaomeng Zhang, Joffrey Degoutin, Carole Poon.

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Cell Biology Program/ Cell Growth & Proliferation 53 Cancer Cell Biology Program/ Differentiation & Transcription

The differentiation and transcription RESEARCH OVERVIEW colon cancer we have also developed confirmed local regulation by CSF-1 of PC line the sub-ventricular zone are defective – Australasian Gastro-Intestinal Trials laboratory investigates mechanisms of Our laboratory studies the regulation of a novel DNA vaccine that targets breast development, either directly, in a juxtacrine/ in c-Myb knock-out mice has profound Group Scientific Meeting, Sydney, 2008 transcriptional control of differentiation proliferation, differentiation and apoptosis and colon cancers in vivo. paracrine manner, or indirectly, by lamina implications for the regulation of cerebral (Invited Speaker). and carcinogenesis in gastrointestinal, in blood, epithelial and neuronal tissues. • Having determined that c-Myb is required propria macrophages. Therefore, CSF- spinal fluid homeostasis The knock-out – Australian Society for Medical Research mammary and neurogenic tissues. This year we were joined by members for adult brain neurogenesis we are now 1R hyperstimulation could be involved in mice have enlarged ventricular spaces (ASMR) Professional Development We are particularly interested in stem of the McKay laboratory following Mike investigating neural stem cell recovery hyperproliferative disorders of the small that can be observed by histology or by Workshop, Melbourne, Vic, August 2008 and progenitor cell regulation in these McKay’s move from Peter Mac to Canberra following radiation damage, a process intestine, such as Crohn’s disease and MRI. Olfactory bulbs are reduced in the (Invited Speaker). compartments. ulcerative colitis. Notably patients with long knock-out mouse brains, indicative of to take up a Professorial appointment in impaired in some patients (particularly – ASMR Professional Development radiation oncology. This personnel merger children) following cranial radiotherapy. term inflammatory bowel disease have defective neurogenesis. Finally, the dentate RESEARCH FOCUS Workshop, Adelaide, SA, 2008 (Invited has led us to formalise our activities in 5-8 fold increased risk of colon cancer. gyrus (DG) has aberrant morphology. . 2008 RESEARCH ACHIEVEMENTS Speaker). • Gastrointestinal epithelial tissue radiation biology and the role of cohesion [Gastroenterology (2009) [Reference: Malaterre et al. (2008), Stem – ASMR, Australian Health and Medical homeostasis and cancer. proteins (which are central to proper CSF-1 is Required for Paneth Cell in press.] Cells 26: 173–81). Research Congress, Brisbane, Qld, 2008 chromosome replication and chromatid Development • Mammary development and (Selected Symposium Speaker). carcinogenesis. segregation) and we are continuing to In our quest to understand the role of – West Australian Institute for Medical • Control of transcriptional elongation. study how these processes impinge CSF-1 in the regulation of homeostasis upon epithelial and neuronal stem cell in the intestine we have discovered that it Research (WAIMR), Perth, WA, 2008 • Radiation effects on stem/progenitor cell populations. is essential for the generation of Paneth (Invited Speaker). populations. • Our key research focus remains on cells (PCs). Paneth cells (PCs) secrete AWARDS AND PRIZES • Translation of basic research discoveries defensins and a range of antimicrobial into new therapies. the essential role of Myb in colon Assoc. Professor Robert Ramsay development and malignancy but other enzymes that contribute to innate – National Health and Medical Research transcription factors of interest include immunity against pathogen infections RESEARCH PERSONNEL Council (NHMRC) Senior Research N-myc, p53, CREB and beta catenin- within the mucosa of the small intestine. Brain specific loss of c-Myb leads to holes in the Head brains of adult mice. Fellowship, 2006–10. LEF-1/TCF4, and the signalling pathways In collaboration with Richard Stanley’s Assoc. Professor Robert Ramsay laboratory in New York we examined the c-myb brain-specific mutants have enlarged that activate them. Accordingly, we have ventricle (V) spaces. Magnetic resonance imaging Sebastian Dworkin Research Officer engineered mouse strains to allow the role of colony stimulating factor-1 (CSF-1) (MRI) micrographs highlight these spaces. – PhD Completion, The University of Dr Jordane Malaterre selective deletion of Myb and CREB in a in PC development using CSF-1–deficient This region of the brain generates new neurons Melbourne, 2008. and CSF-1 receptor (CSF-1R)–deficient (neurogenesis) that migrate to repopulate the variety of tissues. olfactory bulbs (OB) which are smaller in the – Peter Mac Postgraduate Student Medal, Senior Research Officer mice as well as CSF-1 transgenic Dr Huiling Xu • The molecular research focus remains on mutant mice. The second dominant location for 2008. reporter mice. Mice that express only neurogenesis is the dentate gyrus (DG) which is how the c-Myb gene itself is regulated. Research Assistants the membrane-spanning, cell-surface also defective in the c-myb brain-specific mutants. GRANTS AND FUNDING Sally Lightowler We have now confirmed that the MYB CSF-1 isoform were used to investigate – NHMRC Project Grant: $572,500, Senior Shienny Sampurno gene is mutated in most colon cancer regulation by systemic versus local CSF-1. PRESENTATION HIGHLIGHTS cells and this leads to relaxation of Research Fellowship, 2006–10. Yan Yuqian We found that mice deficient in CSF-1 or Assoc. Professor Robert Ramsay transcriptional control and consequently CSF-1R had greatly reduced numbers of – NHMRC Project Grant: $377,625, Postgraduate Students – Institute of Molecular Cancer Research, higher c-Myb levels. mature PCs and reduced numbers of the ‘c–Myb regulates stem–progenitor cell Dilara Akcora University of Zurich, 2008 (Invited • In ERα positive breast cancer MYB proliferating epithelial cell progenitors and cycle entry in colonic crypts providing Sandra Campinteri Speaker). elongation is controlled by oestrogen, lamina propria macrophages. Expression insights into colo–rectal carcinogenesis’, Helen Christenson – Australian Health and Medical Research which is an area of intense investigation of the membrane-spanning, cell-surface 2006–08. Sebastian Dworkin Congress (AHMRC), Colon Cancer in collaboration with Tom Gonda CSF-1 isoform in CSF-1–deficient mice – NHMRC Project Grant: $744,000, Duy Huynh Paneth Cells are absent in new born mice Group, Brisbane, Qld, November, 2008 (Diamantina Institute, Queensland) completely rescued the deficiencies of with defective Colony Stimulating Factor-1 ‘Molecular identification of the causative Yu Rebecca Miao (Invited Speaker), and Melissa Brown (University of PCs, proliferating progenitors, and lamina Receptor function. genetic and epigenetic alterations that Ben Williams Paneth cells (PC) form very rapidly after birth and – AHMRC, Australian Society for Stem Queensland). To intervene in breast and propria macrophages. These results can be readily detected using antibodies that induce or promote colorectal cancer’, Honours Student highlight the enzyme lysozyme. In wild type (WT) Cell Research, Brisbane, Qld, November, 2007–10. Dane Cheasley crypts these appear as dark brown clusters of 2008 (Selected Speaker). cells (red arrow). In CSF-1R-/- mutant crypts the – Cancer Council of Victoria: $210,000, Visiting Scholar PC are hard to find (orange arrow). A graphical – AHMRC, Career Development Session ‘CSF–1 as an essential intestinal Dr Elizabeth Vincan (Dept. Anatomy and representation of these data is displayed to show on Behalf of ASMR and NHMRC, mitogen’, 2006–08. these dramatic differences in PC frequencies. Brisbane, Qld, November 2008 (Invited Cell Biology, The University of Melbourne) Quantitation of an additional mutant mouse that – Queensland Cancer Council: $210,000, Speaker). fails to make CSF-1 (Op/Op) is also shown. ‘Regulation of c–myb the Estrogen Adult brain neurogenesis requires – The 2nd Australia–China Centre for receptor alpha in breast cancer’. c-Myb expression Excellence in Stem Cell Sciences 2008–10. Our brain-specific knock-out studies Workshop, Fingal, Vic, 2008 (Invited confirmed that c-Myb is required for the Symposium Speaker). PUBLICATIONS AND PATENTS maintenance of the neurogenic niche – Ludwig Institute for Cancer Research Publications are listed at the end of the in adult brain. Furthermore, the exciting Symposium, 2008 (Invited Symposium report and include references 113, 196, 248, 325. discovery that the ependymal cells that Speaker and Session Chair). – Department of Surgery, University of Left to right: Assoc. Professor Rob Ramsay, Dilara Akcora, Sandra Carpinteri, Dane Cheasley, Jordane Melbourne, 2008 (Invited Speaker). Malaterre, Cameron McPherson, Huiling Xu, Lloyd Pereira, Shienny Sampurno, Yan Yuqian.

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Cell Biology Program/ Differentiation & Transcription 55 Cancer Cell Biology Program/ Epithelial Stem Cell Biology

The Epithelial Stem Cell Biology laboratory RESEARCH OVERVIEW focus on the role of stem cells in epithelial cell markers and the molecular cross- – Inaugural Melbourne Cell and studies the role of stem cells and their Our laboratory continues to uncover cancer and defining the identity and talk between stem cells and their dermal Developmental Biology Meeting, microenvironment in tissue renewal and new information that promotes a greater molecular role of cancer-associated microenvironment (see Fig 2). Melbourne, Vic, November 2008 carcinogenesis. “fibroblasts” or stroma in tumour understanding of the role of epithelial stem PRIZES AND AWARDS cells in skin tissue regeneration, wound progression. RESEARCH FOCUS healing and cancer – a major cornerstone Dr Pritinder Kaur 2008 RESEARCH ACHIEVEMENTS • Tissue reconstitution ability of epidermal in cancer research given that epithelial – National Health and Medical Research stem cells and their cycling progeny. cancers make up more than 80 per cent of Human skin pericytes are multipotent Council (NHMRC) Senior Research • Role of pericytes in homeostasis, tissue all cancers. Mesenchymal stem cells Fellowship, 2008–12. Using a monoclonal antibody generated repair and cancer. It has been thought for some decades Figure 1: A-C: Organotypic cultures of human Dr Holger Schlueter in our laboratory which recognises the • Molecular profiling of epidermal stem that rapidly renewing epithelial tissues skin epithelia reconstituted from the combined – DFG (German Research Foundation) pericytes of microvessels in the dermis, keratinocyte stem and progenitor compartment cells and their progeny. at various body sites achieve cell Travel Award to attend the 2nd we previously reported on their ability to (A) versus the early differentiating compartment replacement through the combined activity (B). The low intrinsic skin reforming ability of early International Congress on Stem Cell and • Molecular and cellular cross-talk restore the intrinsic limited proliferative of stem cells and committed non-stem differentiating keratinocytes (B) could be enhanced Tissue Formation, Dresden, Germany, between the epidermis and dermal and tissue regenerative ability of early cells (progenitors). More recently, however, by the inclusion of human dermal pericytes in June 2008. microenvironment during tissue renewal, differentiating epidermal cells (non-stem the mesenchymal microenvironment or dermal studies have revealed that committed tissue repair and carcinogenesis. cells) in the absence of angiogenesis. equivalent (C), illustrating a novel role for pericytes Christian Orlowski progenitors in many epithelial tissues have in promoting tissue repair in the absence of This effect is likely to be mediated at least – Australian Postgraduate Award (APA), RESEARCH PERSONNEL a longer lifespan than first thought, and are angiogenesis. D-F: Human dermal skin pericytes in part by synthesis and secretion of the can act as mesenchymal stem cells capable of The University Of Melbourne. Head capable of tissue reconstitution previously a5 chain of the basement membrane differentiating into the fat (D), bone (E) and cartilage Dr Pritinder Kaur thought to be the exclusive domain of (F) lineages. GRANTS AND FUNDING protein LAM-511. Recent studies from stem cells. – National Institutes of Health (NIH) Research Officers our laboratory demonstrate that these THE MOLECULAR PROFILE OF HUMAN Project Grant: US$176,000 pa, ‘Tissue Daniel Blashki Our own published studies in human pericytes are also capable of differentiating SKIN STEM CELLS Dr Stuart Mills skin confirm this latter view – at the same into a number of mesenchymal lineages regenerative capacity of epidermal Dr Holger Schlueter time demonstrating a key role for actively including fat, bone and cartilage, We have previously reported on the use of Figure 2: Skin pericytes secrete laminin-511 in situ progenitors’, 2005–09. cycling progenitors in promoting skin the cell surface markers integrin a6 and the in skin as shown by immunogold EM localization of Postgraduate Students supporting the current notion that pericytes the LAMA5 chain. – NHMRC Project Grant: $92,500 pa, reconstitution ability. from many sites of the body can act as transferrin receptor CD71 to prospectively ‘Understanding Barrett’s oesophagus’, Ingrid Andersen (University of Oslo, isolate viable primary human keratinocyte Norway) We continue to investigate the interactions mesenchymal stem cells (see Fig 1). These PRESENTATION HIGHLIGHTS 2006–08. results have great significance for potential stem cells (KSC) and their committed Lynn Chong between the mesenchymal environment progeny — transient amplifying/committed Dr Pritinder Kaur – NHMRC Project Grant: $150,458 pa, therapeutic regimes to treat mesenchymal ‘Identification of clinically significant Christian Orlowski in which epithelial stem cells reside, with progenitor (TA/CP) cells and early – Timberline Symposium on Epithelial Cell deficits e.g. bone replacement, given the subtypes of head and neck cancer cells’, the aim of defining specific molecular differentiating (ED) cells — from human Biology, Mount Hood, Oregon, USA, accessibility and availability of skin tissue. 2007–09. regulators that are part of the intricate skin using criteria such as quiescence, February 2008 (Invited Speaker). conversation between these two – NHMRC Senior Research Fellowship: cell regenerative capacity and short-term – National Centre for Biological Sciences, compartments of the skin. $107,500 pa, 2008–2012. tissue forming ability. Our laboratory Tata Institute of Fundamental Research, These findings have strong implications recently demonstrated that transplantation Bangalore, India, February 2008 (Invited – NHMRC Project Grant: $167,000 for the ex-vivo expansion of patient cells of these keratinocyte fractions onto SCID Speaker). pa, ‘Patched gene family control of for autografting onto sites of severe mice, using a limit dilution approach, is epidermal development and cancer’. – Australian Health and Medical Research skin loss — such as on burns — while an excellent means of assessing their 2008–10. Congress (AHMRC) Brisbane, Qld, simultaneously improving our knowledge comparative potency to regenerate and November 2008 (Invited Speaker). – Australian Research Council (ARC) of stem cell regulation. Recent research maintain epidermal tissue in the long-term. Project Grant: $81,000 pa, ‘The role of – 5th Australian Scientific Dermatology directions in our laboratory increasingly Transplantation of 100 cells per fraction palmitoylation in hair follicle and stem cell Research (ASDR) Scientific Meeting, revealed that the candidate epidermal biology. 2008–10. KSCs (phenotype a6briCD71dim) were the Sydney, NSW, May 2008 (Invited most potent long-term tissue reconstituting Chairperson). PUBLICATIONS AND PATENTS cells, while the TA/CP cells (phenotype – Peter MacCallum Cancer Centre Publications are listed at the end of the a6briCD71bri) were the first to respond Symposium, Wilson’s Promontory, Vic, report and include references 57, 58. by reconstituting epidermal tissue, albeit October 2008 (Invited Chairperson and transiently. We have recently completed Organiser). (See overview of Symposium, Patent: Keratinocyte stem cells an Affymetrix microarray analysis of the pg 9). Inventors: Pritinder Kaur, Paul Simmons KSC, TA/CP and ED populations from – 33rd Lorne Conference on Protein – Australian patent 760506. neonatal human skin, which represents Structure and Function, Lorne, Vic, – United States patent 6485971. the first study to describe the molecular February 2008 (Invited Co-Chair). signature of human epidermal stem cells – United Kingdom patent 2351296. and their progeny. These data confirm Dr Holger Schlueter the distinct biological properties of the – 2nd International Congress on Stem stem, progenitor and early differentiating Cell and Tissue Formation, Dresden, compartments of the human epidermis, Germany, June 2008 (Poster). Left to right: Dr Pritinder Kaur, Stuart Mills, Lynn Chong, Holger Schlueter, Christian Orlowski. and provide insights into potential pathways of stem cell regulation, new stem

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Cell Biology Program/ Epithelial Stem Cell Biology 57 Cancer Cell Biology Program/ Molecular Radiation Biology

In a two-pronged approach to improving RESEARCH OVERVIEW While it is important to target Auger emitters chosen as the setting for pre-clinical proof- Auger-labelled DNA ligands for PUBLICATIONS AND PATENTS radiation treatment of cancer, our We are working to combat the limits of to DNA, there is also a requirement to target of-principle. The g-H2AX assay, a relatively imaging Publications are listed at the end of the laboratory is developing a topical radiotherapy by reducing damage to healthy the isotopes to the DNA of tumour cells. new, sensitive method for detection of In the receptor-mediated targeting system report and include references 125, 183, 246 radioprotector to protect normal tissue, surrounding tissue and improving the Accordingly, the overall strategy involves radiation-induced DNA damage (see Fig described above, the accumulation of Patent: Halogenated DNA ligand- and a strategy to better target radioactivity effectiveness of the radiation therapy. preparation of conjugates between tumour 1) is proving to be a very useful tool for labeled ligand on nuclear DNA would also to tumours. targeting proteins and DNA ligands labelled evaluation of the new radioprotectors. be advantageous for receptor-specific sensitizers for cancer therapy Our efforts to protect healthy cells with a with Auger emitting isotopes. imaging - for example using a positron Inventor: Roger Martin RESEARCH FOCUS topical application are now at the stage of The protein portion of the conjugates emitting isotope such as I124 for PET – United States patent 5641764 • A new class of DNA-binding radio lead optimisation – where the drugs we’ve imaging. However I124 is also an Auger developed are being refined or optimised in recognises specific receptors on the surface – Japanese patent 3007412 protecting drugs has been developed. of tumour cells. The receptor conjugate emitter, so the DNA-damaging feature preparation for use. Patent: Radioprotectors Refinement of the lead drug, complex is then internalised and degraded, would be an un-wanted side-effect for methylproamine, is underway. To date, we’ve developed new drugs that allowing the release of the labelled DNA- imaging-only applications, for example in Inventor: Roger Martin, David Kelly, • Minor groove-binding DNA ligands decrease the sensitivity of the cells to binding drug and translocation to nuclear non-oncology settings. In this context an Jonathon White important outcome of our recent research labelled with Auger-emitting isotopes ionising radiation, and because many of DNA, and finally accumulation of lethal DNA – Australian patent 717249 are being designed, synthesised and the normal tissues at risk are accessible damage upon decay of the isotope. comes from evaluation of ligands designed – Canadian patent 2228044 evaluated for DNA breakage efficacy and to topical application, this provides the to minimize the extent of damage. In such cytotoxicity. opportunity to target the radioprotector to 2008 RESEARCH ACHIEVEMENTS ligands, the Auger emitting atom (typically – Japanese patent 4125369 normal tissues without risk of protecting 125I) is positioned so it is “pushed away” – United States patent 6194414 • Conjugates of the labelled ligands with Development of DNA-Binding from the axis of the DNA helix, in the the tumour. tumour targeting proteins are being Radioprotector Drugs DNA-ligand complex. The results show prepared and evaluated, both in vitro With the lead drug methylproamine in hand, We have recently developed a collaborative that the efficiency of breakage by decay of (cytotoxicity) and in vivo (distribution in the research program is now in the stage research agreement with Sirtex Medical DNA-associated 125I is steeply dependant tumour-bearing mice). where, in collaboration with colleagues in the (Sydney) to support the Radioprotector upon the distance between the DNA helix University of Melbourne School of Chemistry Project. The funding associated with the and the radioactive atom; indeed, much RESEARCH PERSONNEL Figure 1: Radiation-induced damage in mouse at Bio21, new analogues are now being Research and License Agreement, in more so than anticipated from theoretical Head oral mucosa. The yellow spots (known as g-H2AX designed and synthesised to optimise the combination with an NHMRC development foci) mark the sites of repair of DNA double-strand studies. Clearly, these findings will aid Assoc. Professor Roger Martin properties of the drug. grant for the project, will provide support breaks in the nuclei (stained orange) of cells in in the design of 124I DNA ligands for mouse tongue mucosa. Senior Research Scientist Our other major project focuses on the use of about $2 million over a period of 18 diagnosis-only PET imaging. Dr Pavel Lobachevsky of radioactive isotopes for cancer treatment, months, starting on 1 October 2007. The in which we are looking at a particular class research program is divided into three PRESENTATION HIGHLIGHTS Senior Research Officer phases: lead optimisation, formulation of radio-isotopes called Auger emitters – the Assoc. Professor Roger Martin Dr Tom Karagiannis development and finally pre-clinical proof- chief trait of which is the highly focused – 54th Annual Meeting of the Radiation Research Officer of-principle of topical radioprotection. radiochemical damage associated with Research Society, Boston, USA, Dr Andrea Smith their decay. The lead optimisation phase involves the design and synthesis of new September 2008 (Speaker). Research Assistant Since nuclear DNA is the critical target for all analogues and evaluation in cell culture Li-Jeen Mah GRANTS AND FUNDING radiation effects on the cell, it is necessary for cytotoxicity, radioprotection and other Radiotherapy Research Assistants to target the Auger emitters to DNA for features. During 2008 several promising – National Health and Medical Research Michael May maximum efficacy. Thus we are developing new analogues have emerged. These are Council (NHMRC) Development Grant: Nicholas McGrath DNA binding drugs that are labelled with less cytotoxic than methylproamine, but $264,850, ‘New drugs to reduce the side- Chloe Pandeli Auger isotopes. with equal or better radioprotective activity effects of cancer radiotherapy’, 2007–08. Mervin Quai-Hoi in vitro. Mouse oral mucosa has been This NHMRC grant was supplemented by funding of $1.5 million associated Honours Students with the Licensing Agreement with Sirtex Kenneth Chin Medical. In November 2008, this funding Rebecca Pelzer was increased by $440,000 to support Summer Students enhancements to the Research and Amy Distiller Development Plan. Luke Formosa Jenna Langfield

Left to right: Assoc. Prof. Roger Martin, Pavel Lobachevsky, Chloe Pandelli, Kenneth Chin, Rebecca Pelzer, Jacinta Wubben, Andrea Smith, Tom Karagiannis.

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Cell Biology Program/ Molecular Radiation Biology 59 Cancer Cell Biology Program/ Tumour Suppression

Our laboratory studies the regulation and RESEARCH OVERVIEW The involvement of PML in cancer has function of tumour suppressors, with the been established in mouse models for The Tumour Suppression laboratory aim to manipulate these proteins to kill is incorporated within the Cancer Cell cancer, and in human samples. We have cancer cells. Biology Program. We’ve made major recently demonstrated that E6AP is a key breakthroughs in understanding the body’s regulator of the PML protein. We show RESEARCH FOCUS most important agent for fighting cancer, that E6AP acts to mediate the destruction • Identify key determinants of regulation the cellular protein p53, which plays a key of the PML protein. This finding has of the tumour suppressors p53 and the role in responding to assaults that damage opened up many areas of research with promyelocytic leukemia (PML) protein. DNA, and eliminating potentially cancerous broad and far-reaching implications for our understanding of tumour suppression • Define the regulatory mechanisms and cells by halting their growth. by PML and identification of novel and function of mutant forms of p53. We understand that in more than half of all attractive anti-cancer targets. • Investigate the involvement of the E6AP- human cancers p53 loses its anticancer PML axis in cancer development. properties through mutation, which not only PRIZES AND AWARDS Figure 1: C-Abl is critical for T cell survival and Figure 4: Structural model: Phosphorylation of function. We have recently shown that mice lacking Mdmx on tyrosine 99 is expected to strongly robs it of its ability to prevent cancer, but • Identify novel pathways of cellular stress Assoc. Professor Ygal Haupt c-Abl in their T cells fail to reject transplanted interfere with its binding to p53. Structure of Mdmx response. also boosts it with new cancer promoting tumours as seen in these in vivo imaging of T protein bound to the p53 peptide. Tyrosine 96 – Victorian Endowment for Science, capacity – through chemo-resistance lymphoma cells (Silberman et al.,2008). in zebrafish (equivalent to tyrosine 99 in human) Knowledge & Innovation (VESKI) RESEARCH PERSONNEL and an enhanced potential to proliferate is phosphorylated by c-Abl in response to DNA Fellowship damage (Zuckerman et al., 2009) Head and spread. Assoc. Professor Ygal Haupt Our recent findings demonstrate that the Senior Research Officer tumour suppressor PML is a key positive Dr Sue Haupt regulator of mutant p53. We found that PML is essential for the proliferation of Postdoctoral Fellow cancer cells bearing mutant p53, which Dr Gerard Tarulli suggests the tumour suppression function Research Assistant of PML depends on the status of p53. Paul Canham This work has opened exciting new areas of research, and includes the potential identification of new anti-cancer targets aimed at the mutant p53 pathway. The second major area of research in our lab is based on our recent discovery revealing a novel mechanism that Figure 2: p53 and PML colocalized in the PML regulates the turnover of the PML tumour nuclear bodies. In response to DNA damage, PML suppressor. PML is an important tumour recruits p53 to the PML-NBs where p53 undergoes activation by post-translational modifications. suppressor regulating multiple stress Immunofluorescence staining showing p53 in red, signalling pathways. PML in green and merge in orange (Alsheich-Bartok et al2008).

Figure 3: PML and CK1 colocalize in response to DNA damage: our recent work has shown that PML regulates the phosphorylation of p53 by CK1, and that CK1 and p53 co-localize in the nucleus in Left to right: Paul Canham, Daniel Brown, Ai-Leen Chan, Kamil Wolyniec, Sue Haupt, Gerard Tarulli. response to DNA damage. Immunofluorescence staining shown p53 (red) and CK1 (green) and merge in orange (Alsheich-Bartok et al2008). Assoc. Prof. Ygal Haupt

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Cell Biology Program/ Tumour Suppression 61 Cancer Therapeutics Program/

Integrating basic research Gene Regulation 64 Apoptosis & Natural Toxicity 66 activities, platform technologies, Pfizer/Peter Mac Cancer and pre-clinical model systems Genomics Program 67 Cancer Council Victoria (CCV) to discover, develop, characterise Venture Initiative 68 and refine novel cancer therapeutics for clinical use.

‘As a doctor involved in the treatment of blood diseases, I’ve always been interested in the science behind the medicine. The seamless integration of clinical and laboratory based research, excellent facilities and friendly, collaborative environment at Peter Mac provide the ideal setting to pursue this. The ‘bench to bedside’ ethos at Peter Mac means that our research findings are directly relevant to improving patient outcomes. This is the ultimate goal of every clinician scientist’.

Dr Jake Shortt PhD Student, Cancer Therapeutics Program, & Leukaemia Foundation Scholar

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Therapeutics Program/ 63 Cancer Therapeutics Program/ Gene Regulation

The Gene Regulation laboratory performs RESEARCH OVERVIEW 2008 RESEARCH ACHIEVEMENTS Functional Genomics-based studies – 6th European Workshop on Cell Death, Adrian Wiegmans basic and pre-clinical research aimed to identify novel tumour suppressor Hauenstein, Germany, June 2008 Our laboratory recently initiated a series Mechanisms of action of HDAC – 20th Lorne Cancer Conference, Lorne, genes and genes that regulate at defining the molecular processes of “discovery-based” projects using inhibitors (HDACi) (Invited Speaker, Session Chair and Vic, February 2008 (Poster). required for anti-cancer drug action and chemotherapeutic drug activities Discussion Leader). functional genomics to identify novel genes Our studies on HDACi have utilised highly drug resistance, and the mechanisms of In collaboration with Drs McArthur, Pearson PRIZES AND AWARDS involved in tumour onset and progression. sophisticated genetic models of human – 1st Heidelberg HDAC Inhibitor Workshop, interferon signal transduction. and Hannan, we have initiated whole cancer. Using these pre-clinical models we Heidelberg, Germany, June 2008 (Invited Assoc. Professor Ricky Johnstone With a particular interest in the molecular genome, functional genomics-based have identified key proteins necessary for Speaker and Session Chair). – Pfizer Australia Research Fellowship, RESEARCH FOCUS events necessary for the therapeutic and studies utilising the sophisticated RNA the apoptotic and therapeutic activities of – New Zealand Society for Oncology 2005–10. apoptotic activities of HDACi (histone interference technology available from the • Collaborative basic, translational and HDACi. Moreover, we have demonstrated Conference, Christchurch, New Zealand, deacetylase inhibitors), we are examining it Victorian Centre for Functional Genomics Leigh Ellis clinical research into the anti-cancer that tumour cells, but not isogenically August 2008 (Invited Speaker). both alone and in combination with to identify novel tumour suppressor genes – PhD completion, The Australian National activities of histone deacetylase matched normal cells, are specifically small molecule or antibody-based anti- and genes that regulate the apoptotic – European Union 6th Framework University, 2008. inhibitors. killed by HDACi. Using microarray gene cancer agents. activities of anti-cancer drugs. We have EPITRON consortium Annual Meeting, • Basic and pre-clinical characterisation expression profiling we have identified Nicole Messina utilised advanced human cell lines Tenerife, Spain, October 2008 (Invited of novel apoptosis-inducing therapeutic In most instances, we use genetically apoptosis-regulatory genes that are – Cancer Research Institute Pre-doctoral developed by Prof. Robert Weinberg that Speaker and Discussion Leader). agents used alone and in combination. engineered immunocompetent mouse specifically regulated in tumour cells – but Scholarship. were derived from primary breast epithelial – Peter MacCallum Cancer Centre models of cancer that reflect the genetics, not in normal cells – providing a molecular • Use of functional genomics-based cells and forced to go through stages of Workshop Symposium, Wilson’s – Poster Prize, Australian Society of biology and pathology of human disease. basis for the tumour cell-selective effects screens to identify novel tumour malignant transformation through the step- Promontory, Vic, October 2008 (Invited Immunology Annual Meeting. Evidence shows the combined approach of HDACi. These important mechanistic suppressor genes and genes that wise introduction of four different genetic Speaker and Session Chair). Dr Jake Shortt of tumour cell apoptosis (break down) studies have provided unique insight into regulate the apoptotic response to new elements (SV40 large and small T, hTERT, together with enhancing host immune the mechanisms of action of structurally – Monash Institute of Pharmaceutical – Leukaemia Foundation PhD Scholarship. anti-cancer agents. mutant/active Ras). Pre-malignant breast responses greatly enhances anti-tumour diverse HDACi and identified the genetic Sciences, Melbourne, Australia, October Mr Adrian Wiegmans • Characterisation of novel signal cells are being utilised to identify new efficacy. As such, we’re testing this lesions that can impart resistance to 2008 (Invited Speaker). transduction pathways stimulated by tumour suppressor genes, and the fully – Poster Prize, Lorne Cancer Conference. therapeutic regimen in various mouse HDACi-mediated therapy. (See Fig1) Dr Amber Alsop type I and II interferons. models of haematological malignancies transformed breast cells are being used GRANTS AND FUNDING to identify genes necessary for apoptosis – 20th Lorne Cancer Conference, Lorne, RESEARCH PERSONNEL and solid cancers to identify the induced by vorinostat and other anti- Vic, February 2008 (Poster). – Cancer Council Victoria Venture Grant: molecular mechanisms of these $850,000 over three years, ‘Identification Head cancer agents. Dr Chris Clarke combination strategies. of novel tumour suppressor genes in Assoc. Professor Ricky Johnstone – 20th Lorne Cancer Conference, Lorne, Another important focus of the laboratory Functional crosstalk between type I breast cancer and lymphoma using Senior Research Officer Vic, February 2008 (Poster). has been the study of interferon-induced and II interferon shRNA-mediated functional genomics Dr Chris Clarke signal transduction pathways. We have It has been known for some time that Dr Geoff Matthews screens’, 2007–09. Technical Officers recently identified a novel mechanism of exposure of cells to type I interferons – 20th Lorne Cancer Conference, Lorne, – NHMRC Project Grant: $2.16 Million pa, Kellie Banks crosstalk between type I and II interferons (interferons a and b) “primes” those Vic, February 2008 (Poster). ‘Immune regulation, effector function and Kym Stanley that we predict will result in a shift in cells to respond rapidly and robustly to – Thoracic Society of Australia and New therapy’, 2007–12. paradigm regarding the molecular other cytokines such as type II interferon Research Officers Zealand (TSANZ) Annual Scientific – Susan G. Komen for the Cure Foundation events that are necessary for a full and (interferon g). Until now, it has been Dr Amber Alsop Meeting, Melbourne, Vic, March/April (USA): $US200,000 pa “Combination robust interferon-mediated anti-tumour unclear how these two different signalling Dr Michael Bots 2008 (Poster). chemo-immunotherapy for established immune response. pathways communicate, however recent Dr Vanessa Solomon – Peter MacCallum Cancer Centre breast cancer” (Co-Chief Investigator work from our laboratory has identified a Workshop Symposium, Wilson’s with Mark Smyth) 2008–10. Research Assistants Figure 1: Luciferase imaging of mice transplanted key molecular event that underpins this with p53 deficient AML1/ETO9a + Nras leukaemia. Promontory, Vic, October 2008 (Poster). Leonie Cluse process. We have demonstrated that small – Pfizer Australia Senior Research Linda Hii ‘priming’ quantities of type I interferon Jessica Bolden Fellowship for Assoc. Professor Ricky Ben Martin enhance cellular responses to IFNγ by – 16th Annual International Cancer Johnstone: $200,000 pa, 2005–10. Postgraduate Students maintaining basal levels of STAT1, a key Immunotherapy Symposium, New York, – Cancer Council Victoria: $70,000 pa, Helen Arthur transcription factor necessary for the USA, September 2008 (Poster). ‘Histone deacetylase inhibitors: novel Jessica Bolden activation of cellular genes necessary to – 20th Lorne Cancer Conference, Lorne, anti-cancer drugs’, 2006–08. Leigh Ellis mediate a cellular response to type Vic, February 2008 (Poster). II interferon. PUBLICATIONS AND PATENTS Ailsa Frew Ailsa Frew Nicole Messina Publications are listed at the end of the PRESENTATION HIGHLIGHTS – 20th Lorne Cancer Conference, Lorne, 76, 100, 119, 154, Andrea Newbold report and include references Vic, February 2008 (Poster). 191, 213, 225, 250, 287. Dr Jake Shortt Assoc. Professor Ricky Johnstone Andrea Newbold Adrian Wiegmans – 2nd International Meeting on New For more information on related Directions in Leukemia Research, – 20th Lorne Cancer Conference, Lorne, research, see: Vic, February 2008 (Poster). Sunshine Coast, Qld, March/April 2008 – Cancer Immunology Program [pg 12] (Invited Speaker). Kym Stanley – 99th Meeting of the AACR, San Diego, – The Australian and New Zealand USA, April 2008 (Invited Speaker). Laboratory Animal Association (ANZLAA) Left to right: Assoc. Prof. Ricky Johnstone, Inge Verbrugge, Belinda Kelly, Andrea Raitsma, Ailsa Frew, – AACR Special Workshop on Cancer Annual Conference, Sydney, NSW, Rachel Ralli, Mark Bishton, Alison West, Ben Martin, Michaela Waibel, Jake Shortt, Leonie Cluse, Kellie Epigenetics, Boston, USA May 2008 September 2008 (Poster). Banks, Ashley Robertson, Geoff Matthews, Adrian Wiegmans, Jason Brady, Nicole Messina. (Speaker).

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Therapeutics Program/ Gene Regulation 65 Cancer Therapeutics Program/ Cancer Therapeutics Program/ Apoptosis & Natural Toxicity Pfizer / Peter Mac Cancer Genomics Program

Our laboratory is dedicated to cytotoxic T cells and natural killer cells, are will be sufficient to re-sensitize tumours to The goal of the Pfizer/Peter Mac Cancer RESEARCH OVERVIEW signature” using a continuous predictor understanding the critical processes cells of the immune system that kill tumour immune mediated clearance by natural Genomics Program is to identify tumour Cancer develops as a result of multiple model and principal component analysis that control cell death, and using this cells or cells infected by virus. killer cells. signatures that will guide the use of gene mutations and individuals with the based feature reduction that is 95 per knowledge to develop ways to either reset, chemotherapy to cancer patients who are cent accurate in classifying cells as either Cytotoxic lymphocytes use granzyme B to same type of cancer often have dissimilar or bypass, defects in cell death pathways PRESENTATION HIGHLIGHTS most likely to respond. resistant or sensitive to a drug that targets kill their targets by apoptosis, but can also genetic defects; these differences underlie which have contributed to tumourigenicity. Dr Nigel Waterhouse the clinical spectrum of disease outcomes, the PI3 kinase pathway. kill cells in which apoptosis is blocked. In RESEARCH FOCUS progression and drug effectiveness. One RESEARCH FOCUS addition, cytotoxic lymphocytes that are – The European Workshop on Cell Death, FUNDING deficient in granzymes A and B cannot Hauenstein, Germany, 2008 (Invited • Melanoma and ovarian cancer. of the major challenges in treating cancer • Understanding the molecular trigger granule mediated apoptosis, but Speaker). • Screening tumours for drug sensitivity. is the selection of the most effective – $3.3 million under ‘Peter MacCallum mechanism of apoptotic cell death. Pfizer Translational Oncology Research they can kill their targets by non-apoptotic – Cell Death Society International Meeting, • Using genomic, proteomic and chemotherapy agents for individual Collaborative Hub (TORCH)’, 2008–10. • Defining the critical regulators of mechanisms Because mice lacking Shanghai, China, 2008 (Invited Speaker). metabolomic profiling to obtain a drug patients. To address this challenge the aim apoptotic cell death that contribute granzyme A and B are viable, survive of the Pfizer/Peter Mac Cancer Genomics – Hunter Valley Cell Biology Meeting, predictive signature. For more information on related to cancer. diverse infections and do not develop Program is to generate Proteomic, research, see: Hunter Valley, NSW, 2008 (Invited • Functional genomic RNAi screens spontaneous tumours, understanding Metabolomic and Genomic Profiles of • Understanding how cytotoxic Speaker). to identify genes associated with – Cancer Immunology Program [pg 12] the way that cytotoxic lymphocytes kill human tumours and use this information to lymphocytes utilise granzymes to resistance. – Growth Control and Differentiation their targets by non-apoptotic/caspase- – Fluorescence Imaging Group, predict drug effectiveness in patients. cancer cells. Program [pg 36] independent mechanisms is likely to Melbourne, Vic, 2008 (Invited Speaker). • Investigating how small molecule RESEARCH PERSONNEL As a first step toward achieving this goal uncover targets for future cancer therapies. – IgV Master Class, Melbourne, Vic, 2008 – Translational Research Program [pg 70] inhibitors of Bcl-2 re-sensitize cancer Program Leaders we are screening a panel of human ovarian (Invited Speaker). tumour and melanoma cell lines for their cells to cytotoxic lymphocyte mediated 2008 RESEARCH ACHIEVEMENTS Assoc. Professor Rick Pearson cell death. – University of Melbourne, Melbourne, Vic, Assoc. Professor Wayne Phillips sensitivity to Pfizer drugs. Concurrently Apoptotic signal transduction by NK 2008 (Seminar Speaker). these cells are being profiled using Program Manager RESEARCH PERSONNEL cell granzyme B genomic, proteomic and metabolomic – University of Barcelona, Spain, 2008 Dr Karen Sheppard Head Human granzyme B (hGraB) preferentially (Seminar Speaker). approaches. Bioinformatics analysis is Chief Investigators Dr Nigel Waterhouse induces apoptosis via Bcl-2-regulated – The Hanson Centre, Adelaide, SA, 2008 then being employed to look for signatures mitochondrial damage but can also Assoc. Professor Ross Hannan that predict drug efficacy. Genomic Research Assistant (Seminar Speaker). directly cleave caspases and caspase Assoc. Professor Ricky Johnstone Profiling is being achieved by using Karen Sedelies substrates in cell-free systems. How hGraB – St Vincents Hospital, Melbourne, Vic, Assoc. Professor Grant McArthur microarray technology to determine gene Postgraduate Student 2008 (Seminar Speaker). kills cells when it is delivered by cytotoxic Postdoctoral Scientist expression and gene copy number, and Olivia Susanto lymphocytes (CL) and the contribution of PRIZES AND AWARDS Dr Joanna Chan gene mutations are being identified using hGraB to CL-induced death is still not clear. a broad candidate approach utilising exon RESEARCH OVERVIEW Dr Nigel Waterhouse Research Assistants capture and next generation sequencing. A We showed that primary human NK cells, – NHMRC RD Wright Fellowship 2005–09. Amelia Neilsen candidate Proteomic approach using both Our laboratory is particularly interested in which specifically used hGraB to induce Gwyn Ng Reverse Phase Protein arrays and Western the process of apoptosis, which is a form target cell death, were able to induce GRANTS AND FUNDING Analysis is been undertaken to identify of cell death by which the body naturally apoptosis of cells whose mitochondria – NHMRC Project Grant: $738,000, key signalling pathway components eliminates many billions of dangerous or were protected by Bcl-2. Purified ‘Regulation of Leukocytes Lifespan by that are altered in these cells. Cellular unwanted cells every day. hGraB also induced apoptosis of Bcl- granzyme B and PI-9’, 2008–10. and excreted metabolites are being The importance of the research is in its 2-overexpressing targets but only when – NHMRC Project Grant: $321,750, analysed by gas chromatography and potential to better understand and treat delivered at 5 to 10 times the concentration ‘Molecular mechanisms of death in cells Mass Spectrometry in collaboration with cancer cells, which often contain defects required to kill cells expressing with defective apoptotic pathways’, Metabolomics Australia at Bio21. To date in cell death pathways – making them endogenous Bcl-2. Caspases were critical 2007–09. we have successfully generated a “gene resistant to pro-death stimuli including in this process as inhibition of caspase many chemotherapeutic drugs. activity permitted clonogenic survival – NHMRC RD Wright: $426,250 of Bcl-2-overexpressing cells treated ‘Mechanisms of CL mediated cell We know that MOMP (mitochondrial outer with hGraB or hNK cells but did not death; integration of multiple cell death membrane permeabilisation) is critical for protect cells that expressed only pathways, 2005–09. cell death, including in the use of most endogenous Bcl-2. chemotherapeutic drugs, however, many PUBLICATIONS AND PATENTS cancers contain defects in pathways that Our data therefore showed that only Publications are listed at the end of the regulate MOMP. hGraB triggers caspase activation report and include references 270, 292. via mitochondria-dependent and Our research on apoptosis is focused on mitochondria-independent mechanisms understanding how MOMP occurs, how that are activated in a hierarchical manner, MOMP is regulated, and how to resensitise and that the combined effects of Bcl-2 cells to apoptosis when pathways that and direct caspase inhibition can block regulate MOMP are defective. cell death induced by hGraB or primary Apoptosis is the predominant form of hNK cells. [Reference: Sedelies K et al., physiological cell death, but it is not the (2008) Cell Death and Differentiation 15: only form of cell death tolerated by the 708–17]. These experiments suggest that Left to right: Assoc. Prof. Rick Pearson, Jason Ellul, Kylie Morgan, Amelia Neison, Karen Sheppard, Joanna body. Cytotoxic lymphocytes, including restoring defects in one of these pathways Chan, Gwyn Ng, Assoc. Prof. Wayne Phillips.

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Therapeutics Program/ Pfizer / Peter Mac Cancer Genomics Program67 Cancer Therapeutics Program/ Cancer Council Victoria (CCV) Venture Grant Initiative

RESEARCH FOCUS LABORATORY OVERVIEW initially respond, but later relapse, as their Our laboratory is focused on the Our two major aims include singling tumours become “drug-resistant” and identification of novel breast cancer tumour out the genes that affect the onset and much more difficult to treat. suppressors and genes which regulate progression of cancer, and the genes Taken together, these studies will sensitivity to cancer therapeutics. that are necessary for anti-cancer drugs significantly advance our knowledge of to work. the genes and molecular pathways that RESEARCH PERSONNEL The first of two major aims is the are deregulated in cancer and will provide Heads identification of new tumour suppressor important information about how anti- Assoc. Professor Ricky Johnstone genes with a particular focus on breast cancer therapeutics kill cancer cells and Assoc. Professor Ross Hannan cancer using RNA interference (RNAi)- how tumour cells evade such treatments. Assoc. Professor Rick Pearson based gene knockdown technology. The Our studies will provide novel tools and Assoc. Professor Grant McArthur approach enables us to eliminate the identify new cancer targets to advance our efforts to develop new diagnostic and Postdoctoral Fellows expression of all known human genes one therapeutic strategies. Dr Christine Hauser at a time, thus carrying out genome-wide Dr Kathy Jastrzebski functional genomics screens. Studies performed as part of the CCV Venture Grant Initiative grant initiative Research Assistant To date, we have identified several putative use cutting edge gene knockdown Greg Leong breast cancer tumour suppressors and are now in the process of further validation technologies from the Victorian Centre for Honours Student and characterisation of their mechanisms Functional Genomics (VCFG) to identify Elaine Chilcott of action. Our approach includes looking the genetic changes that underpin cancer Summer Student at cells that already have a number of formation, and to determine how to best Figure 2 – Schematic of the genome-wide FUNDING Fiona Bell use anti-cancer drug therapies. RNAi-based screening approach. Pools of RNAi defined cancer-causing “genetic hits” and constructs are transduced into human mammary – Cancer Council Victoria (CCV) CCV have moved some of the way along the epithelial cells and sorted for Green Fluorescent Venture Grant Scheme through the transformation process, but require one Protein (GFP) expression with cells marked that generous support of the John T Reid last “hit” to form a tumour. This enables have successfully taken up the constructs. Cells are then put through a selection procedure - growth Charitable Trusts, $317,000, 2008. us to single out new tumour suppressor independent of anchorage or in the presence of For more information on related genes that can regulate the onset and therapeutic - and DNA from these and reference research, see: progression of cancer. cells is extracted. This genomic DNA is used as template for PCR wherein the RNAi hairpin – Cancer Immunology Program [pg 12] Our second aim is to identify genes is amplified and elements required for high throughput Next Generation Sequencing (NGS) are – Growth Control and Differentiation that are required, for existing and newly added. This generates a library which, following Program [pg 36] developed anti-cancer therapeutics, to kill sequencing on the Genome Analyser II (Illumina), Figure 3 – Loss of PP2A function leads to cancer cells. To do this, we have screened can be used to rank hairpins that have been anchorage independent growth. Expression of the – Translational Research Program [pg 70] a number of therapeutics for their ability enriched for in the selected samples. This analysis catalytic subunit of PP2A (PPP2CB) was attenuated Figure 1 – Anchorage independent growth of generates a list of putative tumour suppressors or in pre-tumourigenic human mammary epithelial to kill breast cancer cells and, using gene RNAi construct-transduced mammary epithelial genes which regulate sensitivity to therapeutics. cells expressing the catalytic subunit of telomerase, knockdown technology, we are now in cells. Phase contrast (phase) and fluorescence These genes are then validated individually and SV40 large T antigen and oncogenic Ras using microscopy (GFP) of two representative colonies of their mechanism of action characterized. a specific RNAi construct. Cells were grown the process of identifying genes that are transformed human mammary epithelial cells grown necessary for their activity. These studies in soft agar for 2.5 weeks to assay anchorage in soft agar for 2.5 weeks. Images were taken on a independent growth and stained with MTT to will allow us to determine why some Leica inverted microscope under 10x magnification. visualize colonies. cancer patients do not respond to a given Scale bar 200μm. anti-cancer drug and/or why patients may

Left to right: Assoc. Prof. Ricky Johnstone, Assoc. Prof. Ross Hannan, Kathy Jastrzebski, Assoc. Prof. Grant McArthur, Assoc. Prof. Rick Pearson, Greg Leong, Christine Hauser.

Peter MacCallum Cancer Centre – Research Report 2008 Cancer Therapeutics Program/ Cancer Council Victoria (CCV) Venture Grant Initiative 69 Translational Research Program/

Using basic research, clinical Translational Research Laboratory 72 Molecular Imaging Laboratory 74 trials and collaboration with Centre for Blood Cell Therapies 76 industry to maximise the future Haematology Immunology Translational Research 78 impact of research findings for Molecular Pathology 80 cancer patients.

‘As a translational researcher at Peter Mac I am privileged to work with basic scientists, imaging specialists and clinicians. Our ongoing challenge is to identify markers that predict tumour response to novel molecularly targeted therapies thereby facilitating the use of more effective cancer treatments in patients’.

Dr Carleen Cullinane Scientific Manager Translational Research Laboratory

Peter MacCallum Cancer Centre – Research Report 2008 Translation Research Program/ 71 Translational Research Program/ Translational Research Laboratory

As part of the Centre for Molecular RESEARCH OVERVIEW the PI3K/AKT pathway therefore has – International Melanoma Working Group, – NHMRC: $128,125 pa, ‘Inhibition of Imaging and Translational Medicine, Our research program brings together potential to enhance the therapeutic effect Florence, Italy, May and Florida, USA, CHK1 Kinase for Cancer Therapy’, the Translational Research Laboratory functional imaging and powerful tools in of radiation. The PI-3-kinase inhibitors November 2008. 2008–10. investigates the application of new cell and molecular biology to understand LY294002 and wortmannin have been – World Meeting of Interdisciplinary – Victorian Cancer Agency: $339,000, targeted therapies for cancer by integrating and predict responses to targeted shown to enhance the effects of radiation Melanoma Centres, Florida, USA, ’The Melbourne Melanoma Project’, cell biology, molecular biology, functional therapies. in a broad range of tumour models, but November 2008. 2008–09. imaging and clinical trials. these compounds lack selectivity and – Royal Australian Chemical Institute – Pfizer Collaborative Research funding: Our work focuses on four main lines have pharmacological properties that Annual Meeting, Qld (Plenary Lecture). $15 million, ’Peter MacCallum RESEARCH FOCUS of investigation: developing specific preclude clinical use. Recently, more – The University of Melbourne, Lecture Translational Oncology Research • Investigation of inhibitors of protein and strategies to provide proof-of-mechanism selective novel compounds with improved Series: Defence Mechanisms and Their Collaborative Hub: TORCH’ 2008–10. lipid kinases using laboratory and for the activity of targeted cancer therapies pharmacological properties have been Failure (510-310) The Principles of – Cancer Council Victoria Venture clinical studies. in early phase clinical trials with a strong developed and have entered early phase focus on functional imaging; investigation clinical trials. We have demonstrated Chemotherapy, May 2008 (Lecturer). Grant: $1,200,000, ‘Identification of • Identification and validation of of biomarkers of tumour hypoxia to predict that one of these agents, BEZ235 Professor Rod Hicks novel breast cancer suppressor and biomarkers to predict response to response to targeted and traditional cancer chemotherapeutic drug sensitivity (Novartis, Basel, Switzerland), a novel – The Endocrinological Society of Australia targeted therapeutics. therapies; investigation of molecular genes using shRNA-mediated functional dual inhibitor of PI3K and mammalian Annual Scientific Meeting, Sydney, NSW, • Mechanism of action of therapeutics mechanisms of response to small genomics screens’, 2007–10. target of rapamycin (mTOR), can cause May 2008. targeting signalling, cell cycle and cell molecule inhibitors of protein and lipid significant radiosensitisation. The Figure 1: Representative Comet Assay images – Transport Accident Commission/Victoria of ionizing radiation induced DNA damage in the Dr Carleen Cullinane surface receptors. kinases; and combining novel targeted mechanisms involved in this interaction Neurotrauma Initiative: $433,522 (in presence of vehicle (A) or BEZ235 (B). Unrepaired – American Association for Cancer • The role of hypoxia in responses to therapies with conventional radiation involve enhancement of radiation-induced DNA damage is evident by the DNA comet tail in 2008), ‘Longitudinal in vivo study of cancer therapies. therapy or cytotoxic chemotherapy. DNA damage as a result of impaired the BEZ235 treated cells. Research (AACR) Annual Meeting, San hippocampal structure and function repair of DNA double stranded breaks Diego, USA, April 2008 (Poster). and relationship to neurocognitive, RESEARCH PERSONNEL We use a range of technologies to Nilotinib activity characterisation using (Fig 1). We are now studying the cellular neurobehavioral and epileptic outcomes, interrogate these processes, including FDG-PET PRIZES AND AWARDS Head transgenic and gene targeted models consequences of BEZ235-mediated in a model of human traumatic brain Treatment of gastrointestinal stromal tumour Assoc. Professor Grant McArthur Assoc. Professor Grant McArthur of cancer, PET imaging, functional radiosensitisation, including effects on cell injury’, 2007–10. (GIST) has been revolutionised by the – Sir Edward Dunlop Clinical Cancer Co-Head ultrasound, genetic modification of cancer cycle progression, apoptosis, senescence, – Federal Government of Australia and autophagy, in addition to vivo studies targeted agent, imatinib. GIST response Research Fellowship, Cancer Council Professor Rod Hicks cell lines, cell imaging using fluorescence to imatinib is associated with a rapid Collaborative Research Consortium microscopy, immunohistochemistry and of the combination effect of BEZ235 and Victoria, 2006–10. Grant: $4 million, CRC for Biomedical Scientific Manager reduction in tumour cell metabolism as electron microscopy and quantitative radiation. These preclinical studies will – Medical Media Award for his tireless Imaging Development (with partners, Dr Carleen Cullinane detected by fluorodeoxyglucose positron provide a rationale for clinical studies commitment to the media to honour the protein analyses. emission tomography (FDG-PET). We Monash University, ANSTO, Cyclotek Pty Physician Scientist of novel signal transduction inhibitors in dying wish of 26 year old Clare Oliver – are investigating the antitumour activity Ltd, GE Medical Systems Inc, and IBM Dr Ben Solomon 2008 RESEARCH ACHIEVEMENTS combination with radiotherapy. that the message about the danger of of a novel c-KIT inhibitor, nilotinib against Inc., total grant: $23.2 million), 2005–12. sun bed tanning reach as many people Postdoctoral Scientists Radiosensitisation with novel imatinib sensitive and resistant tumours and – Leukemia and Lymphoma Society USA as possible. Dr Petranel Ferrao inhibitors of phosphatidylinositol-3 evaluating the utility of FDG-PET imaging Project Grant: US$600,000, ‘A phase I Dr Kathryn Kinross kinase as a biomarker of nilotinib response in Dr Ben Solomon study investigating the tolerability, safety Dr Jeanette Raleigh The phosphatidylinositide 3-kinase (PI3K)/ vivo. Using a novel preclinical model we – Peter Mac New Investigator Grant and biological parameters of an infusion Dr Titaina Potevin AKT pathway is known to be activated have shown that tumour cells expressing 2008–09, $25,000. of autologous peripheral T-lymphocytes by ionizing radiation and accumulating an imatinib resistant c-KIT mutation were transduced with an anti-Lewis-Y chimeric Research Assistants sensitive to nilotinib in vitro but in vivo, these GRANTS AND FUNDING receptor gene in patients with LewisY Ekaterina Bogatyreva evidence indicates that it may be a major cells were resistant to both nilotinib and progressive multiple myeloma’. 2005–08. Athena Hatzimihalis contributor to radioresistance of cancer – National Health and Medical Research imatinib. These studies are fundamental to Anthony Natoli cells. Inhibition of signalling through Council (NHMRC) Project Grant: – Peter Mac New Investigator Grant defining the clinical utility of nilotinib for the Kelly Waldeck $500,125, ‘Predicting Outcomes of 2008–09, $25,000 treatment of imatinib sensitive and resistant Richard Young Treatment in Head and Neck Cancer’, c-KIT driven tumours. 2006–08. PUBLICATIONS AND PATENTS Technical Assistants – NHMRC Project Grant: $143,250 pa, Publications are listed at the end of the Kerry Ardley PRESENTATION HIGHLIGHTS ‘Imaging functional changes during report and include references 27, 28, 29, 35, 55, Susan Jackson Assoc. Professor Grant McArthur molecularly targeted therapy in a 66, 68, 73, 94, 99, 108, 112, 123, 134, 139, 158, 162, 177, 182, Alison Slater – New Directions in Leukemia Research, new model of gastrointestinal stromal 193, 194, 199, 208, 215, 239, 242, 260, 306, 317, 328, 341, 346. Rachael Walker Sunshine Coast, Qld, March–April 2008. tumour’, 2006–08. Jeannette Valentan For more information on related – Pfizer Oncology Forum, Melbourne, Vic, – NHMRC Project Grant: $429,750, research, see: Advanced Medical Science Students April 2008 (Speaker). ‘Mechanisms of uptake of 18F-FDG in an Molecular Oncology [pg 42] Brent Corcoran (2007–08) in vivo model of c-kit induced neoplasia’, Heny Yao (2008–09) – 17th Annual Congress, Association Cancer Therapeutics Program [pg 62] of Regulatory and Clinical Scientists 2006–08. Molecular Imaging Research [pg 74] (ARCS), Sydney, NSW, May 2008. – Cancer Council Victoria, Sir Edward Centre for Molecular Imaging [pg 90] – AGITG Trials in Action Annual Scientific Dunlop Clinical Research Fellowship: Meeting, Sydney, NSW, May 2008. $144,500 pa, 2006–10. Medical Oncology & Early Phase Clinical Left to right: Prof. Rod Hicks, Assoc. Prof. Grant McArthur, Carleen Cullinane, Kerry Ardley, Athena – National Institutes of Health (USA): Trials [pg 106] Hatzimihalis, Mark Devlin, Rachel Walker, Anthony Natoli, Susan Jackson, Jeanette Raleigh, Richard – Australian Society of Medical Research, Young, Jeannette Valentan, Kelly Waldeck, Arun Azad, Ekaterina Bogatyreva, Alison Slater, Anna Caldwell, Research Week Seminar, Monash US$702,400, ‘Defining Molecular Gastrointestinal [pg 110] Margarete Kleinschmidt, Titaina Potdevin. Markers of Hypoxia’, 2006–10. Institute of Medical Research, June 2008. Melanoma & Skin [pg 120]

Peter MacCallum Cancer Centre – Research Report 2008 Translational Research Program/ Translational Research Laboratory 73 Translational Research Program/ Molecular Imaging Laboratory

As part of the Centre for Molecular Imaging RESEARCH OVERVIEW the Cooperative Research Centre for (ANSTO) and the CRCBID, we have tracers are particularly exciting for brain apoptotic death would be very helpful to and Translational Medicine, our laboratory We’re providing crucial imaging data Biomedical Imaging Development synthesised a novel BZA compound that tumour localisation and characterisation. assess effectiveness, especially with novel uses in vivo imaging of tumour biology (CRCBID) to develop novel PET tracers can be labelled with 18-fluorine (18F), or experimental therapies. A common and researching improved imaging PET imaging of somatostatin receptors in models of human cancers to develop and technologies. Our aim is to image making it an outstanding candidate as a method for assessment of apoptosis in methods to better understand and map in neuroendocrine tumours new therapies and improved imaging behaviour of tumours as they grow or cancer related processes such as diagnostic imaging agent for melanoma. tissue culture cells uses a fluorescently technologies for cancer patients. hypoxia, angiogenesis and apoptosis, We have developed high yielding Neuroendocrine tumours (NET) are rare labelled annexin that binds to lipids on the respond to therapy. Our particular focus tumours usually occurring in the gut, is the development and use of molecular and to visualise molecular targets such chemistries for 18F labelling of this surface of apoptotic cells. When labelled RESEARCH FOCUS as cell surface receptors or altered compound, which has shown excellent lung and pancreas that are resistant to with 18F for PET imaging, however, imaging techniques in patients – chiefly conventional cancer therapies. NETs • Targeting molecular pathways involved signalling proteins in tumours. Further imaging properties in animal models annexin often loses its binding properties. using PET (positron emission tomography). often have low uptake of FDG and are in metabolism, amino acid transport and we are developing PET tracers targeting of metastatic melanoma (See Fig 1). In We are working on better labelling not well visualised by FDG-PET. NETs apoptosis for cancer imaging. Using two small animal PET scanners, specific tumour types, including metastatic addition, we are developing a mouse methods and modifications of annexin to we capture changes in tumour biology in melanoma and neuroendocrine tumours. model to test 18F-BZA for PET imaging are characterised by high expression of improve its properties for PET imaging • Imaging receptor activation and hypoxia murine models of cancer. With positron- of sentinel lymph nodes in melanoma. somatostatin (SST) receptors, especially of apoptosis. in tumours. emitting tracers we are able to assess 2008 RESEARCH ACHIEVEMENTS This new tracer has potential as a highly SSTR2, and this has been exploited for • Developing novel agents and important functional changes in tumours single photon emission tomography GRANTS AND FUNDING Melanoma Imaging effective clinical PET imaging agent to technologies for PET imaging of as they grow or respond to therapy, (SPECT) imaging using indium-labelled Malignant melanoma is among the most improve diagnosis and treatment of – Federal Government of Australia melanoma, neuroendocrine cancers and including processes such as metabolism, SST peptide analogues (111-In-octreotide). aggressive and invasive tumour types, metastatic melanoma. First-in-human Collaborative Research Consortium lymph node metastasis. proliferation, amino acid transport and However, SPECT imaging lacks the high for which current treatments are rarely clinical trials are planned for late in 2009. Grant: CRC for Biomedical Imaging • Developing advanced chemistries and hypoxia. Our imaging technologies are resolution of PET and is less effective effective, making it an important target Development. Grant value $23.2 automation procedures to produce also used to test and explore functional for visualisation of small metastatic for improved diagnostic and therapeutic million dollars to all participants with radiopharmaceuticals for clinical effects of genetic mutations in tumour lesions, reducing its usefulness for methods. A class of compounds called approximately $4 million to Peter Mac, applications. models in an effort to reveal how staging or treatment monitoring. We benzamides (BZAs) has been suggested 2005–12. specific mutations can affect therapeutic have characterised a model system for as possible melanoma imaging agents RESEARCH PERSONNEL outcomes. the development of 68-gallium labelled – National Health and Medical Research as these bind tightly and irreversibly to Council (NHMRC) Project Grant: Head octreotides for PET imaging. Our recent Alongside PET, we also use ultrasound melanin, a pigmented protein found in $429,750, ‘Mechanisms of uptake of Professor Rod Hicks acquisition of a gallium generator will make and high resolution autoradiography for large amounts in most melanoma cells. it possible to develop improved imaging 18F-FDG in an in vivo model of c-kit Co-Head preclinical and basic imaging research, Because of this tight binding property, capabilities for NET, including development induced neoplasia’, 2006–08. Assoc. Professor Grant McArthur with a focus on early clinical translational BZAs have the potential to act as of individualised dose and therapeutic studies. In ultrasound experiments it is PUBLICATIONS AND PATENTS Project Leader ‘diagnostic/therapeutic pairs’– that is, combination planning. possible to determine extent of tumour Dr Donna Dorow when labelled with a PET radionuclide, Publications are listed at the end of the vascularisation and fluid balance – this they can be used for diagnostic imaging Imaging tumour hypoxia report and include references 27, 28, 29, 55, 66, Research Officer enables us to quantify effects of anti- of metastatic lesions or recurrences, then Figure 1. Ga-68 octreotate is a peptide suitable Many rapidly growing solid tumours lack 68, 108, 112, 139, 162, 177, 193, 194, 195, 215, 239, 242, 306, Dr Delphine Denoyer cancer therapies that target angiogenesis labelled with a high energy therapeutic for PET imaging of neuroendocrine tumours normal blood flow and thus have low 318, 328. in tumours. expressing the somatostatin subtype 2 and 5 oxygen tension in central regions. Cells Research Assistant radionuclide for treatment. Past studies receptors. Availability of a Ga-68 generator has populating these hypoxic areas exit the For more information on related Laura Kirby High resolution ex vivo autoradiography have concentrated on BZA analogues enabled development of this imaging technique to interrogate animal models and human disease. cell cycle and enter a resting phase in research, see: further enables us to determine functional labelled with isotopes of iodine for both Radiopharmaceutical Chemists imaging and therapy. However, iodine High excretion through the kidney leads to low which they are extremely resistant to most Molecular Oncology [pg 42] properties of tumour sub-regions and background activity in most normal tissues apart Peter Roselt anti-cancer therapies. These hypoxic Cancer Therapeutics Program [pg 62] assess individual cellular masses within isotopes suitable for PET imaging are from tumours containing the appropriate receptor. Oliver Neels cells can remain after treatment and seed a tumour. virtually unavailable in Australia and very Translational Research [pg 70] difficult to access worldwide. Together with Targeting amino acid transport for repopulation once they re-enter the cell Centre for Molecular Imaging [pg 90] The research component of our collaborators at the Australian Nuclear cancer imaging cycle. Drugs exist that can specifically work includes a collaboration with Science and Technology Organisation Due to the increased metabolic rate of sensitise hypoxic cells to therapy if Gastrointestinal [pg 110] many tumour types, 18-Fluorine labelled their presence can be identified before Melanoma & Skin [pg 120] glucose (FDG) is an extremely effective treatment. We have improved methods agent for PET imaging of cancers. In for 18-F labelling of a compound that tissues with high intrinsic metabolic rates binds to proteins in hypoxic conditions. such as brain or heart, or in settings This compound has proved to be highly of inflammation or diabetes, FDG-PET effective for PET imaging of hypoxic has reduced sensitivity. In addition to tumour cells in mouse models of human high glucose utilisation, growth and cancers. Pre-clinical imaging underpins a proliferation of tumour cells require strong clinical program in hypoxia imaging continual production of protein, leading to in which Peter Mac is recognised to be increased expression of many cancer cells internationally competitive. have increased expression of amino acid transporters. We have developed methods Imaging apoptosis in cancer cells for 18F-labelling of tyrosine and methionine Treatment with targeted therapeutics has analogues which have now been used the potential to cause rapid apoptosis successfully for preclinical and clinical in tumour cells but detectable shrinkage Left to right: Prof. Rod Hicks, Dr Delphine Denoyer, Laura Kirby, Margarete Kleinschmidt, of the tumour mass may take weeks Assoc. Prof. Grant McArthur. imaging for specific tumour types. These or months. The ability to directly image

Peter MacCallum Cancer Centre – Research Report 2008 Translation Research Program/ Molecular Imaging Laboratory 75 Translational Research Program/ Centre for Blood Cell Therapies

The Centre for Blood Cell Therapies RESEARCH OVERVIEW tumour cells in acute myeloid leukemia, look at correlations between collection – Taiwan Haematologists Meeting, Taipei, institutions for cell therapy projects’, develops and manufactures cell- and With expertise in cell and tissue therapies multiple myeloma and myelodysplastic conditions and transplant outcomes. Taiwan, January 2008 (Invited Speaker). 2007–12. tissue-based treatments arising from both we take inventions from translational syndrome. CBCT also initiated another Dr Dominic Wall – NCRIS Cap5 Project, $50,000 , our own discoveries and the discoveries of in-house clinical protocol, treating patients PRESENTATION HIGHLIGHTS projects and develop new treatments – 2nd Melbourne Gene Therapy ‘Maintenance of TGA licence no. our clinical and commercial partners. with multiple myeloma using the patient’s for application in clinical trials. We act as Professor Miles Prince Symposium, Melbourne, Vic, May 2008 149827’, 2008. own tumour cells in conjunction with ex- advisors to Australian and international – Australian Myeloma Foundation, (Invited Speaker). – NCRIS Cap5 Project, $100,000, RESEARCH FOCUS vivo manufactured dendritic cells. groups interested in entering our rapidly Adelaide, SA, February 2008 (Invited – 2008 BIO International Convention, ‘Developing a DC vaccine in Myeloma’, • Development and production of novel expanding field. Development and production of novel Speaker). San Diego, USA, June 2008 (Invited 2008. cell therapy treatments. Recently, we’ve participated in allogeneic cell therapy treatments – Leukemia Foundation, February 2008 Speaker). – NCRIS Cap5 Project, $50,000, • Innovative regenerative medicine and master cell banks used for treating cancer CBCT continued to develop other cell (Invited Speaker). – Global Regulatory Perspectives, Miami, ‘Autologous T-cells transduced with an immunotherapies. with genetically modified and processed therapies, with a focus on regenerative – Novartis Asia Pacific Meeting, Shanghai, USA, May 2008 (Meeting Chair and anti-LewisY chimeric receptor gene’, • Cell tracking studies. tumour cells, and in two Australian medicine for repair of damaged tissue China, March 2008 (Invited Speaker). Organizer). 2008. based upon ex-vivo expansion and • Autologous peripheral blood stem cell landmark studies using mesenchymal – China Center for Pharmaceutical – NCRIS Cap5 Project, $92,000, ‘Cell differentiation of cells. This is covered by – Bureau of Food and Drug Analysis, 3rd transplants. progenitor cell master cell banks for repair International Exchange, Shanghai, China, tracking of immune-regulatory cells’, TGA manufacturing licences and under Annual Taipei International Symposium of human tissue. March 2008 (Invited Speaker). 2008–09. RESEARCH PERSONNEL their auspices we have conducted studies on Human Cell and Tissue-based We continued to build upon our strengths – Managing Multiple Myeloma, Sydney, Products, Taipei, Taiwan, October 2008, – NCRIS Cap5 Project, $68,000, ‘Genvax Director demonstrating the safety and effectiveness in immunotherapy, enhancing vaccine NSW, April 2008 (Meeting and Session (Invited Speaker). immunotherapy’, 2008–09. Professor Miles Prince of these treatments on acute focal injuries. treatments for patients with multiple We have extended our manufacturing Chair). – AusBiotech 2008, Melbourne, Vic, – NCRIS Cap5 Project, $50,000, ‘Lipotek myeloma, whilst also developing and Deputy Director collaborations, working with the National – Roche HOTT Symposium, Sydney, NSW, October 2008 (Invited Speaker). production’, 2008–09. Assoc. Professor David Ritchie applying world-first imaging strategies to University of Malaysia Hospital in Kuala May 2008 (Session Chair). – National Health and Medical Research determine the fate and distribution of these PRIZES AND AWARDS Operations Director Lumpur, as well as with groups in South Council Program Grant: $10,810,800, cells after administration in animal models – 29th Australasian Dermatopathology Dr Dominic Wall Australia, Sydney and Queensland. Professor Miles Prince ‘Immune Regulation, Effector function and humans. Society Conference, Melbourne, Vic, We are supporting the cell banking for – Honorary Professor, Monash University Managing Director Cell Therapies P/L August 2008 (Invited Speaker). and Human Therapy’, 2007–11. Our work is supported by commercial mesenchymal progenitor cell-based Department of Medicine (Cabrini Hospital) Ray Wood – HSANZ Perth Chapter, WA, August 2008 – Peter Mac Foundation, Morris Grant: partners Cell Therapies Pty Ltd, and therapies for tissue repair at two clinical (Invited Speaker). Dr Kirsten Herbert $343,000, ‘Immunotherapy for Myeloma’, Deputy Production Manager collaborators at the Australian Red Cross sites in Melbourne as well as supporting – Cancer Council of Victoria (CCV) Early 2005–08. Kerrie Stokes Blood Service. a new application for a ground-breaking – Cancer Council Western Australia Public Forum, Perth, WA, August 2008 (Invited Career Clinician Researcher Fellowship, – Peter Mac Foundation, Vaccari Grant: Cryopreservation study on neural tissue repair with an 2008 RESEARCH ACHIEVEMENTS Speaker). 2008–11. $540,000, ‘Murine Models for Myeloma’, Peter Gambell international sponsor for treatment of Peter Gambell 2007–09. Ayse Mouminoglu Innovative regenerative medicine and patients in Melbourne and Brisbane. – American Society of Haematology (ASH) Annual Scientific Meeting, San Francisco, – HSANZ 2008 Medical Laboratory – Peter Mac Foundation Project Grant: immunotherapies Autologous Peripheral Blood Stem Cell Manipulation USA, December 2008 (Session Chair). Scientist Travel Grant. $330,000, ‘Immunology of novel Alannah Evans CBCT’s capabilities now include Cells – Satellite Symposium at ASH, San therapies in myeloma’, 2007–10. Dayna Jackson manufacturing of allogeneic master cell CBCT holds a TGA licence for manufacture GRANTS AND FUNDING banks for vaccine-based treatments for Francisco, USA, December 2008 (Invited – Victorian Cancer Agency, Clinical Stream, Lucy Kravets of autologous haemopoietic progenitor – Australian Cancer Research Foundation: patients with melanoma, using irradiated Speaker). $250,000, ‘‘Developing a DC vaccine in Maureen Loudovaris cells (HPCs) and produces approximately $1,200,000, ‘Australian cell therapy genetically-modified tumour cell lines, Myeloma’, 2007–08 Tanya Pisanelli 10% of all Australian treatments. HPCs can Assoc. Professor David Ritchie clinical trials’, 2007–08. Gillian Treloar as well as novel treatments based be harvested in patients during remission – Lymphoma Forum of Excellence, – Cancer Council of Victoria: $225,000, – Celgene Australia, $150,000, ‘Developing Garth Cameron upon tumour vaccine cell fragments. or consolidation treatment for indefinite Melbourne, Vic, February 2008 (Invited Early Career Clinician Researcher a DC vaccine in Myeloma’, 2008–2009. Valerie Costa We obtained Therapeutic Goods storage and subsequent transplantation Speaker). Fellowship 2008–11. Administration (TGA) CTX approval for a if required. During 2008 we extended – Health Research Council of NZ, Program Javier Haurat – Novartis Education, Sydney, NSW, May PUBLICATIONS AND PATENTS human clinical trial using gene-engineered the scope of this service and continue to Grant: $1,226,960, ‘Immunology of Jude Moloney 2008 (Invited Speaker). Angela Morgan T-cells directed against Lewis Y expressing Cancer and Infective Disease’, 2005–10. Publications are listed at the end of the – Volker Diehl Lecture, Melbourne, Vic, 11, 12, 25, 76, 91, Apheresis – Leukaemia and Lymphoma Society (US) report and include references June 2008 (Session Chair). 120, 135, 143, 156, 227, 228, 242, 291, 322. Mel Darby Project Grant: $1,000,000, ‘Anti-Lewis-Y – Victorian Oncology Pharmacists, chimeric receptor gene in multiple Senior Scientists Melbourne, Vic, June 2008, (Invited myeloma’, 2006–11. Paul Neeson, Speaker). – Leukaemia Lymphoma Society Project Senior Research Associates – HSANZ Haematology Groups, Adelaide, Grant: USD$600,000, ‘Autologous T-cells Professor Rod Hicks SA, August 2008, and Perth, WA, transduced with an anti-Lewis Y chimeric Dr Simon Harrison September 2008 (Invited Speaker). receptor gene’, 2005–08. Dr Kirsten Herbert – HSANZ Annual Scientific Meeting, Perth, – National Collaborative Research October 2008 (Session Chair). Infrastructure Strategy, Capability 5 – Taiwan Society of Infectious Diseases, Project (NCRIS Cap5): $7,600,000, Taipei, Taiwan, January 2008 (Invited ‘Cell Therapy capacity development Speaker). in Australia to be awarded to various

Left to right: Dr Damian Wall, Kerry Stokes, Professor Miles Prince.

Peter MacCallum Cancer Centre – Research Report 2008 Translational Research Program/ Centre for Blood Cell Therapies 77 Translational Research Program/ Haematology Immunology Translational Research

We investigate the anti-tumour efficacy RESEARCH OVERVIEW 2008 RESEARCH ACHIEVEMENTS Figure 1. Gene-modified CD8+ T cells Figure 1. of novel immunotherapeutics to human Gene-modified CD8+ T cells polarize to central or Our current research is testing the ability Investigation of the functional status effector memory functional phenotype following haemopoietic disease. We focus on of specific therapies to induce cell death in of gene-modified T-cells for adoptive retroviral transduction and expansion. Normal donor induction of human immune system tumour cells, and also trigger an immune immunotherapy of multiple myeloma PBMCs were activated and expanded in vitro. At response to disease as a hallmark of 3 time points, cells were stained and analyzed for response in the body – in turn controlling This project examines the functional status the frequency of CD8 T cells expressing a naïve control over residual disease. the spread of the cancer. of gene-modified T cells (redirected to (N), central memory (CM), effector memory (EM) The Haematology Immunology or effector (Eff) phenotype by FACS. Dot plots Our major interests are: attack tumour cells that express the Lewis are displayed for differential expression of CCR7/ Translational Research Laboratory (HITRL) Y antigen) prior to adoptive transfer. The CD45RA by CD8 T cells and correlated with CD27, is housed within and supported through – The induction of tumour cell apoptosis by ability of adoptively transferred T cells to CD28 and perforin. In normal donors at day 0, the Cancer Immunology Program. It novel combination therapies. induce a clinical regression is related to the CD8+ T cells were divided into four functional subsets (upper panel) including N, CM, EM and provides translational research support, – Endocytosis of apoptotic tumour cells by persistence (likely due to T cell memory) Eff cells. By day 10 (lower panel) this had changed particularly the development of new assays dendritic cells (DCs). in the patient. We have demonstrated that to CD8 T cells with a mixture of EM and CM-like phenotype. and analysis of clinical trial samples in – Licensing of the DCs. the gene-modified T cells have a central haematology and immunology. or effector memory-like phenotype (Fig – Induction of an anti-tumour T cell – Australian Myeloma Foundation, 1); furthermore, they respond to Lewis Y See Cancer Immunology Program [pg 12]. response. Adelaide, SA, February 2008 (Speaker). antigen on tumour cells by secreting IFN-γ, The iDCs mature over a 48-hour period – Allogeneic transplantation review; – Leukemia Foundation, February 2008 We’re researching the hypothesis that novel low levels of IL-2 and TNF, they proliferate RESEARCH FOCUS displaying CD80/CD86/CD83 and Novartis Education, Sydney, 2008 (Speaker). therapies being used in clinical trials induce rapidly and also kill the tumour target. upregulate MHC classII. Ongoing studies (Speaker). • Translational research. tumour cell apoptosis (death) for multiple Ongoing studies are exploring whether Dr Hang Quach will examine the process of endocytosis by • Investigation of novel immunotherapy myeloma and myelodysplastic syndrome, contact with LeY expressing tumour cells is – 11th Western Pacific Congress on – American Society of Hematology, video microscopy and compare myeloma for human multiple myeloma and and will also spark a tumour cell-specific T required for full polarisation to memory or Chemotherapy and Infectious Diseases San Francisco, USA, December 2008 apoptotic body uptake following treatment lymphoma. cell (immune) response – and that the result effector cells and the requirement for CD4 (WPCCID), Taipei, Taiwan, December (Speaker). with different novel therapies. In addition, of this will be the control of residual disease T cells in this process. 2008 (Speaker). • Investigation of human immune system we will also examine whether the type of Dr Simon Harrison from emerging and spreading. – Taiwan Haematologists Meeting, Taipei, responses to multiple myeloma in Immunogenic Death in Multiple Myeloma novel drug used to induce myeloma cell – Haematology Society of Australia and response to novel immunotherapy. Taiwan, January 2008 (Invited Speaker). Our approach to this hypothesis has been This is an ongoing project examining death has a downstream effect on the New Zealand Annual Scientific Meeting, • Modelling the effect of novel vaccines to ask specific questions within each clinical whether novel therapies can induce both myeloma-specific T cell response. Dr Paul Neeson October 2008, Perth, Australia (Speaker). trial research project. We are doing this to multiple myeloma in a humanised myeloma cell death and simultaneously – Haematology Society of Australia and – American Society of Hematology, by clinical trial design as well as timing Novel combination therapy targeting mouse model. promote an endogenous immune New Zealand Annual Meeting, Perth, WA, San Francisco, USA, December 2008 of sample collection to address therapy- TRAIL receptor and proteosome • Investigation of graft-versus-host disease response to myeloma. Evidence to date October 2008. (Speaker). related effects on the immune system and inhibitor to induce synergistic cell in allogeneic transplantation. indicates that tumour cells can display – American Association for Cancer malignant disease. death in multiple myeloma – Peter MacCallum Cancer Centre signature molecules on apoptotic bodies Research (AACR) 99th Annual Meeting, RESEARCH PERSONNEL This in vitro project investigated the Workshop Symposium, Wilson’s In addition, we are establishing a or release them from necrotic cells; efficacy of Mapatumumab (Mapa) San Diego, USA April 2008. Promontory, Vic, October 2008 (Speaker). Heads humanised model system to answer these molecules incite dendritic cell (DC) combined with low dose bortezomib (BTZ) Professor Miles Prince Assoc. Professor David Ritchie mechanistic questions that we believe will maturation. DC maturation, following GRANTS AND FUNDING to induce human myeloma cell death. BTZ – Novaritis Asia Pacific Meeting, Shanghai, Dr Paul Neeson contribute insights that may be translated endocytosis of tumour cell apoptotic has a number of deleterious effects on DC China, March 2008 (Speaker). – National Health and Medical Research Post-doctoral Fellow more readily into the clinic for treatment of bodies, leads to display of tumour-derived biology, including inhibiting activation and Council (NHMRC) Project Grant: $1.27 – The Center for Pharmaceutical Dr Joanne Davis haemopoietic malignancy. peptides to antigen-specific T cell and maturation as well as antigen presentation. million, 2007–11. induction of the endogenous response. International Exchange (CCPIE) of the First established in March 2007, our We have established that we can kill – Peter MacCallum Foundation Project Clinical Fellow We demonstrated that bortezomib (a State Food and Drug Administration, laboratory continues to act as the interface human myeloma cells using Mapa plus Grant: $50,000, ‘Treg in Lymphoma’, Dr Hang Quach proteasome inhibitor), and to a lesser Shanghai, China, 2008 (Speaker). between Peter Mac’s clinical Haematology low dose velcade. Importantly, we also 2007–08. Research Assistants extent Mapatumumab-treated (anti- showed that DC function is retained in – Satellite Symposium at Annual Department and the Cancer Immunology – Victorian Cancer Agency Project Grant: Tsin Tai TRAIL-R1) myeloma cells, form apoptotic these conditions, in particular the ability Hematology Meeting: Solving the Program. $250,000, ‘Developing a DC vaccine in Karen Chen bodies which are rapidly endocytosed to endocytose apoptotic myeloma cells Challenges of Hematologic Malignancies Myeloma’, 2007–08. Mandy Shin by autologous immature DCs (iDCs). and respond to toll-like receptor signalling. through Translational Science – Clinical Kellie Tainton Ongoing studies will explore whether DCs Results of Novel Histone Deacetylase – Gloucester Pharmaceuticals: $50,000 Inhibitors, San Francisco, USA, ‘Anti-myeloma effect of depsipeptide Visiting Scholar can process myeloma versus pathogen December 2008. when used as mono- or combination Patries Herst protein to peptides and incite an antigen- specific T cell response. – 29th Australasian Dermatopathology therapy with TRAIL-R1 agonistic Clinical Collaborators Society Conference, Melbourne, Vic, antibody’, 2008. Prof. Miles Prince PRESENTATION HIGHLIGHTS August 2008 (Speaker). – Victorian Cancer Agency Project Dr Simon Harrison Assoc Professor David Ritchie – Peter MacCallum Cancer Centre Grant: $50,000, ‘Clonagenic Myeloma Dr Stefan Peinert Progenitor Cells’, 2008–09. – Understanding the Australian and New Workshop Symposium, Wilson’s Advanced Medical Science Student Zealand Antifungal Guidelines, Adelaide, Promontory, Vic, October 2008 PUBLICATIONS AND PATENTS Kate Fielding (2008–09) SA, and Perth, WA, 2008 (Speaker). (Speaker). Publications are listed at the end of the – Haematology Society of Australia and – Lymphoma Forum Of Excellence, report and include references 3, 11, 25, 27, 76, Melbourne, VIC, 2008 (Speaker). New Zealand Annual Scientific Meeting, 91,107, 109, 110, 112, 120, 127, 135, 138, 143, 206, 212, 227, Perth, Australia, October 2008 (Speaker). – Advances in Hodgkin Lymphoma, 241, 242, 252, 253, 254, 291, 322, 343. – Cancer Council of Western Australia, Left to right: Dr Paul Neeson, Andy Hsu, Tsin Tai, Reece Cordy, Karen Chen, Kellie Tainton. Victorian Oncology Pharmacists, Melbourne, VIC, 2008 (Speaker). August 2008 (Speaker).

Peter MacCallum Cancer Centre – Research Report 2008 Translation Research Program/ Haematology Immunology Translational Research 79 Translational Research Program/ Molecular Pathology

The Molecular Pathology Research and RESEARCH OVERVIEW potential drug toxicity and inefficient use of As aberrant MGMT methylation can be GRANTS AND FUNDING an early event in tumour development, Development laboratory aims to perform The genomic era has brought a paradigm limited heath resources. – Victorian Cancer Agency (VCA): basic and translational research with the we tested the hypothesis that normal $150,000, ‘Development of a Centre shift to laboratory medicine such that The growth factor family of epidermal goal of achieving personalised cancer individuals possessing the T allele may for the Molecular Pathology of Cancer’, many tumours now require molecular growth factor (EGFR and HER2) are medicine. be predisposed to somatic methylation 2007–08. characterisation for accurate prognostic recognized to be implicated in such at the MGMT promoter. Peripheral blood assessment and appropriate treatment – VCA : $482,781, ‘Establishment of a RESEARCH FOCUS endocrine resistance through activation monononuclear cell DNA from 89 healthy stratification. The Molecular Pathology of mitogen-activated protein kinase/ individuals was genotyped at rs1690625 breast cancer biomarker discovery and • Translational and clinical research into Research and Development laboratory extracellular signal-related kinase and/ and assessed for the methylation status evaluation program to improve patient breast, lung, colorectal, urological and prides itself on being at the cutting edge or the phosphatidylinositol 3’-kinase of the MGMT promoter region using outcomes’, 2007–10. haematological cancers. of this exciting new era, introducing novel (PI3K)/AKT/molecular target of rapamycin independent quantitative methodologies – Cancer Australia/National Breast Cancer testing technologies and transferring such Figure 1: Expression of markers of resistance • Identification of predictive markers (mTOR) pathway. In vitro studies have (hypoxia-inducible factor 1{alpha}, p44/ capable of detecting low level methylation. Foundation Project Grant: $600,000, enabling appropriate stratification of tests into the clinical environment. We shown that after long-term estrogen p42, mitogen-activated protein kinase) and There was a strong association between ‘Germline BRCA1 and BRCA2 mutations patients for individualised treatment. oversee the platform selection and the deprivation, i.e., during long-term responsiveness (phosphorylated estrogen receptor presence of the T allele and detectable in the Australian Ovarian Cancer Study design, introduction and accreditation of aromatase inhibitor administration, breast {alpha}) in a tumour with no clinical response and • Development of clinical diagnostics. a tumour with a complete clinical response. methylation (p=0.00005) in the peripheral (AOCS)’, 2008–11. such new tests. tumour cells exhibit an activation of the • Adoption of novel molecular platforms blood DNA. Furthermore, when a MSP – Cancer Australia/National Breast Cancer PI3K/AKT/mTOR pathway as an adaptive Developing assays for personalised and methodologies for genetic and Our laboratory also performs basic and assay flanking the SNP was used to amplify Foundation Project Grant: $367,000, phenomenon of breast cancer cells to the medicine. epigenetic analysis. translational research in three principle methylated sequences in heterozygotes, ‘Rapid detection of carrier status for areas: the effect of angiogenesis and low estrogen environment. To address The personalisation of medicine will only the T allele was methylated. Thus, BRCA1/2 mutations in breast, ovarian and RESEARCH PERSONNEL microenvironmental factors (particularly whether measurement of members of depend on being able to rapidly perform detectable somatic methylation of the prostate cancer using multiplex parallel these pathways could be used clinically, Heads hypoxia) on tumour behaviour; the role of screening assays for markers that MGMT promoter in normal individuals is high resolution melting analysis’, 2008–10. we conducted a randomized phase II trial will predict response to therapy. High Professor Stephen Fox epigenetic change in the predisposition strongly associated with the T allele of the – National Health and Medical Research based on letrozole (LET arm) with or without resolution melting (HRM) is a rapid and Assoc. Professor Alex Dobrovic to cancer; and identification and use of rs16906252 MGMT promoter SNP. We are Council Project Grant: $332,725, ‘metronomic’ oral cyclophosphamide. PI3K, efficient method of screening that relies genetic and epigenetic markers capable of currently examining the involvement of this ‘Histopathological, magnetic resonance Pathology Research Fellow AKT, and mTOR were assessed on tumour on the precise monitoring of the melting predicting responses to conventional and SNP in cancer predisposition. (MR) & ultrasoumammographic density Dr Max Yan specimens collected before and after of a DNA duplex. We have developed novel therapies. in BRCA1/2 mutation carriers.’, 2008–10. Postdoctoral Scientists treatment in patients randomized in this sensitive HRM screening assays for PRESENTATION HIGHLIGHTS – Department of Human Services, Victoria, Dr Chelsee Hewitt 2008 RESEARCH ACHIEVEMENTS trial. The aims were to explore the changes multiple changes in cancer, notably Professor Stephen Fox New Technology Grant: $610,955, ‘Rapid Dr Thomas Mikeska of these molecular targets before and after mutations in the KRAS, TP53, BRAF and Predicting the response of hormonal – Novartis Symposium, Sydney, NSW, determination of carrier status for breast Dr Renato Salemi treatment, and to evaluate the relationship KIT genes and epigenetic changes in the therapy in breast cancer subsets. January 2008 (Invited Speaker). cancer predisposition genes using high Dr Angela Tan between these targets and conventional MGMT and BRCA1 genes. Some of these Endocrine therapies that interfere with clinical and biological prognostic variables assays are now being used diagnostically, – Merck Serono Colorectal Symposium, resolution melting point technology’, Research Officers estrogen receptor (ER) function have and to correlate the changes of these particularly the KRAS mutation assay Hong Kong, China, July 2008 (Invited 2007–08. Heather Hondow contributed to a dramatic reduction in targets with clinical response and that is being used to determine patients’ Speaker). – NHMRC Project Grant: $1,648,750, ‘A Elena Takano breast cancer mortality. To date, aromatase patient outcome. resistance to therapy with EGFR inhibitors. – Ludwig Institute of Cancer Research, randomised Phase III study of radiation inhibitors have been shown to be the Research Assistants However, mutation detection in clinical Austin Hospital, Melbourne, Vic, July doses and fractionation schedules in most effective endocrine treatment in We conclude that Letrozole inhibits key Ida Candiloro tumour samples is challenging when the 2008 (Invited Speaker). non-low risk ductal carcinoma in situ postmenopausal women with ER- molecules in the PI3K pathway. Changes Lasse Kristensen in these molecules may have prognostic proportion of tumour cells, and thus mutant – International Academy of Pathologists, (DCIS) of the breast’, 2007–11. positive breast cancer. However, not all alleles, is low. We have developed an Postgraduate Students significance. These results should be taken Sydney, May 2008 (Invited Speaker). – CLL (Chronic Lymphocytic Leukemia) ER-positive breast cancers respond to adaptation of HRM, limited copy number Hongdo Do into account when planning prospective – 27th International Congress of the Global Research Foundation: endocrine manipulation and many initially HRM (LCN-HRM) which utilises the ability Katie Huang trials testing up-front aromatase inhibitor International Academy of Pathologists, $US100,000, ‘Identifying therapeutic responding tumours develop resistance. of HRM to detect heteroduplexes when Dan Mellor with drugs targeting the PI3K/AKT/mTOR Athens, October 2008 (Invited Speaker). targets by profiling DNA repair in CLL’. Currently we cannot identify patients likely variant sequences are present. Multiple Renuka Sivapatham signalling pathway. (see Fig 1). – Susan Komen Breast Cancer Research to respond to such therapies, which leads replicate reactions with a limited number of Assoc. Professor Alexander Dobrovic to overtreatment, exposure of patients to Foundation: $US249,000, ‘Identifying AMS Students (The University of target sequences per reaction readily allow – Familial Cancer Research & Practice therapeutic targets by profiling DNA Melbourne) low frequency mutations to be detected Combined Meeting, Couran Cove, Qld, repair in breast cancer’, 2006–09. Ken Rantshalanine (2007–08) by their aberrant melting patterns. LCN- August 2008 (Invited Speaker). Michael Chung (2008–09) – National Breast Cancer Foundation: HRM is an effective and rapid single step – AGITG GIST Start-Up Meeting, $500,000, ‘Novel Strategies for Prediction method to enable levels of sequence September 2008 (Invited Speaker). variation below the normal sensitivity and Control of Advanced Breast Cancer – Peter MacCallum Cancer Centre of dideoxynucleotide sequencing to via Nanoscaled Epigenetic-Based Workshop Symposium, Wilson’s be detected in a way that then allows Biosensors‘, 2008–12. Promontory, Vic, October 2008 identification by sequencing. – NHMRC Project Grant: $60,000, (Conference Convenor). (See overview of ‘Biomarkers and EGFR treatment of Lung The role of SNPs in the predisposition Symposium, pg 9). Cancer’, 2007–09. to somatic methylation – Australian Health and Medical Research Methylation of the CpG island in the Congress, Brisbane, Qld, November PUBLICATIONS AND PATENTS MGMT promoter region is a frequent event 2008 (Invited Speaker). Publications are listed at the end of the in several cancer types. A correlation report and include references 2, 13, 20, 39, 72, Left to right: Prof. Stephen Fox, Assoc. Prof. Alex Dobrovic, Katie Huang, Thomas Mikeska, Elena Takano, between methylation and the T allele 73, 77, 105, 172, 173, 254, 267, 280, 295, 298, 307, 322, 331, Toni-Maree Rogers, Chelsea Hewitt, Giada Zapparoli, Heather Hondow, Ida Candiloro, Hongdo Do, of the SNP rs16906252 in colorectal Angela Tan. 332, 333. carcinomas has previously been reported.

Peter MacCallum Cancer Centre – Research Report 2008 Translation Research Program/ Molecular Pathology 81 Clinical & Allied Health Research/

Progressing the clinical Division of Radiation Oncology 84 Division of Surgical Oncology 88 management of cancer patients Centre of Molecular Imaging 90 through the development Familial Cancer Centre 92 onTrac@PeterMac of individualised approaches Victorian Adolescent & Young Adult Cancer Service 94 to treatment. Nursing & Supportive Care Research 96 Infectious Diseases 98 Nutrition 99 Pharmacy 100 ‘Peter Mac is a great place to be able Psycho-Oncology Research Unit 102 to look after patients and be able to do research, and more importantly to carry all that research into clinical practice’.

Dr Gillian Mitchell Head of Familial Cancer Centre

Peter MacCallum Cancer Centre – Research Report 2008 Clinical & Allied Health Research/ 83 Clinical Overview/ Clinical & Allied Health Research/ Division of Radiation Oncology

The focus of research in the division is to Dr Amy Teh RESEARCH OVERVIEW enhance the treatment of cancer patients, Dr Greg Wheeler As an integrated division, our research using radiotherapy, both as a single Dr Scott Williams efforts range from basic science in modality and in combined modality therapy Dr Kirsty Wilshire cancer biology and physics, through to with novel chemotherapy and targeted Dr Andrew Wirth (Box Hill) translational research using molecular therapy agents. Research Manager biological and imaging methods and onto clinical trials of innovative RESEARCH FOCUS Ms Virginia Tuckwell treatment strategies. • Clinical trials of innovative treatment Study Co-ordinators strategies. Dr Kylie Hewitt - East Melbourne Our group brings together the expertise Clinical research at Peter Mac Dr Jessica Faggian - Moorabbin of Peter Mac’s divisions of Radiation • Gated Radiotherapy: Improving the Ms Cathy Anderson - Bendigo Oncology, Physical Sciences, Radiation encompasses a broad and delivery of radiotherapy to tumour Therapy Services, Diagnostic and Physicists volumes which move with respiration. Molecular Imaging and Dental Oncology. Professor Tomas Kron - diverse portfolio of interest and • Adaptive Radiotherapy: Achieving Principal Research Physicist Research in our division is growing at a better dose targeting to tumours via Assoc. Professor Annette Haworth - rapid rate. As well as clinician researchers expertise that complements the application of a custom shaped Clinical Research Physicist we have a very active group of physicists beam of radiation on a daily basis Mr Jim Cramb - Director and radiation therapists. Much of the our activities in the basic and with the support of 3D Image Guided Dr Jim Hagekyriakou research is investigator-initiated and Radiotherapy to track target movement multidisciplinary, and is increasingly translational arenas. within the body. Radiation Therapists attracting peer-reviewed funding. • Assessing the utility of molecular imaging Aldo Rolfo - Director Radiation Therapy in staging, biological characterisation Services Our division is also actively involved in and treatment and response assessment Yolanda Aarons clinical trials. We have strong links with the Therese Chesson Trans Tasman Radiation Oncology Group The research undertaken in our Clinical for adapting radiation therapy fields on Our clinician researchers in all areas are using proven and novel tracers. Alison Cray (TROG) and recently became a member Divisions continues to expand with a daily basis to patients undergoing developing their programs in anticipation RESEARCH PERSONNEL Sarah Everitt of the Radiation Therapy Oncology Group increasing contributions from different treatment for bladder cancer to improve of the co-location of Peter Mac with the Robyn French (RTOG) – one of only three groups outside professional groups, growing collaboration tumour targeting. An increasing emphasis other Institutions at Parkville, creating a Director Rebecca Height North America. We have affiliations with with the Research Division and externally, on all aspects of supportive care research world class cancer research precinct, and Professor Gillian Duchesne Kellie Knight RMIT and Melbourne, Monash, Sydney and the development of new areas of has developed during 2008, culminating enhancing the collaborations which will Radiation Oncologists Karen McGoldrick and Wollongong universities, and research interest. Several key research in the establishment of an overarching lead to improved delivery of care to the Assoc. Professor Michael MacManus - Belinda McInnes collaborations outside of our division efforts in the Clinical and Allied Health Supportive Care program, which will be a cancer patient. Associate Director, Research Julie Miller include both applied and basic research programs have been seed-funded by major research emphasis in the coming Assoc. Professor David Ball - Deputy The following sections highlight the clinical Richard Oates and the Australian Synchrotron facility. competitive grants from the Peter Mac years. We continue to contribute strongly research leadership fostered at Peter Mac Director, DRO Rebecca Owen Foundation, and the programs are then to the national and international arenas in as we work to provide patients with new Dr David Bernshaw Andrea Paneghel 2008 RESEARCH ACHIEVEMENTS successfully attracting peer-reviewed many areas of clinical research, including and better treatment options. Dr Sinead Brennan Cate Sproston funding to support the ongoing work. the research work in the younger age Numerous areas of productive research Dr Pat Bowden - Site Director, Epworth Mike Sproston groups with cancer in the onTrac program, were pursued by the Division of Radiation It is difficult to select the research Dr Marie-Pierre Campeau Ann Thompson and the newly established Australian Oncology. Many are included under the highlights of the year from the many Dr Sarat Chander Sylvia van Dyk Sarcoma Group and Australian and New Tumour Streams & Clinical Trials [see page competing candidates. Strong Assoc. Professor Boon Chua David Willis Zealand Urogenital and Prostate Cancer Professor Gillian Duchesne 104]. Other major areas of activity are: collaborations continue to grow in Dr Margaret Chua Kate Wilkinson Group. Director of Radiation Oncology translational research between Molecular Dr Julie Chu Jacky Wong Gated Radiotherapy Imaging and the Clinical Services. A Dr June Corry Improving the delivery of radiotherapy Diagnostic Imaging Dr Ieta D’Costa to tumour volumes which move with number of technological projects have Professor Rod Hicks Dr Steven David respiration. This research aims to assess borne fruit, including developing protocols Dr David Binns Dr Farshad Foroudi and detect the range of tumour movement Dr Jean-Mathieu Beauregard Dr Francois Germain with respiration and deliver radiotherapy Dr Rob Ware Professor Rod Hicks only when the tumour is present within Dr Annette Hogg Dr Andrew Hui the target zone. This approach, known as Ms Elizabeth Drummond Dr Pearly Khaw gated treatment delivery, aims to improve Dr Trevor Leong (Moorabbin) Molecular Imaging the dose delivered to cancerous cells whilst Dr Michael Lim-Joon Dr Eddie Lau minimising the effect on healthy tissues. Dr Chen Liu Dr Clair Shadbolt Assoc. Professor Kailash Narayan Dr Nick Ferris Managing organ deformation and Dr Sam Ngan patient compliance Professor Lester Peters Postgraduate students This is being studied via the Dr Claire Phillips Sarah Everitt implementation of a structured patient Dr Gail Ryan Rebecca Owen preparation program for daily radiotherapy Dr Matthew Seel Kate Wilkinson for men with localised prostate cancer. Dr Alison Stillie Rebecca Height Dr Keen Hun Tai Richard Oates

Peter MacCallum Cancer Centre – Research Report 2008 Clinical & Allied Health Research/ Division of Radiation Oncology 85 Clinical & Allied Health Research/ Division of Radiation Oncology

RTS seed funded early research Kellie Knight PRIZES AND AWARDS GRANTS AND FUNDING – Merck Sharpe & Dohme: $350,000, ‘A PUBLICATIONS AND PATENTS program Phase I/II study of cetuximab, carboplatin – AIR research Symposium, Melbourne, Andrea Paneghel – National Health and Medical Publications are listed at the end of the In addition to dedicated research Vic, October 2008 (Invited Speaker). and radiotherapy for patients with Locally 15, 17, 26, 53, 54, – Best Scientific Paper, AIR National Research Council (NHMRC) Project report and include references positions, protected time has also been Advanced Head and Neck Cancer 55, 66, 78, 79, 81, 82, 92, 93, 174, 175, 177, 179, 189, 193, 194, – William Buckland Radiotherapy Centre Conference 2008. Grant: $385,000, ‘Radiotherapy vs granted to six clinical Radiation Therapists Department Research Seminar, chemotherapy for low-grade gliomas (LAHNC). TROG 07.04’, 2007–11. 195, 200, 202, 210, 219, 235, 266, 269, 300, 326, 327, 329. undertaking smaller research projects Melbourne, Vic, November 2008 (Invited stratified for genetic 1p loss: efficacy and – NHMRC Project Grant: $738,250, For more information on related within RTS. Speaker). quality of life benefits’, 2008–12. ‘TARGIT, an international randomised research, see: Paediatric Research Team – ASMMIRT Workshop, Melbourne, Vic, – NHMRC Project Grant: $320,522, controlled trial to compare targeted intra- operative radiotherapy with conventional Centre for Molecular Imaging [pg 90], Two radiation therapists, Dave Willis and April 2008 (Invited Speaker). ‘Determination of unwanted radiation post-operative radiotherapy after Tumour Streams and Clinical Trials [pg Dave Tongs, produced a book and DVD for dose outside of the radiotherapy Belinda McInnes conservative breast surgery for women 104], or visit http://www.petermac.org/ children receiving radiotherapy. treatment field’, 2008–10. – Australian Lung Cancer Conference, with early stage breast cancer’, 2006–10. Research/TumourStreamResearch – Victorian Cancer Agency (VCA) Clinical 1st National Australian Institute of Gold Coast, Qld, August 2008 (Speaker). Trial Funding (Tumour Stream): $250,000, – NHMRC Enabling Grant: $1.39 million, Radiography (AIR) Research Forum Rebecca Owen ‘A prospective study investigating the Clinical Trial Resources (TROG), 2005–09. Participation and leadership of the 1st – European Society for Therapeutic impact of serial PET/CT scans on the National AIR Research Forum by Peter Radiology and Oncology (ESTRO) radiation therapy treatment of patients Mac Radiation Therapists. conference, Göteborg, Sweden, with lung cancer’, 2008–10. September 2008 (Speaker). PRESENTATION HIGHLIGHTS – VCA Clinical Trial Funding (Pilot): $65,100, Aldo Rolfo ‘A study of online adaptive radiation Radiation Oncologists – TROG 20th Annual Scientific Meeting therapy for bladder cancer’, 2008. See Tumour Streams (pg 104) for Radiation (Technical Research Workshop and – Peter Mac Foundation Collaborative Oncologists’ presentation highlights. General Sessions), Alice Springs, NT, grant: $6553, ‘New children’s radiation May 2008 (Invited Speaker). Physical Sciences Figure 1: Radiation dose targeting a tmour of the therapy information book’, 2008. Professor Tomas Kron – ASMMIRT Workshop, Melbourne, Vic, head and neck region. Dose is focussed on the – NHMRC Project Grant: $342,250 ‘A – Engineering and Physical Sciences April 2008 (Speaker). tumour (red region) while avoiding the adjacent jaw bone (outlined in blue). prospective single arm trial of involved in Medicine Conference EPSM 2008, Sylvia van Dyk field radiotherapy alone for stage I-II Figure 2: Intense radiation dose (red) is sculpted Christchurch, New Zealand, November to irradiate a tumour located in the chest wall, – Australasian Brachytherapy Group 17th low grade non-gastric marginal zone while avoiding dose to the adjacent sensitive 2008 (Speaker). Annual Scientific Meeting, Sydney, NSW, lymphoma’. 2007–11. lung tissue. Assoc. Professor Annette Haworth July 2008 (Speaker) – NHMRC Project Grant: $1.65 million, ‘A – Engineering and Physical Sciences Dave Willis randomised phase III study of radiation in Medicine Conference EPSM 2008, – Varian Research Partner’s Symposium, doses and fractionation schedules in Christchurch, New Zealand, November Austin, USA, April 2008. non-low risk ductal carcinoma in situ 2008 (Speaker). – TROG 20th Annual Scientific Meeting (DCIS) of the breast’, 2007–11. Radiation Therapy (Technical Research Workshop), Alice – NHMRC Project Grant: $150,000, Sarah Everitt Springs, NT, May 2008 ‘A multicentre feasibility study of accelerated partial breast irradiation – ASCO/ASTRO/IASLC Multidisciplinary – Varian Users Group Meeting, Sydney, using three-dimensional conformal Symposium in Thoracic Oncology, NSW, June 2008. radiation therapy for early beast cancer’, Chicago, USA, 2008 (Poster). Man Man Fan 2007–09. – Australian Institute of Radiography – The Hong Kong College of – NHMRC Project Grant: $2.3 million Research Symposium, Melbourne, Vic, Radiographers and Radiation Therapists ‘Value of androgen deprivation and 2008 (Speaker). (HKCRRT) Inauguration Conference, Hong Kong, China, December 2008 bisphosphonate therapy in patients (Speaker). treated by radiotherapy for localized prostate cancer’, 2007–11. Joy Brumby, Lyn Cheetham, Anne Collins, Alison Cray, Robyn French, Janet Gawthrop, Katherine Jansons, Marcus Laferlita, Cathy Markham, Kristie Matthews, Karen McGoldrick, Richard Oates, Osbourne G, Aldo Rolfo, David Taylor, Cate Sproston, Mike Sproston, Anne Thompson, Dave Willis, Jacky Wong. Presentations at 5th Annual Scientific Meeting of Medical Imaging and Radiation Therapy (ASMMIRT) Melbourne 2008.

Peter MacCallum Cancer Centre – Research Report 2008 Clinical & Allied Health Research/ Division of Radiation Oncology 87 Clinical & Allied Health Research/ Division of Surgical Oncology

Surgical Oncology is an academic Miss Melanie Walker RESEARCH OVERVIEW 2008 RESEARCH ACHIEVEMENTS GRANTS AND FUNDING PUBLICATIONS AND PATENTS discipline. We are committed to conducting Mr Jeremy Wilson The Division of Surgical Oncology Surgical Oncology is involved in many – National Health and Medical Publications are listed at the end of the clinical research in surgical oncology to Mr Gavin Wright comprises Surgical Oncology, areas of research, many of which are listed Research Council (NHMRC) Project report and include references 22, 46, 50, 136, determine optimal diagnostic, prognostic Mr Terry Wu Anaesthetics, Day Surgery, General under the Tumour Streams & Clinical Trials Grant: $542,750, ‘Biological and 137, 192, 231, 233, 301, 303. and therapeutic interventions for patients Anaesthetists Practice Liaison, Surgical Visiting Medical section [see page 104]. Other areas of clinical characterisation of human with malignant disease. For more information on related Dr David Skewes – Director of Anaesthesia Specialists, Intensive Care Medicine, HMO research activity include: phosphatidylinositide 3-kinase research, see: Dr Roger Claydon Management, Operating Suite/CSSD, mutations’, 2006–08. RESEARCH FOCUS Surgical Audit Database Tumour Streams and Clinical Trials [pg 104], Dr Charles Hackman Pre-admission Clinic and the Surgical – NHMRC Project Grant: $277,500, ‘In vivo The research conducted is closely linked The Surgical Oncology Database is or visit http://www.petermac.org/Research/ Dr Adrian Hall Oncology Laboratory. models for understanding the cellular to the affiliated clinical and basic science an ongoing data collection of surgical TumourStreamResearch Dr Hilmy Ismail and molecular pathogenesis of Barrett’s programs, particularly in the following Surgical Oncology research encompasses procedures and outcomes including Dr Christopher Scarff a wide area of research activity and allows oesophagus’, 2006–08. areas: Dr Richard Smith surgical related complications, morbidity the development of investigator-driven – NHMRC Project Grant: $450,000, Dr Julia Fleming and mortality. • Gastro-oesophageal. protocols that suit the needs of Peter ‘Predicting response to • Colorectal cancer and lower Dermatologists Mac patients. This includes, though is not HMO Research Program chemoradiotherapy in patients with gastrointestinal. Dr Michelle Goh limited to, the clinical science and technical All surgical HMO’s rotating through advanced rectal cancer’, 2008–10. Surgical Oncology for 6-12 weeks • Breast. Dr Chris McCormack aspects of surgery, the evaluations of – ARC Discovery grant: $400,000, ‘The are encouraged to undertake a short Dr Catherine Scarff outcomes after surgical management, role of retinoic acid signalling in the • Melanoma. an understanding of tumour behaviour, term research project, which relates Quality Coordinator development of the oesophageal • Head & Neck particularly when relevant to the discipline to the evaluation of either an outcome Jodi Lynch epithelium’, 2008–10. • Hepatobiliary. of surgery, and an understanding of pre- from treatment, or a technical aspect – Cancer Council NSW Strategic Research Clinical Research Coordinator malignant disease and those at genetically of a surgical treatment program. The • Clinical trials. Partnership Grant: $1,250,000, ‘PROBE- Ann-Marie Power high risk of cancer development. implementation of this program has been NET: Progression of Barrett’s Esophagus • Basic science, with a focus on Barrett’s Furthermore, it allows the clinical work very successful and we have produced oesophagus and the PI3-kinase Research Coordinator to Cancer Network’, 2008–12. Rachel Greaney in the division to be interfaced with over 20 excellent research projects as signalling pathway. laboratory-based research. The Surgical a result. – NHMRC Project Grant: $1,303,750, Senior Research Fellow Oncology Laboratory is focused on using ‘Increasing appropriate screening for RESEARCH PERSONNEL Gastro-oesophageal Assoc. Professor Wayne Phillips molecular and cellular approaches to colorectal cancer patients and first Director • Molecular understanding of Barrett’s Postgraduate Students understand the development, progression degree relatives’, 2008–10. Professor Robert Thomas OAM mucosa Lauren Hare and treatment of gastrointestinal cancers. – NHMRC Project Grant: $925,625, ‘Risk Deputy Head • Family history in Barrett’s mucosa Dr Mirette Saad Surgical Oncology research is also factors for gastro-oesophageal reflux Assoc. Professor Michael Henderson • Oesophageal mucosa stem cell model disease & Barrett’s oesophagus in a Advanced Medical Science Students involved in collaboration with local (e.g. prospective cohort study’, 2008–10. Surgeons Jellyca Anton, Universitas Indonesia DRO [see page 85], BaCT [see page • Microarray studies in oesophageal Assoc. Professor David Allen (2007–08) 128]), national (e.g. NHMRC, ANZBCTG), cancer – NHMRC Project Grant $542,750, Mr Phillip Antippa Lucia Cochrane-Davis, University of and international (e.g. ACOSOG, JWCI) • Evaluation of PET in oesophageal cancer ‘Biological and clinical characterization Mr Simon Banting of human phosphatidylinositide 3-kinase Melbourne (2008–09) groups. • Prospective database evaluating Mr Felix Behan mutations’, 2006–08. treatment outcomes Assoc. Professor Alex Boussioutas – Peter MacCallum Foundation Grant: Mr Conrad Brandt Colorectal cancer and lower $80,413, ‘Investigation of neuropathic gastrointestinal Mr Sor Way Chan pain after VATS (video-assisted Assoc. Professor Laurie Cleeve • Microarray studies thoracic surgery) procedures in cancer Professor Anthony Costello • Evaluation of PET patients: incidence, mechanisms and Mr Simon Donahoe • Management of advanced rectal cancer management’, 2008–09. Mr Cuong Duong Miss Sian Fairbank • Process management of surgical Mr Jeremy Goad throughput Mr Stewart Hart Breast cancer Assoc. Prof. Alexander Heriot • A prospective database evaluating Mr Stephen Kleid treatment outcomes Mr Craig Lynch • Micro-metastases in breast cancer Assoc. Professor John Mackay Professor Bruce Mann Melanoma Miss Jane O’Brien • A prospective database evaluating Mr Miklos Pohl treatment outcomes Miss Catherine Poliness • Randomised trial of RT in patients at high Professor Andrew Sizeland risk of recurrent regional failure Mr David Speakman • Melbourne Melanoma Project Mr John Spillane Mr Ben Thomson

Professor Robert Thomas OAM

Peter MacCallum Cancer Centre – Research Report 2008 Clinical & Allied Health Research/Division of Surgical Oncology 89 Clinical & Allied Health Research/ Centre for Molecular Imaging

The Centre for Molecular Imaging RESEARCH OVERVIEW the treatment of neuroendocrine tumours biomarker is an important objective for the comparing PET/CT using a tracer of cell Research laboratory uses in vivo imaging The Centre for Molecular Imaging in eastern Australia, we are developing academic community and pharmaceutical membrane production, F-18 fluorocholine of tumour biology to develop new therapies Research laboratory is focused on quantitative techniques to evaluate the industry, as this is likely to speed drug (FCH), with conventional imaging as a first- and improved imaging technologies for translational application of in vivo relationship between the uptake and development by providing earlier and more line investigation. cancer patients. molecular imaging techniques, particularly retention of peptide receptor ligands and objective response assessment. Towards PRESENTATION HIGHLIGHTS positron emission tomography (PET), for subsequent therapeutic response. This this end, the Centre for Molecular Imaging RESEARCH FOCUS functional imaging of tumours. Employing involves pre-treatment Ga-68 octreotate is coordinating several international trials Professor Rodney Hicks • Improving diagnostic paradigms for two PET/CT scanners, we non-invasively PET/CT scanning and correlative post- evaluating the utility of FDG and FLT PET – 4th Asia Pacific Medical Education cancer staging. image tumour biology, including processes treatment Lu-177 octreotate imaging using to predict and monitor response to various Workshop, Tokyo, Japan, March 2008 SPECT/CT. cancer therapeutic agents. The largest of • Establishment of optimal timing and such as metabolism, proliferation, amino (Invited Speaker). these is an imaging biomarker validation tracer combinations for therapeutic acid transport and hypoxia. A major Improving diagnostic paradigms by study in non-small-cell lung cancer using – The Endocrinological Society of Australia response assessment to novel molecular focus of our research is to understand optimising the use of structural and erlotinib. A further study using FLT was Annual Scientific Meeting. Sydney, NSW, targeted therapies. how tumours respond to therapy. We functional imaging. In addition to our focus performed in collaboration with the Lung May 2008 (Invited Speaker). Figure 2: FLT is a PET tracer that is a substrate are actively collaborating with major on hybrid technologies we are increasingly for TK-1, the rate-limiting enzyme of the thymidine • Development of novel PET imaging Unit and Division of Radiation Oncology – Australian Neuroendocrine Tumour pharmaceutical companies to bring new using co-registration of nuclear medicine salvage pathway of DNA synthesis. Actively agents. during delivery of chemoradiation. (NETs) Consensus Workshop, dividing cells have significantly increased uptake molecular targeted therapeutic agents techniques like PET and SPECT with MRI Preliminary results of a pilot study, Melbourne, Vic, July 2008 (Invited of this tracer and hence both aggressively growing RESEARCH PERSONNEL into clinical use through more robust to further improve diagnostic accuracy and tumours and normal proliferating tissues such performed to establish the optimal Speaker). Heads proof-of-mechanism studies and providing to aid treatment selection and planning. as bone marrow are well visualised. During timing for imaging, are published and an – 10th Annual Scientific Meeting of the chemoradiotherapy it is possible to monitor the Professor Rod Hicks earlier biological read-outs of therapeutic expanded prospective study is underway Australian and New Zealand Head and anti-proliferative effects of treatment on both Assoc. Professor Grant McArthur response. A key focus of our pre-clinical 2008 RESEARCH ACHIEVEMENTS malignant lesions and normal tissues. In this case (see Fig 2). Neck Society, Melbourne, Vic, September program is to establish, in parallel, in vivo Imaging Amino Acid Metabolism a relatively modest response is demonstrated Research Officer imaging biomarkers and ex vivo correlative 2008 (Invited Speaker). in the primary lung cancer despite marked High uptake of FDG in the normal Establishment of optimal diagnostic depression of bone marrow activity. Dr Annette Hogg biomarkers of response that are then – COSA-IACR Joint Scientific Meeting, brain compromises the detection and staging paradigms used to design clinical trials in humans. A Sydney, NSW, November 2008 (Invited – NIH Grant: ‘Defining molecular markers Research Imaging Specialists assessment of the extent of malignant Because of the perceived expense of PET major strength of the program is the short Speaker). of hypoxia’. In collaboration with Stanford Assoc. Professor Eddie Lau brain tumours. During 2008 a comparative it is usually assumed that this technique feedback loop between personnel involved University, 2006–08. Dr Kate Moodie study evaluating the relative diagnostic should be used as a last resort and in pre-clinical and clinical imaging research GRANTS AND FUNDING Research Coordinator and Clinical Trial performance of glucose metabolic imaging particularly to clarify uncertain results PUBLICATIONS AND PATENTS with many individuals involved in both – NHMRC Project Grant: $500,125, Specialists with F-18 FDG and amino acid metabolic of conventional imaging techniques. areas of enterprise. ‘Predicting outcomes of treatment in Publications are listed at the end of the David Binns imaging with F-18 FET was completed However, we are increasingly convinced 27, 28, 29, 35, 55, head and neck cancer’, 2006–08. report and include references Jason Callahan As an adjunct to our pre-clinical research with clinical follow-up and biopsy results that the superior diagnostic accuracy of 66, 112, 139, 158, 177, 193, 194, 195, 215, 239, 242, 266, 306, into novel PET radiopharmaceuticals, to validate the results. This study, now in many PET tracers warrants first-line use of – Federal Government of Australia 318, 328. Radiopharmaceutical Chemists clinical research is being conducted press, demonstrated significant superiority PET/CT as a diagnostic test, particularly Collaborative Research Consortium Dr Peter Roselt in collaboration with the Cooperative of FET PET/CT. Based on these data in those situations where the limitations Grant: $23.2 million (total), $4 million to For more information on related Dr Oliver Neels Research Centre for Biomedical Imaging further prospective studies are underway to of CT and MRI are clearly recognized. As Peter Mac, ‘CRC for Biomedical Imaging research, see: Radiopharmacist Development (CRC-BID)to validate utilise this information for better therapeutic an example, the conventional imaging of Development. Core partners; Peter Molecular Oncology [pg 42] prostate cancer using abdomino-pelvic CT Peter Eu promising agents in clinical trials. Novel planning and therapeutic response MacCallum Cancer Centre, Monash Cancer Therapeutics Program [pg 62] amino acid and melanoma imaging agents assessment. Despite excellent diagnostic and bone scan is known to have relatively University, ANSTO, Cyclotek Pty Ltd, Translational Research Laboratory [pg 72] are planned for first-in-human clinical trials utility in evaluating the presence and low sensitivity in patients with other than GE Medical Systems Inc, and IBM Inc’, in 2009. extent of brain tumours, related to the high a very high risk of metastatic disease. 2005–12. Molecular Imaging Laboratory [pg 74] contrast achieved in the brain through Excluding such patients, we have designed Our translational program is increasingly very low basal uptake in normal brain, and initiated a prospective randomized trial extending into the domain of therapeutic a preliminary study of extra-cranial sites applications. As the major referral site for using FET provided disappointing results. One of the areas of research activity of the CRC-BID is the development of novel amino acid analogues. One of these looks very promising in pre-clinical imaging studies and it is planned that this agent will enter into human studies in 2010 (See Fig 1). Therapeutic monitoring with combined PET metabolic and proliferation assessment Enhanced cellular metabolism and proliferation are hallmarks of most cancers. Their expression and modulation Figure 1: High uptake in the normal compromises detection of low-grade brain tumours using FDG PET by treatment may represent prognostic but lack of uptake of amino acids in the normal brain enables imaging of brain tumours with much higher contrast and, therefore, sensitivity. This can aid localisation to guide surgery and radiotherapy as well as and predictive biomarkers. Validation enabling post-treatment evaluation, as demonstrated in this patient with suspected recurrent brain tumour Professor Rod Hicks and qualification of PET as an imaging that was confirmed and successfully resected following FET PET/CT.

Peter MacCallum Cancer Centre – Research Report 2008 Clinical & Allied Health Research/ Centre for Molecular Imaging 91 Clinical & Allied Health Research/ Familial Cancer Centre

The Familial Cancer Centre investigates Breast and Ovarian Risk Risk Management Clinic, which consists Identification of men with a genetic Dr Belinda Kiely – Prostate Cancer Foundation of Australia: methods of identification and clinical Management Clinic of a multidisciplinary group of clinicians predisposition to prostate cancer: – Leura VI International Breast Cancer $50,000, ‘The IMPACT Study of targeted cancer risk management of individuals Head contributing to familial cancer research. Targeted screening in BRCA1/2 Conference, Sydney, NSW, September prostate cancer screening in men with with a hereditary cancer predisposition Assoc. Professor Kelly-Anne Phillips mutation carriers and controls – 2008 (Poster). BRCA1 and BRCA2 mutations’, 2007–08. syndrome. We also determine the clinical Assoc. Professor David Allen 2008 RESEARCH ACHIEVEMENTS The IMPACT study Dr Alex Boussioutas – CCV: $182, 025, ‘Studies into utility of genes presumed to be associated Assoc. Professor Peter Grant This international prostate cancer Germline BRCA1 and BRCA2 Genetic – 1st Annual Scientific Meeting of Gynaecological Cancers in Hereditary with an increased cancer risk. Assoc. Professor Michael Henderson screening study is targeted at men with Profiling in the Australian Ovarian Singapore Gastric Cancer Consortium, Nonpolyposis Colon Cancer’, 2007–10. Dr Stewart Hart Cancer Study (AOCS) an increased risk of developing prostate RESEARCH FOCUS Singapore, July 2008 (Speaker) – NHMRC Project Grant: $213, 000, Dr Tom Manolitsas Mutations in the BRCA1 and BRCA2 cancer as a consequence of inheriting a – Peter Mac Callum Cancer Centre ‘Germline mutations in mismatch repair • Identifying carriers of mutations in known Dr Jane Mc Neilage genes account for the majority of families germline mutation in either of the BRCA1 Colorectal Cancer Workshop: A genes: prevalence, risk of cancer, and cancer predisposition genes. Dr Gillian Mitchell with multiple cases of breast and ovarian or BRCA2 genes. The study opened in Multidisciplinary Meeting, Melbourne, environmental modifiers of risk’, 2006–09. Dr Jane O’Brien cancer. Preventive approaches to the Australia in early 2007, and is led by Dr • Health services research in developing Vic, March 2008 (Speaker). – CCV, Dr John Colebatch Clinical Dr Meron Pitcher disease require targeting efforts on an Gillian Mitchell at Peter Mac, together clinical management pathways Research Fellowship: $722,500, Dr Cathy Poliness identified cohort of women most at risk with Assoc. Professor Geoffrey Lindeman – Grand Rounds, Western Hospital, for families with hereditary cancer ‘Reducing the Burden Of Breast Cancer’, Ms Mary Shanahan of developing the disease due to either (Royal Melbourne Hospital) and Dr Alan Melbourne, Vic, September 2008 predisposition syndromes. 2006–11. Mr David Speakman environmental and/or genetic risk. Recent Stapleton (Repatriation General Hospital, (Speaker). • Investigating the psychosocial SA). Australia has recruited approximately – National Health and Medical Research GI Risk Management Clinic publications suggest that the background consequences of hereditary cancer one quarter of all participants worldwide to PRIZES AND AWARDS Council (NHMRC) Project Grant: predisposition syndromes. Assoc. Professor Alex Boussioutas prevalence of BRCA1/2 in the general population of women with ovarian cancer date. Recruitment has already begun at five Dr Gillian Mitchell $698,575, ‘kConFab Follow–Up Project: • Investigating the clinical utility of genes Mr Alexander Herriot familial cancer centres around Australia; a prospective study of non–genetic risk Mr Craig Lynch is higher than previously estimated, and – PhD Completion, University of London, presumed to be associated with an much higher in subpopulations such as five more are to be opened in 2009. 2008. modifiers in women at high risk for breast increased cancer risk. cancer’, 2007–09. Endocrine Risk Management Clinic those with a family history. Prognosis in BRCA1 and BRCA2 Lucinda Hossack – NHMRC Project Grant: $410,250 RESEARCH PERSONNEL Dr Gillian Mitchell Dr Mitchell and Professor Bowtell are Carriers With Breast Cancer – Victorian Travelling Fellowship: Dr Warrick Inder The Australian component of this ‘Statistical analyses of breast cancer Familial Cancer Centre leading translational research to genotype Department of Human Services and international study is led from Peter Mac risks for Australian BRCA1 and BRCA2 Head the participants of the Australian Ovarian Victorian Quality Council, 2006–08. RESEARCH OVERVIEW by Associate Professor Kelly-Anne Phillips mutation carriers’, 2007–09. Dr Gillian Mitchell Cancer Study (AOCS). Commencing – 3rd Prize for Poster, Familial Cancer Ours is chiefly a collaborative effort and funded by the US National Institutes – NHMRC Project Grant $1,145,775, in 2008, this study is investigating the Research & Practice Combined Meeting, Senior Genetic Counsellor bringing together the relevant expertise of Health. The study aims to determine ‘Psychosocial predictors of developing prevalence of BRCA1/2 mutations in the Couran Cove, Qld, August 2008. Mary-Anne Young for research into the identification of general population of women with ovarian whether BRCA status independently breast cancer in women from high risk Kelly-Anne Phillips breast cancer families’, 2007–11. Senior Research Officer individuals at increased risk of cancer due cancer and will permit other planned affects breast cancer prognosis. See also – Cancer Council Victoria (CCV), Dr John Rebecca Doherty to family history, and the ongoing physical studies to investigate the responsiveness kConFab Follow Up Study, page 34. – National Institutes of Health (USA): and psychological management of that to chemotherapy of BRCA1/2 mutation Colebatch Clinical Research Fellow $US6,500,000 ‘Australian Breast Cancer Research Officer PRESENTATION HIGHLIGHTS increased risk. carriers, the molecular profiling of sporadic 2006–2011. Family Registry’, 2006–11. Sarah Pratt Our centre develops investigator-driven ovarian cancers and an investigation into Dr Gillian Mitchell GRANTS AND FUNDING Grants in which Peter Mac is a Research Coordinators research as well as collaborating in studies the psychosocial aspects of participants in – Familial Cancer Research & Practice – CCV and Cancer Council South Australia: collaborating research partner Kate Drew driven by other Victorian, Australian and genetic profiling studies. Combined Meeting, Couran Cove, Qld, $285,000, ‘The IMPACT Study of targeted – ARC Discovery Grant: $640,000, ‘A Joanne McKinley internationally-based researchers – this August 2008 (Speaker and Poster). Research is also investigating the uptake prostate cancer screening in men with Functional nonlinear optical endoscopy collective approach guarantees sufficient Research Assistant of risk-reducing bilateral salpingo- – Leura VI International Breast Cancer BRCA1 and BRCA2 mutations’, 2005–08. the third generation optical endoscopy Kathryn Alsop numbers of participants to generate results ophorectomy (RRBSO) as a disease Conference, Sydney, NSW, September technology toward early cancer detection – The Jack Brockhoff Foundation: with acceptable statistical power. prevention measure in women with known 2008 (Speaker). at a cellular level’. Gu M, Boussioutas, Nurse Coordinator $87,000, ‘The Peter MacCallum BRCA mutations and exploring their post- Xie H, 2008–2010. Mary Shanahan Affiliated with the Familial Cancer Centre at – Australian Sarcoma Group 2008 Annual Hereditary Gastrointestinal Cancer Risk Peter Mac is the Breast and Ovarian Cancer RRBSO experiences. Scientific Meeting, Melbourne, Vic, – NHMRC Project Grant $535,000, Research/Data Manager and Bendigo Management Clinic’, 2006–08. October 2008 (Speaker). ‘Molecular markers of the progression of Clinic Nurse – Jack and Robert Smorgon Families intestinal metaplasia to gastric cancer’ Morgan Murphy Mary-Anne Young Foundation and the Victor Smorgon Boussioutas A, Giraud A, and Bowtell D, – Familial Cancer Research & Practice Foundation: $104,000, ‘A state Postgraduate Students 2007–2009. Combined Meeting, Couran Cove, Qld, demonstration pilot project for breast Kathryn Alsop August 2008 (Speaker and Poster). MRI screening of women at high genetic – NHMRC Project grant: $645,250, Lucinda Hossack ‘Validation of STAT3 as a therapeutic Rebecca Doherty risk of breast cancer’, 2006–08. Affiliated Clinical Researchers target in diseases arising from its – Department of Human Services, New Dr Yoland Antill – Familial Cancer Research & Practice inappropriate activation by gp130 Technology Grant, Victoria: $610,955, Dr Alex Boussioutas Combined Meeting, Couran Cove, Qld, cytokines’. CIA M. Ernst; CIB P. Hoffman. ‘Rapid determination of carrier status for Dr Marion Harris August 2008 (Poster) AI A. Boussioutas, 2007–2009. breast cancer predisposition genes using Dr Paul James Lucinda Hossack high resolution melting point technology’, PUBLICATIONS AND PATENTS Dr Sue-Anne McLachlan – Familial Cancer Research & Practice 2007–08. Dr Belinda Kiely Combined Meeting, Couran Cove, Qld, Publications are listed at the end of the Dr Carmel Pezaro August 2008 (Poster). – Peter Mac Foundation: $96,000, ‘BRCA1 report and include references 32, 45, 68, 71, 126, and BRCA2 mutations in a subset of 146, 181, 201, 214, 232, 295, 324. – Leura VI International Breast Cancer Left to right: Dr Gillian Mitchell, Rebecca Doherty, Kathryn Alsop, Sarah Pratt, Lucinda Hossack. the Australian Ovarian Cancer Study Conference, Sydney, NSW, September (AOCS)’, 2007–09. 2008 (Poster).

Peter MacCallum Cancer Centre – Research Report 2008 Clinical & Allied Health Research/ Familial Cancer Centre 93 Clinical & Allied Health Research/ ontrac@PeterMac: Victorian Adolescent & Young Adult Cancer Service onTrac@PeterMac is Australia’s first RESEARCH OVERVIEW appointment of Executive Officer Dr Sally outcomes in adolescents & Young PRESENTATION HIGHLIGHTS Services to Adolescents and Young and leading adolescent and young Whyte was made in March 2008. The Adults; Principal Investigator (PI): Assoc. Adults Living with Cancer’, 2007–08. Our team is tackling one of the most onTrac@PeterMac Victorian adult oncology service bringing under-researched areas within oncology group also had its inaugural scientific Professor David Thomas, Dr Lisa Orme. Adolescent and Young Adult – Victorian Cancer Agency (VCA) Clinician together research and clinical service – cancer during adolescence and early meeting in October 2008, and initiated its • Initiation of a multi-site study: ASSG05 Cancer Service Scientist Fellowship, $150,000 per year, development. This unique service model first clinical studies. In August 2008, the adult life. Despite its prevalence, relatively International adolescent & young adult – Cancer Nurses Society of Australia 11th 2008–10. offers young people access to the latest ASSG Board of Directors was formally little is known about the biologic, genetic, sarcoma meta-analysis; PI: Assoc. Winter Congress Workshop, Gold Coast, cancer therapies and clinical trials while installed. Since that time the Group has PUBLICATIONS AND PATENTS epidemiologic, therapeutic, psychosocial Professor David Thomas. Qld, June 2008 (Invited Speaker). simultaneously providing the most established a constitution, a Board with and economic factors that affect the • Improving Palliative Care Services for Publications are listed at the end of the comprehensive evidence-based and representation from the major states – Davidoff Cancer Centre Seminar Series, 19, 30, 67, 216, incidence, disease outcomes and quality Adolescents & Young Adults living with report and include references age-appropriate psychological, social and and disciplines relevant to sarcoma care Tel Aviv, Israel, November 2008 (Invited 281. of life for young people diagnosed cancer; PIs: Dr Odette Spruyt & Assoc. emotional support. and has activated a scientific advisory Speaker). with cancer. Professor David Thomas. committee, a pathology committee and – Western & Central Melbourne Integrated For more information on related RESEARCH FOCUS onTrac@PeterMac has developed a a working group to set up the clinical • An Exploratory Study into Oncology Cancer Services (WCMICS) Supportive research, see: Specialists Perceptions of the Healthcare • onTrac@PeterMac is committed to psychosocial, basic and translational and database and biospecimen bank. Care Conference, Melbourne, Vic, Sarcoma Genetics & Genomics [pg 30] Preferences of Young People Living with undertaking internationally outstanding clinical research program into adolescent October 2008. Medical Oncology & Early Phase Clinical and young adult cancers, ensuring that Australian Adolescent and Young Adult Cancer; PIs: Kate Thompson, Gavin clinically focused research aimed at – Australian Music Therapy Association, Trials [pg 106] clinical and scientific discoveries are cancer outcomes study Dyson, Assoc. Professor Lynette Joubert, influencing health care and health policy Brisbane, Qld, September 2008 Good evidence indicates that adolescents Assoc. Professor David Thomas. Sarcoma [pg 124] in the field of adolescent and young translated into practical applications. and young adults (AYAs) with cancer do (Speaker). adult oncology. • A longitudinal study: Investigating the 2008 RESEARCH ACHIEVEMENTS badly compared to children with similar psychosocial impact of cancer on PRIZES AND AWARDS RESEARCH PERSONNEL cancers. We reviewed Australian registry The Australian Sarcoma Kindred Study the adolescent & young adult cancer Kate Thompson, onTrac@PeterMac data on 14,824 cancers of adolescence population; PIs: Dr Susan Palmer, Medical Director/Oncologist This is a world-first prospective familial – 2008 Victorian Public Healthcare Awards: and young adulthood seen between Assoc. Professor David Thomas, Kate Assoc. Professor David Thomas cancer study in adult-onset sarcoma, and Highly Commended Premiers Award for 1982-2002 and a detailed substudy of Thompson. Collaborators: Gavin Dyson, Manager was funded by a generous philanthropic Excellence in Improving Cancer Care in clinical characteristics were analysed from Dr Giselle Withers. Kate Thompson donation. The study was initiated with 179 AYAs with Hodgkin lymphoma (HL), Victoria. the recruitment of Dr Mandy Ballinger • Building Cancer Support groups: A Paediatric Oncologist Ewing sarcoma (ES) or osteosarcomas – Member, Inaugural COSA AYA Steering in 2008. In addition the ASK study has facilitated peer and psycho-educational Dr Lisa Orme (OS) treated at a single institution. Despite Committee. made a prominent link with kConFab. The significant improvements in survival for support based support group for Senior Clinician Assoc. Professor David Thomas ASK study will use the existing research both groups over the period in question, adolescent and young adults living with Ilana Berger – Queensland Cancer Council Sam nurse network located at major treatment for acute lymphoblastic leukaemia, cancer; PIs: Kate Thompson & Dr Susan Sciacca Travelling Fellow. Senior Psychologist centres and will employ infrastructure and rhabdomyosarcoma, ES, OS and HL, Palmer. Dr Felicity Sleeman protocols developed by kConFab for case survival for AYAs was worse than for • Using Emerging Technologies to Improve – Associate Professor with title of ascertainment, biospecimen collection children. For ES, OS and HL, the survival Supportive Care for Young Adults Living Principal Research Fellow, University of Social Worker and processing, and coordination of the Kerryn Fulton gap occurred almost entirely in males with Cancer; PIs: Assoc. Professor Melbourne. management team. In December 2008, (Hazard ratios compared to female AYAs David Thomas & Dr Frank Vetere. – Victorian Public Healthcare Awards: Clinical Nurse Consultant the executive committee was formulated of 1.8 [P<0.01], 1.4 [P=0.03] and 1.5 Collaborators: Dr Hilary Davis, Dr Shaun Highly Commended Premiers Award for Tina Griffiths and strategic planning for the project [P<0.01] respectively). Survival outcomes Ashkanasy, Dr Penny Schofield, Kate Excellence in Improving Cancer Care in was generated. Palliative Care Nurse Consultant from ES, OS and HL for female AYAs Thompson, Gavin Dyson, Dr Giselle Victoria. Gayle Jones The Australian Sarcoma Study Group were not significantly different from Withers. – Chair, Inaugural COSA AYA Steering children of either sex. For brain tumours Psychiatrist (ASSG) • Connecting with music: Effects of a Committee. and thyroid cancers, which are primarily Brendan Spence We have established a national research song creation group for adolescent and – Victorian Cancer Agency Clinician treated surgically, there were no gender- co-operative group in sarcomas in young adult (AYA) cancer patients; PI: Scientist Fellowship, 2008–10 Music Therapist 2008 with Cancer Australia funding. The related differences in outcomes. While no Pip Barry. Collaborators: Kerryn Fulton, Pip Barry differences in tumour stage or compliance Assoc. Professor David Thomas, Kate GRANTS AND FUNDING were identified, male AYAs experienced Education Advisor Thompson. – Cancer Australia: $220,000, Australian less toxicity and lower response rates Nicole Edwards • The relevance of music for adolescents Sarcoma Study Group, 2008. to chemotherapy (p=0.008). Young and young adults (15-25 years) Research Officer males account almost entirely for excess – Cancer Australia: $95,000, ‘Building diagnosed with cancer; PI: Dr Clare Gavin Dyson mortality from chemosensitive cancers Cancer Support Groups: A facilitated O’Callaghan. Collaborators: Pip Barry Lucy Holland of adolescence and young adulthood peer support and education based and Kate Thompson. Research Fellow compared to children, which may be support group for adolescent and young • An Investigation into the Learning Dr Ken Khamly due to relative underdosing with current adults living with cancer,’ 2007–08. chemotherapy dosing algorithms. of students absent from school for – Cancer Australia: $40,000, ‘Using Australian Sarcoma Study Group prolonged periods due to chronic illness, Emerging Technologies to Improve Dr Sally Whyte, Executive Officer Ongoing AYA Studies but connected to their school studies Supportive Care for Young Adults Living Dr Mandy Ballinger, Study Manager The following studies were ongoing from with Information & Communication with Cancer’, 2007–08. 2008; Technologies, PI: Nicole Edwards. – Department of Health and Ageing: • Cross disciplinary study of $380,000, ‘Improving Palliative Care pharmacologic factors affecting cancer Assoc. Professor David Thomas

Peter MacCallum Cancer Centre – Research Report 2008 Clinical & Allied Health Research/ onTrac@PeterMac: Victorian Adolescent & Young Adult Cancer Service 95 Clinical & Allied Health Research/ Nursing & Supportive Care Research

We aim to develop, evaluate and deliver PhD Students 2008 RESEARCH ACHIEVEMENTS and Ovarian Cancer Centre and Cancer Dr Penelope Schofield – Victorian Cancer Agency: $258,671, new knowledge about nursing and Jenny Anderson Details of our research are available in the Council Victoria that developed evidence- – Living with Cancer Education ‘Supportive Care Fellowship – Supporting supportive care for people affected by Miranda Goh Supportive Care Research report 2007- based communication guidelines Conference, Melbourne, Vic, December the patients with advanced lung and cancer. Our research is relevant and Kerryann Lofti-Jam 2008, available at: http://www.petermac. and a communication skills training 2008 (Invited Speaker). breast cancer and their family: Making a responsive to the needs of these people. Donna Milne org/Research/NursingSupportiveCare program for health professionals. These – Sydney Cancer Conference, Sydney, difference’, 2008–2010. Anna Ugalde guidelines have been accepted as the NSW, July 2008 (Invited Speaker). – NHMRC Project Grant: $508,050, ‘A RESEARCH FOCUS Improving pre-chemotherapy Consumer Research Members national standard and form the basis trial of a multidisciplinary, group-based education for patients PRIZES AND AWARDS • To improve patient experiences of care Helen Anstis of a training program, which includes intervention to meet the needs of men This pre-chemotherapy education program workshop manuals for both facilitators and through delivering new interventions Wal Crelin Dr Carrie Lethborg with prostate cancer’, 2008–10. aimed to reduce the burden and distress participants to support the implementation informed by engagement with people Dorothy King Naomi Stearns Scholarship, awarded – Cancer Australia: $40,000, ‘Using associated with cancer chemotherapy of the workshop. affected by cancer. Ian Roos emerging technologies to improve and the physical and psychosocial at the Association of Oncology Social • To reduce supportive care needs of Beryl Shaw The Supportive Needs Screening Tool supportive care for young adults living effects that cause significant distress. It Workers 25th Annual Conference in people affected by cancer by developing Leonie Young with cancer’, aimed to tailor education about preparing The Supportive Needs Screening Tool Savannah, USA. and testing innovative and sustainable patients for potentially threatening medical (SNST) was developed to screen newly 2008–09. interventions that can be easily integrated RESEARCH OVERVIEW Kerryann Lofti-Jam procedures to the individual situation of the diagnosed cancer patients for supportive – National Breast Cancer Foundation: into clinical settings. Our research is driving impeccable Travel grant to attend Clinical Oncology patient, to coach the patient to implement care needs. In 2008, a grant from the $352,114, ‘Can a peer support program assessment and optimal care so as to Society of Australia Annual Meeting. • To promote and assess the adoption evidence-based self-care behaviours, Western & Central Melbourne Integrated for cancer gene mutation carriers reduce meet the physical, social, emotional, of evidence-based health delivery and and to use stress reduction techniques Cancer Service (WCMICS) was obtained to GRANTS AND FUNDING distress? A randomised controlled trial’, informational, psychological, spiritual and effective new models of care over the across the course of treatment. The nurse- enable the incorporation of the SNST into 2008–11. – Western & Central Melbourne Integrated entire illness trajectory. practical needs of patients during the delivered intervention consisted of four the patient electronic medical record, with Cancer Service (WCMICS): $21,466, • To improve patient outcomes by the pre-diagnostic, diagnostic, treatment and key resources and a structured delivery programming for this project still ongoing. PUBLICATIONS AND PATENTS follow-up phases of cancer. ‘Development and testing of a scannable rigorous assessment of quality of life in framework: Publications are listed at the end of the PRESENTATION HIGHLIGHTS version of the Peter Mac Supportive clinical trials of novel therapies for cancer. report and include references 10, 141, 147, 148, We are a multidisciplinary group with links • An educational DVD – preparing patients Needs Screening Tool (SNST)’, 2008–09. extending across nursing, behavioural Dr Sanchia Aranda 149, 167, 168, 169, 170, 171, 186, 236, 267, 268, 290, 309. RESEARCH PERSONNEL for chemotherapy and self-management science, clinical psychology, biological – WCMICS: $28,868, ‘Meeting the of common side effects. – UICC World Cancer Congress, Geneva, Head science, haematology, medical oncology, Switzerland, August 2008 (Invited information needs and reducing distress Professor Sanchia Aranda radiation oncology, surgical oncology, • Chemotherapy DVD question prompt Speaker). of patients beginning chemotherapy at list – a checklist of questions relating the Peter MacCallum Cancer Centre’, Senior Researchers radiation therapy, pharmacy, palliative care, Dr Michael Jefford social work, physiotherapy, occupational to specific content areas of the 2008–09. Dr Sibilah Breen – UICC World Cancer Congress, Geneva, therapy and dietetics. chemotherapy education DVD, with – National Breast Cancer Foundation: Dr Jessica Faggian Switzerland, August 2008 (Invited space for additional patient questions/ $96,243, ‘Providing tailored preparatory Assoc. Professor Michael Jefford Our current research interests include: concerns. Speaker). Dr Meinir Krishnasamy information about radiation therapy Dr Meinir Krishnasamy Dr Linda Mileshkin • Evidence-based practice change. • Patient drug information sheets: outlining for women with early breast cancer: a Donna Milne • Psycho-educational interventions. chemotherapy treatment protocols, their – Inaugural National Cancer Care feasibility study’, 2008–09. side effects and sensory and procedural Coordinators Conference 2008, Perth, Assoc. Professor Penelope Schofield • Symptom management. – Peter MacCallum Cancer Foundation information about treatment. WA, October 2008 (Invited Speaker). Grant: $80,000, ‘Development and Researchers • Models of care and workforce utilisation. • Patient self-care brochures: outlining – International Society of Nurses in Cancer testing of novel strategies to support Rachid Annab • Survivorship. common chemotherapy side effects. Care Conference, Singapore, August adult survivors of colorectal cancer’, Carl Baravelli • Instrument development. 2008 (Invited Speaker). 2008–09. Catherine Coyne In a trial of the program, patients showed Kerryann Lofti-Jam Our work is improving care frameworks, reduced concerns about treatment Dr Carrie Lethborg – WCMICS: $25,000, ‘Establishment of Kerith Sharkey which identify, explore and further develop and symptoms compared to patients – Association of Oncology Social Workers a dietician/nurse-led clinic to optimise Anna Ugalde knowledge and improve the provision of educated in the usual manner. This 25th Annual Conference in Savannah, nutritional status in patients diognosed evidence-based supportive care services. program has potential widespread USA, May 2008 (Speaker). with head and neck cancer tumours, Clinician Researchers This encompasses a strong commitment applications in chemotherapy units, through minimising weight loss and Dr Linda Mileshkin llana Berger to evidence-based practice and the nationally and internationally. In 2008 a effectively managing pain related to Andrea Dolence application of research findings to both grant was obtained from the Western & – Australian Lung Cancer Conference, mucositis, oesophagitis and accute Tracey Dryden practice and policy. Central Melbourne Integrated Cancer Surfers Paradise, Qld, August 2008 radiotherapy skin reactions’, 2008–09. Catherine Grima (Speaker). Service (WCMICS) to implement this new – Internal Director of Nursing Office: Allison Hatton Strengths of a multidisciplinary approach education program in the Chemotherapy – WCMICS Supportive Care Conference, $23,380, ‘Nurse Co-ordinator Evaluation Rebecca McMillan include the broad scope of research Day Unit at Peter Mac. Melbourne Vic, October 2008 (Speaker). Project,’ 2008. Andrew Murnane interest and the coalescence of significant Cathie Pigott proficiency in terms of clinical perspective, Effectively discussing complementary Kerryann Lotfi-Jam – National Health and Medical Research Ronnie Pope research background and proficiency and alternative therapies Annual Scientific Meeting of the Clinical Council (NHMRC) Palliative Care Grant: Kath Schubach in the application of research findings Patients and doctors do not routinely Oncological Society of Australia, $50,000, ‘Exploring functional decline Lisa Sheeran to effect changes in clinical practice. discuss and often have very different November 2008 (Speaker) in patients with advanced lung cancer‘, We actively promote genuine consumer views about the use of complementary 2008–10. Postdoctoral Fellow Donna Milne collaboration, and our work encompasses and alternative medicines (CAM). A Dr Carrie Lethborg – 8th International Seminar on Cancer – Cancer Australia: $40,000, ‘Patients with many other Australian and international successful collaboration was formed Nursing, Tokyo, Japan, 2008 (Invited lung cancer and their carers: Supporting research institutions. between Peter Mac, the National Breast Speaker). through novel information models’, 2008.

Peter MacCallum Cancer Centre – Research Report 2008 Clinical & Allied Health Research/ Nursing & Supportive Care Research 97 Clinical & Allied Health Research/ Clinical & Allied Health Research/ Infectious Diseases Nutrition

Our department aims to conduct high RESEARCH OVERVIEW role in the prevention of adverse patient The Nutrition department aims to be RESEARCH OVERVIEW PRESENTATION HIGHLIGHTS quality clinical research that will contribute outcomes related to underlying immuno- recognised as the leading group of Our research group includes infectious The department is developing nutrition Nicole Kiss to the care of the immuno-compromised compromised diseases or their treatment. oncology dietitians in Australia and diseases physicians who have focused research work which underpins – Australian & New Zealand Head and patient. Inclusion of cancer specific decision beyond. appointments across multiple institutions – patient care. This work will continue to Neck Society 10th Annual Society enabling us to perform high quality clinical support tools such as assessment of grow within the context of the department’s RESEARCH FOCUS RESEARCH FOCUS Meeting, September 2008 (Poster). research projects that influence patient risks for adverse outcome from fever and mission statement (see above). Jenelle Loeliger • Development of local and national care in haematology/oncology units across neutropenia into Guidance-DS is being • Striving for excellence, ensuring that our Notably, in December 2007 the department evidence-based clinical guidelines the state. Current projects are varied and evaluated. The Guidance–DS system clinical practice is evidence based. – Australian & New Zealand Head and was awarded a Victorian Cancer Agency for the management of the immuno- focus on best practice and surveillance. is now used in many other hospitals in Neck Society 10th Annual Society compromised patient. Victoria and interstate. RESEARCH PERSONNEL (VCA) research funding grant. This was Meeting, September 2008 (Speaker). the first research money of this magnitude 2008 RESEARCH ACHIEVEMENTS Dietitian/Nurse Led Clinic – Clinical Oncological Society of Australia, • Development of epidemiological tools PRESENTATION HIGHLIGHTS which had successfully been granted Senior Clinical Dietitians November 2008 (Invited Speaker). for the surveillance of infections in Clinical guidelines for the management within the nutrition team. In 2008 the Assoc. Professor Monica Slavin Nicole Kiss cancer patients. of fever and neutropenia research profile of the team continued to – 48th Annual Interscience Conference on Jenelle Loeliger • Study and report the outcomes of Consensus and evidence-based build with the development of evidence Antimicrobial Agents and Chemotherapy infections in cancer patients, including guidelines for the management of fever Research Assistant based nutrition care pathways; involvement (ICAAC), Washington DC, USA, October newly emerging infections such as and neutropenia in the haematology Olivio Rocio Granados in this nutrition specific research, and 2008 (Invited Speaker and Symposium influenza H1N1 (swine flu). and oncology population are being the presentation and dissemination of Chair). Improving Allied Health Data systems developed with funding from the these findings at high level professional • Study the clinical, molecular and project infection-control factors associated Integrated Cancer service (ICS). This has – International Society for Human and conferences. involved literature review, development Animal Mycology (ISHAM), 2008 (Invited Department Manager with healthcare-associated infections, Anna Boltong including infection due to multi-resistant of a baseline questionnaire and liaison Speaker and Symposium Chair). 2008 RESEARCH ACHIEVEMENTS organisms in the immuno-compromised with key stakeholders in Australia and – 13th International Congress for Infectious Project Officer • Awarded Victorian Cancer Agency patient. a consensus model will be followed. A Diseases (ICID), Kuala Lumpur, Malaysia, Melanie Voevodin Supportive Care Infrastructure Grant: pharacoeconomic analysis of approaches • Develop new strategies for improving June 2008 (Invited Speaker and $70,000, Establishment of a dietitian / to management will also be undertaken. outcomes of infections in cancer Symposium Chair). nurse led clinic. Led by Nicole Kiss patients. Evaluation of the requirements for Dr Karin Thursky • Awarded WCMICS Grant: $65,000 for effective surveillance of bloodstream – Australian Society of Infectious Diseases, improving Allied Health data systems RESEARCH PERSONNEL and catheter-related bloodstream Australian Society of Microbiology, and and enabling input data to be linked with Head infections in haematology patients, International Federation of Biomedical improved patient outcomes. Led by Assoc. Professor Monica Slavin and a trial of alcohol locks to prevent Modelling (Invited Speaker). Anna Boltong. central line infection (in conjunction • Ongoing recruitment to the study “The Senior Researcher with the Royal Melbourne Hospital – 18th European Congress of Clinical Effect of Early Nutrition Support in High Dr Karin Thursky haematology and BMT unit) Microbiology and Infectious Diseases (ECCMID), Helsinki, Finland, August Nutritional Risk Conditioning Regimens Research Assistants Bloodstream infections and catheter- 2008 (Speaker). for Autologous Stem Cell Transplant”. Vivien Leung related bloodstream infections are an Led by Nicole Kiss Adrian Tramontana important cause of morbidity, mortality and Dr Leon Worth healthcare expenditure in patients with – Victorian Infection Control Practitioner • Completion of Peter Mac’s in-house Postgraduate Students Clinical Research Fellowship Program Dr Leon Worth malignancy. However, no standardised (VICPA) Conference, October 2008 methods have been developed (Invited Speaker). (CRF) by Senior Clinician Jenelle Dr Michelle Ananda-Rajah Loeliger: “Nutritional rehabilitation for Senthil Lingaratnum for surveillance in this population. Fundamental questions regarding GRANTS AND FUNDING H&N patients following chemoRT: What Visiting Fellow feasibility, cost-effectiveness and timeliness – National Health and Medical Research is the evidence?” Dr Peng Shyan Wong of recognising changes in infection rate Council (NHMRC) Project Grant: $1.2 must be explored in this population at high- million, ‘The clinical value of serology and risk of infection. A randomized study of molecular tests for diagnosing Invasive alcohol locks for central catheters is being Aspergillosis in at-risk hematology performed at RMH. patients’ (ASPID study), (2004–08). Implementation of a decision support PUBLICATIONS AND PATENTS tool to facilitate improved antimicrobial Publications are listed at the end of the stewardship in the immuno- report and include references 44, 206, 234, 274, compromised and adaptation of this 275, 302, 310, 335, 336, 337, 338. software for cancer patients Electronic decision support tools are a necessary and important way of optimising clinical practice, auditing prescribing practices and monitoring the use of restricted antimicrobial agents. In the immuno-compromised patient population, antimicrobial therapy plays an important

Peter MacCallum Cancer Centre – Research Report 2008 Clinical & Allied Health Research/ Nutrition 99 Clinical & Allied Health Research/ Pharmacy

The Pharmacy Service conducts high RESEARCH OVERVIEW - Firstly, we will provide a description of when cytotoxic drug safety cabinets are of medicines management as they move Dermatology Skin Infections and quality research that will contribute Recent research has contributed to current clinical practices in management used by pharmacy personnel to prepare into and out of the acute hospital setting. Antibiotics Edition 14 (work ongoing positively to the drug therapy outcomes of continual improvement in patients’ drug of febrile neutropenia across Australia, by cytotoxic chemotherapy. As reported This project utilises health improvement 08/09) our patients. way of an electronic survey administered in the Journal of Pharmacy Practice approaches centred on a single- therapy outcomes with safe, rational and GRANTS AND FUNDING cost effective pharmaceutical care. To this to haematologists, oncologists and and Research, this study confirmed the participation evaluation and monitoring RESEARCH FOCUS end, our department is actively involved infectious disease physicians from presence of cytotoxic drug contamination cycle (or Plan-Do-Study-Act) conducted – Department of Human Services (DHS) • Medication safety. in a number of research activities relating all cancer treatments centres around on a variety of surfaces in the cytotoxic in three phases – pre-intervention, Project Grant: $50,000, DHS: ‘Evaluating Australia; private and public; rural drug preparation areas that used cytotoxic intervention and post-intervention – in order Effectiveness of Participation’, 2007–08. • Chemotherapy drug dosing. to drug therapy, many of these involving and metropolitan. Key stakeholder drug safety cabinets. This highlighted to assess outcomes over time. The initial – Roche Pharmaceuticals, ‘Investigation • Population pharmacokinetics and collaborations within Peter Mac and state organisations and professional body the potential risk of exposure to cytotoxic phase of the study was a planning phase of private health insurance pharmacodynamics. and national drug usage groups. associations such as the Australasian drugs that exists in the workplace despite based on qualitative data gleaned from reimbursement practices for high-cost A number of current projects are • Adverse drug reactions in oncology. Lymphoma and Leukaemia Group adherence to the recommended safe patient surveys, and focus group sessions non-Pharmaceutical Benefits Scheme components of Masters and PhD projects. • Pharmacy practice. (ALLG), Medical Oncology Group of handling guidelines. [Siderov et al., J involving nurses, pharmacists and doctors. pharmaceuticals’, 2007–08. The pharmacy supports clinical drug trials Australia (MOGA), Australasian Society Pharm Pract Res 2009; 39: 117-21]. Qualitative and quantitative data collated • Symptom control. – Victorian Integrated Cancer Services and participates in pharmacy practice of Infectious Diseases (ASID) will be during this phase informed design of Investigation of private health Grant: $100,000 “Global projects” • New therapies. research activities. A particular focus engaged to distribute the survey tool to intervention strategies, including raising insurance reimbursement practices for Funding Program, 2008–2009. • Use of electronic tools to improve includes pharmacokinetics, drug stability, their members. We will seek assistance awareness, documentation systems, high-cost non-Pharmaceutical Benefits medication safety. adverse drug reactions and chemotherapy from Victorian integrated cancer services health profession skills improvements, and Scheme pharmaceuticals drug dosing. and interstate colleagues to ensure that structured medication information forms By identifying reimbursement trends and RESEARCH PERSONNEL a comprehensive description of practices for patient-held and GP-faxed information practices of private health insurance firms Director of Pharmacy 2008 RESEARCH ACHIEVEMENTS Australia-wide is captured. at discharge. A project reference group for pharmaceuticals that are currently not Sue Kirsa Integrating cost-effectiveness was formed to oversee the project, review - Secondly, findings of the survey will funded under the Pharmaceutical Benefits evidence into the development of the findings of consumer and health Infectious Disease Physiscians be presented at a series of consensus Scheme (PBS), we are better informed Australian consensus guidelines for professional consultation and refine the Dr Karin Thursky meetings, to which survey respondents about patients’, options for accessing the management of febrile neutropenia intervention strategies. Subsequent phases Assoc. Professor Monica Slavin will be invited to attend. An expert panel high-cost pharmaceuticals. The Private in adult haematology and oncology involve implementation and evaluation of will be commissioned to oversee meeting Health Insurance project examined barriers Health Economist cancer patients the set of strategies. proceedings and to identify and draw and opportunities for funding of high cost Mr Craig Bennett This initiative is aimed at formulating consensus in areas of clinical practice pharmaceuticals by Health Funds with clinical practice guidelines (CPG) for the PRESENTATION HIGHLIGHTS Medical Oncologist where there is currently significant an extensive review of the legislative and management of febrile neutropenia in Dr Linda Mileshkin contention or where evidence is lacking. published data on health fund expenditure Dan Mellor adult haematology and oncology cancer - Finally, clinical and cost-effectiveness on pharmaceuticals and a survey directed – GlaxoSmithKline, Melbourne, Vic, August Haematology Oncologists patients in Australia. It seeks to standardise evidence will be evaluated by a to the Health Funds to tease out their 2008 (Invited Specialist Induction). Professor John Seymour clinical practice in areas where there is multidisciplinary CPG Working Party approach to such funding. Assoc. Professor Miles Prince currently much variability and much desire – Annual Pharmamed Logistics comprising of haematologists, medical Conference, Sydney, NSW, September Pharmacist and Projects Officer for clinical guidance. The molecular and epigenetic oncologists, infectious disease Senthil Lingaratnam determinants of response to therapy 2008 (Invited Speaker). These areas are: specialists, pharmacists and nurses in cancer – Presentation on the use of Off-label and Postgraduate Students from key stakeholder organisations. (i) The use of risk stratification in unlicensed medicines in the oncology Senthil Lingaratnam Levels of evidence and grades of Dan Mellor, Deputy Director of Pharmacy, differentially managing high and low risk setting, Bangkok, Thailand, September Dan Mellor recommendations proposed in the is undertaking a part-time PhD in the patients including management in the 2008 CPG will be adapted from the NHMRC. Molecular Pathology Research and ambulatory care setting Detailed cost-analysis of healthcare Development lab under the supervision Gail Rowan (ii) empiric antibiotic recommendations that interventions will be performed and and guidance of Professor Stephen Fox – Monash University – Master of Clinical take into account patient risk, severity of reported separately to the CPG. and Assoc. Professor Alex Dobrovic. Pharmacy course, Melbourne, Vic, 2008 illness and emerging antibiotic resistance Dan’s research is focused on the area of (Invited Lecturer). Surface Contamination of Cytotoxic Pharmacogenomics - the molecular and (iii) use of bacterial prophylaxis and colony Chemotherapy Preparation Areas epigenetic determinants of response to PRIZES AND AWARDS stimulating factors in the management of in Australian Hospital Pharmacy therapy in cancer. This research is being Departments Sue Kirsa neutropenic patients conducted in collaboration with the Faculty Studies from Europe, the US and Australia – Fellowship from the Society of Hospital In keeping with the National Health and of Pharmacy and Pharmaceutical Science, have shown measurable levels of cytotoxic Pharmacists of Australia Medical Research Council (NHMRC) Monash University. contamination in health facilities. Despite processes for formulating clinical practice Senith Lingaratnam the use of biological safety cabinets, Improving medication safety through guidelines, particular regard is given – Master in Public Health, La Trobe cytotoxic drug residue has been detected consumer participation in the to economic evaluations guiding best University in the air and on surfaces in pharmacy medication reconciliation process practice. Verna Wallroth drug preparation and administration The consumer participation in medication A consensus based approach will be areas. This multicentre study, conducted reconciliation project, funded by – Fellowship of the Australasian pursued towards formulating a CPG. A at ten hospital pharmacy departments in the DHS and led by project officer Association for Quality in Health Care high level steering committee has been Melbourne, was one of the first studies Senthil Lingaratnam, examined the (FAAQHC) Christchurch, Sep 08) convened to oversee project undertakings. in Australia to investigate if surface opportunities for consumers to assist – Invited member, Therapeutic Guidelines This project will occur in stages: contamination with cytotoxic drugs occurs health professionals to ensure continuity Expert Editorial Groups for both

Peter MacCallum Cancer Centre – Research Report 2008 Clinical & Allied Health Research/ Pharmacy 101 Clinical & Allied Health Research/ Psycho-Oncology Research Unit

Our aim is to be a national centre of RESEARCH OVERVIEW 2008 RESEARCH ACHIEVEMENTS An investigation of levels of A couple-focused psychological PRIZES AND AWARDS excellence in clinical interventions, psychological distress (depression intervention for men with early stage With a research focus on the potential The Psycho-Oncology Research Unit Dr Ann Boonzaier and anxiety) and unmet needs among prostate cancer and their partners research and implementation of specialist to improve clinical and psychological has developed an active research people diagnosed with head and – New Investigator Grant Peter Mac evidence-based psychological and outcomes, our unit includes staff from agenda in the past two years. As a Psychiatry staff, with involvement from neck cancer Foundation, 2007–08. psychiatric care for people with cancer and departments of clinical psychology and result of successful grant applications, psychology staff, are currently recruiting Annabel Pollard their families. psychiatry. Our leading researchers are three research projects have begun that Psychology and psychiatry staff are couples for a study of Cognitive Existential providing benchmark care models to exemplify the important nexus of clinically- collaborating on this project. Head and Couples Therapy (CECT) for men with – Victorian Cancer Agency Scholarship RESEARCH FOCUS improve psychological outcomes for driven research and clinical practice. This neck cancer patients are required to prostate cancer and their partners. This PhD, 2007–10. • Develop and drive the implementation undergo some of the most distressing study is extending previous research, cancer patients and families. collaborative research between medical GRANTS AND FUNDING of an overarching psycho-oncology colleagues and the treating team is aimed and disfiguring treatments among all which identified that, following a prostate We’re identifying needs and developing research strategy. at drawing the best possible outcomes cancers. However, rates of survival are cancer diagnosis, partners, rather than – Peter Mac Foundation: $25,000, strategies that promote provider and from the patient experience of cancer high, thus many patients who are cured the patients, report elevated psychological ‘Interpersonal couples therapy for • Facilitate statewide and national research patient adherence to recommended care, care. The following research projects have live with chronic functional impairment and distress. CECT has previously been women with advanced breast cancer’, collaborations. including assessment of survivor risk been established by the Psycho-oncology disfigurement for many years. Psychosocial successfully used in a group for women 2007–08. • Drive the clinical application of evidence- for adverse effects, promoting healthy Research Unit. research in this group is relatively sparse, with breast cancer. CECT aims to foster – Victorian Cancer Agency: PhD based improvements in psycho- behaviours and facilitating return to life yet existing studies indicate a high level living in the present with a satisfying sense Scholarship, $75,000, ‘A randomised oncology care. after cancer. Pilot study of interpersonal couple of need and psychological distress. The of meaning, purpose and self-fulfilment. controlled trial of exercise behaviour in therapy group for women with • Raise the awareness of psycho-oncology Research in Australia has led to the project is addressing a critical gap in the breast cancer survivors’, 2007–10. as a collaborative field of research. advanced breast cancer understanding of the prevalence Exercise behaviour in breast cancer development of specifically designed survivors – Beyond Blue: $97,000, ‘An investigation • Keep abreast of and disseminate Psychology staff have developed a group of specific morbidity, depression and psychological therapies with demonstrated This is a randomised controlled trial of of levels of psychological distress information about new developments intervention for couples dealing with anxiety in an Australian head and neck efficacy for specific cancer contexts a behavioural intervention to promote and unmet needs amongst people and resources. (e.g. Kissane and Bloch, 2002; Scott et advanced cancer based on a theoretical cancer population. model of Interpersonal Therapy (IPT). adoption of exercise in women after diagnosed with head and neck cancer’, • Develop education and training al., 2004). Much has been achieved in There is evidence of a strong relationship treatment for breast cancer. This 2007–09. opportunities for clinical researchers. developing the evidence base, but we are study utilises behavioural theory and now engaged in further efforts to develop between patient and partner distress in PUBLICATIONS AND PATENTS • Contribute to national advocacy efforts cancer and partner support is critical rehabilitation principles to facilitate tailored screening tools to identify those Publications are listed at the end of the related to survivorship research issues. to patient adjustment. If patients and exercise behaviour as a targeted therapy most in need. report and include references 189, 236. • Seek external funding to sustain partners are able to function better, then in this population. and grow the department’s clinical Specific and focused psychosocial the impact on whole families, especially We have established a bi-monthly psycho- interventions and research program. interventions are needed for common families with younger children, will be oncology seminar series, which has cancer scenarios confronting a large and positive. Few interventions have targeted invited speakers from other hospitals and RESEARCH PERSONNEL increasing number of Australians to ensure couples, especially in advanced disease. universities involved in psycho-oncology Head, Dept of Psychiatry that this knowledge is translated into real In addition, previous couple research in research in the cancer context. These Dr Jeremy Couper clinical outcomes. In the psycho-oncology cancer has lacked a coherent, evidence- seminars alternate monthly with the research unit, we aim to develop research based approach to interventions. IPT is Clinical Research Fellow, Psychology seminar series of Nursing and Supportive guidelines, strategies, instruments and a short-term, supportive intervention that Annabel Pollard Care Research. interventions drawn from the best available focuses on the connection between a Research Assistants evidence, or, where evidence doesn’t exist, person’s mood, their interactions with Dr Judy Dunai arrived at through consensus. others and changes in their social role. Dr Kate Neilson Enza De Pino Postgraduate Students Marcelle Gray Karen Mead Clinical Psychologist and Convenor, Group Therapy Working Group Dr Ann Boonzaier Clinical Psychologist and Convenor, Communication Skills Working Group Justine Diggens

Peter MacCallum Cancer Centre – Research Report 2008 Clinical & Allied Health Research/ Psycho-Oncology Research Unit 103 Tumour Streams & Clinical Trials/

Medical Oncology & Early Phase Developing novel, evidence- Clinical Trials 106 based approaches to cancer care Breast 108 and cure and providing patients Gastrointestinal 110 Gynae-Oncology 113 with new and better treatment Haematology 114 options by participating in Head & Neck 116 Lung 118 cutting-edge research studies. Melanoma & Skin 120 Neuro-Oncology 122 Paediatrics & Late Effects 123 ‘What motivates me about clinical trials is Sarcoma 124 Uro-Oncology 126 seeing the amazing discoveries made in Centre for Biostatistics & laboratories translate into very real and very Clinical Trails (BaCT) 128 tangible benefits to our patients with cancer’. Clinical Trials Unit 130

Dr Ben Solomon Medical Oncologist

Peter MacCallum Cancer Centre – Research Report 2008 Tumour Streams & Clinical Trials/ 105 Tumour Streams & Clinical Trials/ Medical Oncology & Early Phase Clinical Trials

The Department of Medical Oncology Medical Oncology Fellow are being led by Peter Mac medical who received standard correspondence For further details on the research runs a large clinical research program Dr Carmel Pezaro oncologists. alone. Information about chemotherapy achievements, presentations and that includes clinical trials of cancer faxed to GPs is a simple, inexpensive funding of these researchers, see also Medical Oncology Fellow Our department also leads significant therapeutics from early phases to definitive intervention that increases confidence Breast [pg 108] Dr Madhu Singh clinical research programs in the areas of phase III trials, as well as studies exploring in managing chemotherapy adverse familial cancer including risk management Gastrointestinal [pg 110] the clinical relevance of new biologic effects and satisfaction with shared care. RESEARCH OVERVIEW and chemoprevention, supportive care Gynae-oncology [pg 113] findings, supportive care research and This intervention could have widespread With broad base research in collaborations including psycho-social interventions, familial cancer research. application. [147. Jefford et al, (2008) J Haematology [pg 114] across Peter Mac with other sector survivorship, and adolescent and young Clin Oncol 26:2272-2277]. Head and Neck [pg 116] RESEARCH FOCUS leaders, we’re delivering bench to adult oncology. bedside outcomes that help deliver better Psychosocial factors and survival of kConFab Follow-up [pg 34] • New drug development and early understandings of cancer and 2008 RESEARCH ACHIEVEMENTS young women with breast cancer Lung [pg 118] phase clinical trials focused on its treatment. The Activity of Imatinib in Treating Life- Many women with early stage breast targeted therapies. Melanoma and Skin [pg 120] cancer believe that psychological factors Our major focus is the clinical trial program Threatening Malignancies Associated Neuro-oncology [pg 122] • Establishing benefit of new therapies will influence whether their cancer will focusing on development of new cancer with Imatinib-SensitiveTyrosine in phase 2 and 3 clinical trials including Kinases. recur, but previous studies showed Nursing and Supportive Care [pg 96] therapeutics, with the spectrum of trials investigator initiated cooperative conflicting results. In this population-based Paediatric and Late Effects [pg 123] extending from ‘first in man’ phase I Imatinib was one of the first targeted group trials. prospective cohort study, 708 Australian trials to definitive phase III trials. Joint therapies in oncology, demonstrating Sarcoma [pg 124] • Supportive care research including women diagnosed before age 60 years appointments with the Research Division remarkable activity in chronic myeloid Uro-oncology [pg 126] with non-metastatic breast cancer were survivorship. help facilitate early drug development leukemia (ABL) and subsequently in followed for an average of 8.2 years. • Familial cancer including risk research, while close cooperation with gastrointestinal stromal tumours (KIT, PUBLICATIONS AND PATENTS Depression, anxiety, coping style, and management and chemoprevention. the Translational Research Laboratory PDGF). This Phase II open-label study Publications are listed at the end of the social support were assessed on average permits bench to bedside research – and investigated the activity of imatinib in report and include references 3, 11, 12, 14, 25, RESEARCH PERSONNEL 11 months after diagnosis. Greater levels opportunities to return to the laboratory to other malignancies that had expression 27, 28, 29, 40, 41, 42, 47, 48, 53, 54, 55, 68, 76, 77, 84, 86, 87, of anxious preoccupation were associated Director, Division of Haematology & explore observations made in the clinic. or activation of potential targets (tyrosine 88, 89, 90, 95, 97, 107, 108, 109, 110, 111, 112, 120, 123, 127, Medical Oncology kinases) of imatinib. One hundred and with younger women with more aggressive 134, 135, 143, 144, 162, 163, 165, 176, 199, 223, 227, 228, 235, The early phase trials involve Professor John Zalcberg OAM eighty-six patients with 40 different cancers (higher grade, more nodes 240, 241, 242, 252, 253, 254, 272, 282, 298, 305, 306, 313, 315, predominantly targeted therapies, which malignancies were enrolled. Notable involved). The measured psychosocial Head, Department of Medical Oncology 321, 328, 341, 342, 343. frequently require complex biomarker activity of imatinib was observed in five factors did not influence risk of recurrence Assoc. Professor Danny Rischin and imaging ancillary studies. Phase I tumour types (aggressive fibromatosis, or survival. Treating psychological issues, Deputy Head, Department of Medical trials are often conducted in collaboration dermatofibrosarcoma protuberans, such as anxiety and depression, is Oncology with other members of the Cancer Trials hypereosinophilic syndrome, important to optimise quality of life, but Assoc. Professor Michael Jefford Australia Phase I group working closely myeloproliferative disorders, and systemic such treatment should not be expected to with pharmaceutical and biotechnology improve survival. [232. Phillips et al. (2008) Consultant Medical Oncologists mastocytosis). Clinical benefit was largely collaborators. Another area of clinical trial J Clin Oncol 26:4666-4671] Assoc. Professor Grant McArthur confined to diseases with known genomic expertise is the study of novel therapeutics Assoc. Professor Kelly-Anne Phillips mechanisms of activation of imatinib target with radiation. GRANTS AND FUNDING Assoc. Professor David Thomas kinases. The results indicate an important Assoc. Professor Guy Toner Members of the department also have key role for molecular characterization of – Joint Cancer Councils: $181,500, Dr Ben Brady leadership and investigator roles in most tumours to identify patients likely to benefit ‘Enhancing informed consent in Dr Jayesh Desai of the national cooperative clinical trial from imatinib treatment. This is becoming cancer clinical trials: development and Dr Prudence Francis groups (ANZBCTG, AGITG, ANZGOG, part of a new treatment paradigm in evaluation of a question prompt sheet’, Dr Marisa Grossi ASSG, ANZUP, ALTG, TROG). Several oncology with the advent of targeted 2006–09. Dr Ross Jennens independent phase III trials run under therapies requiring molecular screening of – NHMRC Project Grant: $401,755, Dr Ken Khamly the auspices of the cooperative groups tumours to identify patients with tumours ‘Psychological morbidity, unmet needs Dr Sherene Loi that are likely to benefit from the therapy. and patterns of care in culturally and Dr Michael Michael [134. Heinrich et al. (2008), Clin Cancer linguistically diverse cancer patients in Dr Linda Mileshkin Res 14(9)] Australia’, 2007–09. Dr Gillian Mitchell (Consultant Oncologist) The impact of tailored chemotherapy Dr Benjamin Solomon information for the general practitioners Dr Allan Zimet on managing adverse effects and Targeted Therapies Fellow satisfaction with shared care Dr Bianca Devitt In this randomized trial, the impact of faxing information tailored to a particular Oncology Registrars patient’s chemotherapy regimen, to Dr Michael Franco their general practitioner was assessed Dr Andrew Weickhardt versus usual correspondence alone. Breast Cancer/Genetics Fellow GPs receiving the chemotherapy sheet Dr Belinda Kiely correspondence were significantly more confident and found the information Professor John Salzberg OAM more useful and instructive than GPs

Peter MacCallum Cancer Centre – Research Report 2008 Tumour Streams & Clinical Trials/ Medical Oncology & Early Phase Clinical Trials 107 Tumour Streams & Clinical Trials/ Breast

The Breast Service has a major Familial Cancer Centre A phase I/II study of external beam kConFab clinical Follow-up study Lucinda Hossack – NHMRC Project Grant: $426,000, commitment to research at all phases of Dr Gillian Mitchell partial breast irradiation in early [K.A. Phillips] – Victorian Travelling Fellowship: ‘Cohesin: Role in germ cell chromosomal the patient’s journey with breast cancer. Dr Yoland Antill breast cancer This study is led from Peter Mac and is a Department of Human Services and segregation’, 2006–08. Kathryn Alsop [B.H. Chua, Principal Investigator] long-term study designed to prospectively Victorian Quality Council, 2006–08. – Cancer Council Victoria, Dr John RESEARCH FOCUS Linda Cicciarelli A multidisciplinary team of researchers evaluate the impact of environmental Dr Katherine Field Colebatch Clinical Research Fellowship: Rebecca Doherty have successfully completed patient modifiers on cancer risk in individuals from • Breast cancer genetics. – American Society of Clinical Oncology $722,500, ‘Reducing the Burden Of Lucinda Hossack accrual to this national clinical trial breast cancer families. For details, see the • Breast cancer prevention. Merit Award 2008 Breast Cancer’, 2006–10. Mary Shanahan investigating the novel technique of partial kConFab Follow-up report on page 34. – VCA Clinical Trial Infrastructure Grant: • Early stage breast cancer. Mary-Anne Young breast irradiation using external-beam – MA Henderson Vellar Family Memorial $213,000, ‘A web based support tool for • Locally advanced breast cancer. three-dimensional conformal radiation PRESENTATION HIGHLIGHTS Lecture Breast Cancer in the New RESEARCH OVERVIEW Millenium. breast cancer trials across Victoria’, 2008. • Metastatic breast cancer. therapy for women with early breast cancer. Professor Michael A Henderson This clinical trial is funded by the National – VCA Supportive Care Fellowship: • Survivorship issues. Ours is one of the largest clinical service – Royal Australasian College of Surgeons GRANTS AND FUNDING Health and Medical Research Council $258,671, ‘Supporting patients with providers for breast diseases in Australia, Annual Scientific Meeting, Hong Kong, RESEARCH PERSONNEL supported by a strong multidisciplinary (NHMRC). A phase III randomised study – National Institutes of Health (USA): advanced lung and breast cancer China, May 2008 (Speaker). $US6,500,000 ‘Australian Breast Cancer and their family: making a difference’, Chair, Breast Services clinical and translational research is in development to further investigate program encompassing the entire disease the role of partial breast irradiation using – Biennial Breast Cancer Update St Family Registry’, 2006–11. 2007–09. Assoc. Professor Michael Henderson Vincent’s Hospital, Melbourne, Vic, (Surgical Oncology) spectrum. external beam conformal radiation therapy – NHMRC Project Grant: $1,648,750, ‘A – Peter MacCallum Cancer Foundation: in women with early breast cancer. February 2008 (Speaker). randomised Phase III study of radiation $25,000, ‘Interpersonal therapy couple Many of the breast service members are Deputy Head Assoc. Professor Boon H. Chua doses and fractionation schedules in non- group for women with advanced breast Assoc. Professor Boon Chua (Radiation active investigators in a broad range of Analysis of low radiation dose outside – Breast International Group Scientific low risk DCIS of the breast’, 2007–11. cancer’, 2007–08. Oncology) studies. A number of the members are of the treatment field to cancer patients also leading investigators who chair large undergoing radiotherapy Meeting, Berlin, Germany, April 2008 – NHMRC Project Grant: $1,145,775, – Jack and Robert Smorgon Families Medical Oncology scale national and international research [T. Kron, D. Willis, B.H Chua] (Speaker). ‘Psychosocial predictors of developing Foundation and the Victor Smorgon Dr Prue Francis initiatives focusing on breast cancer This study aims to develop a Monte – International Breast Cancer Study Group breast cancer in women from high risk Foundation: $104,000, ‘A state Dr Marisa Grossi prevention, management of early-stage Carlo dose calculation tool to determine Scientific Meeting, Budapest, Hungary, breast cancer families’, 2007–11. demonstration pilot project for breast MRI Dr Ross Jennens and advanced disease, and survivorship the low radiation dose outside of the April 2008 (Speaker). – NHMRC Project Grant: $738,250, screening of women at high genetic risk of Dr Linda Mileshkin breast cancer’, 2006–08. issues. main radiation fields in cancer patients – Royal Australasian College of Surgeons ‘International randomised controlled Dr Gillian Mitchell undergoing radiotherapy. This low radiation Annual Scientific Congress, Hong Kong, trial to compare targeted intra-operative – Department of Human Services, Victoria, Assoc. Professor Kelly-Anne Phillips 2008 RESEARCH ACHIEVEMENTS dose has the potential to cause long-term China, May 2008 (Invited Speaker). radiotherapy with conventional post- New Technology Grant: $610,955, ‘Rapid complications such as cardiovascular operative radiotherapy after conservative determination of carrier status for breast Radiation Oncology A sample of the many projects – Interdisciplinary Radiation Oncology side-effects and the induction of second breast surgery for women with early stage cancer predisposition genes using high Dr Michelle Bishop underway is presented below. For Seminar no. 9, Sydney, NSW, 2008 malignancy. The calculation tool will breast cancer’, 2006–10. resolution melting point technology’, Dr Steven David information about additional studies, (Invited Speaker) Dr Roslyn Drummond visit http://www.petermac.org/Research/ allow assessment of risks associated – NHMRC Project Grant: $698,575, 2007–08. – Trans Tasman Radiation Oncology Group Dr Mary Dwyer BreastCancerResearch. with this low dose and provide clinicians ‘kConFab Follow-Up Project: a – NHMRC Project Grant: $287,000, (TROG) Annual Meeting, Alice Springs, Dr Chen Liu and patients with data that can assist in prospective study of non-genetic risk ‘Tailored Treatments for Premenopausal Micro-metastases in early stage breast NT, May 2008 (Speaker). Dr Claire Phillips decision making for individual patients. modifiers in women at high risk for breast Women with Endocrine Responsive cancer The study is funded by the NHMRC and is Assoc. Professor Kelly A. Phillips Surgical Oncology cancer’, 2007–09. Breast Cancer’, 2008–10. [A. Dobrovic, M.A. Henderson, S. Lade] currently in progress. – Australian and New Zealand Breast Mr Stewart Hart This is an observational study of micro- – NHMRC Project Grant: $320,522. – National Breast Cancer Foundation: Ms Jane O’Brien BIG 02–98 (IBCSG 20–98) Cancer Trials Group Annual Scientific ‘Analysis of low radiation dose outside $352,114, ‘Can a peer support program metastatic disease in lymph glands, bone Symposium, Wellington, New Zealand, Dr Catherine Poliness [P. Francis, Principal Investigator] of the treatment field received by cancer for cancer gene mutation carriers reduce marrow and circulating tumour cells using July 2008 (Invited Speaker). Assoc. Professor David Speakman immuno-bead enrichment. Identification This international adjuvant Taxotere patients undergoing radiotherapy’, distress? A randomised controlled trial’, – American Society of Clinical Oncology, Ms Melanie Walker of minimal tumour burden may lead to trial tests the effects of docetaxel 2009–11. 2008–11. Chicago, USA, June 2008 (Poster). Pathology new treatments and improved selection in an anthracycline-based adjuvant – NHMRC Project Grant: $150,000, – National Breast Cancer Foundation: Professor Stephen Fox of treatments for patients, and improve chemotherapy program in node positive PRIZES AND AWARDS ‘A multicentre feasibility study of $96,243, ‘Providing tailored preparatory understanding of metastatic process. breast cancer, and determines optimal accelerated partial breast irradiation information about radiation therapy Radiology treatment strategy. Recruitment is Dr Prue Francis using three-dimensional conformal for women with early breast cancer: a Dr Robin Cassumbhoy completed (2,887 patients entered – Doctor of Medicine (MD), The University radiation therapy for early breast cancer’, feasibility study’, 2008–09. Dr Kate Moodie 1998–2001). Five-year analysis has been of Melbourne, Australia 2008. 2007–09. – Cancer Council Victoria: $1,200,000, Breast Nurse Coordinator conducted and results published in 2008, Assoc. Professor Boon Chua – NHMRC Project Grant: $286,750, ‘Identification of novel breast cancer Sarah Pratt with follow-up and translational analyses – TROG Trial Excellence Award, 2008. ‘Cognitive effects of adding ovarian suppressor and chemotherapeutic drug planned. sensitivity genes using shRNA-mediated Clinical Psychology Assoc. Professor Kelly-Anne Phillips function suppression to adjuvant hormonal therapy in premenopausal functional genomics screens’, 2007–10. Maria Ftanou Targeted chemotherapy for women – Cancer Council Victoria, Dr John breast cancer’, 2007–11. Social Work with breast and ovarian cancer Colebatch Clinical Research Fellowship PUBLICATIONS AND PATENTS associated with germline BRCA1 and Maree Ryan 2006–2011. – NHMRC Project Grant: $410,250, BRCA2 mutations ‘Statistical analyses of breast cancer Publications are listed at the end of the 45, 71, 85, 90, 96, Data Management [G. Mitchell] Dr Linda Mileshkin risks for Australian BRCA1 and BRCA2 report and include references 208, 222, 229, 232, 247, 251, 269. Kylie Hewitt See the Familial Cancer Centre report on – Victorian Cancer Agency (VCA), A mutation carriers’, 2007–09. Ann-Marie Power Supportive Care Fellowship. page 92. – NHMRC Project Grant: $434,000, ‘Clinical Radiosensitivity: Role of DNA Assoc. Professor Michael Henderson repair’, 2006–08.

Peter MacCallum Cancer Centre – Research Report 2008 Tumour Streams & Clinical Trials/ Breast 109 Tumour Streams & Clinical Trials/ Gastrointestinal

The Gastrointestinal Service is a Dr Sarat Chander Our service has also contributed to other – Gastric cancer: Development of potential to make a significant change to – Specialist Certificate in Clinical Research multidisciplinary therapeutic program Dr Julie Chu therapeutic trials through the AGITG chemo-radiotherapy regimens for the management of this disease. (Oncology), The University Of Melbourne, for patients with upper and lower Dr Kirsty Wishire and TROG as well as pharmaceutical patients with high-risk resected gastric May 2008 (Speaker). The development of randomised gastrointestinal cancers, with a research companies, which have focused on colon cancer in order to reduce the risk of local Nurse Coordinator Phase II trial of Docetaxel + Cisplatin – American Society of Clinical Oncology program directed from institutional to cancer, gastrointestinal stromal tumours, recurrence and improvement of overall Meg Rogers +/- Cetuximab with radiotherapy in (ASCO) Annual Meeting, Chicago, USA, international levels – our push is towards rectal and pancreatic cancers. survival; characterising the heterogeneous patients with resectable oesophageal June 2008 (Speaker and Poster). the evaluation of new therapeutic strategies Clinical Nurse Consultant biological behaviour of this malignancy. The clinical research program has been cancer (The DECO Trial). – Roche/Sanofi Aventis Post-ASCO 2007 to provide optimal individualised care for Claire Sage strongly reinforced by parallel translational – Rectal cancer: Developing novel The trial is being led by Dr Michael Michael Lung Update: Melbourne, Vic, June 2008 our patients. Senior Research Fellow studies in oesophageal, gastric, rectal chemo-radiotherapy regimens for patients of the GI Service and was based on the (Speaker). Assoc. Professor Wayne Phillips RESEARCH FOCUS and anal cancers, formulated to develop with locally advanced, locally recurrent promising results of a Phase I trial of the – Monash University, Victorian College Quality and Research Coordinator biomarkers of response and to enable the and metastatic disease, evaluating intra- same chemotherapy backbone developed of Pharmacy, Clayton, Vic, July 2008 • Understanding the biological and Jodi Lynch individualisation of therapy. operative radiation therapy, and developing at Peter Mac. The trial has been opened (Speaker). genetic nature of Barrett’s Oesophagus translational studies in rectal cancer. through several sites in Australia under the Research is also focusing on predicting – Australian Medical Research Congress, and other oesophageal, gastric and RESEARCH OVERVIEW auspices of the AGITG and TROG. rectal tumours. chemotherapy induced hepatic toxicity in The GI Service is participating in the Brisbane, Qld, November 2008 Our experts have become global leaders patients receiving chemotherapy prior to following clinical studies: (Speaker). • Identifying genetic, clinical and functional PRESENTATION HIGHLIGHTS in the development of chemo-radiotherapy resection of isolated hepatic metastases imaging predictors of: – AGITG/TROG Phase III trial of Assoc. Professor Sam Ngan treatments for certain gastrointestinal from colorectal cancer. The research Assoc Prof. J Mackay neoadjuvant chemoradiotherapy – Colorectal Cancer Conference: A - Response to chemoradiotherapy for cancers, and stand out as leaders in program has been further supported by the – Colorectal Cancer Conference: A vs chemotherapy in patients with Multidisciplinary Approach, Melbourne, oesophageal, rectal and anal cancers intra-operative radiation therapy for evaluation of functional imaging in disease Multidisciplinary Approach, Peter resectable gastric cancer (The Vic, March 2008 (Speaker). - Chemotherapy-induced hepatic rectal cancers. staging, radiation treatment planning and MacCallum Cancer Centre, Melbourne, TOPGEAR Trial). This trial (designed and injury following neoadjuvant therapy treatment response assessment. Vic, March 2008 (Speaker). – Australia & New Zealand Joint Oncology With the chief aim of providing a national led by Assoc. Professor Trevor Leong) for isolated hepatic metastases from Scientific Meeting, Christchurch, New platform for cutting-edge clinical research Novel therapy paradigms developed and is based on an initial phase II trial – Tripartite Colorectal Meeting, Boston, colorectal cancer Zealand, August 2008 (Poster). in both upper and lower gastrointestinal for the treatment of upper and lower completed at Peter Mac and whose results USA, June 2008 (Speaker). – Royal Australian and New Zealand • Intra-operative radiation therapy for tract cancers, our major research efforts gastrointestinal malignancies include: have been presented internationally. The Assoc Prof. Alexander Heriot rectal cancer. reflect our referral base of oesophageal, phase III trial commenced in 2008 and has College of Radiologists (RANZCR) 59th – Cutting edge neoadjuvant – Royal Australasian College of Surgeons gastric and rectal cancers, Barrett’s the potential to represent a major Annual Scientific Meeting, Adelaide, SA, • Novel therapy paradigms for the chemoradiotherapy regimens and Annual Scientific Meeting, Hong Kong, Oesophagus and, increasingly, colon step forward in the treatment of operable October 2008 (Speaker). treatment of upper and lower radiation planning techniques for locally China, May 2008 (Speaker). cancer. We’ve led the field both locally gastric cancer. Assoc. Professor Trevor Leong gastrointestinal malignancies. advanced oesophageal, gastric and – 29th Annual Turnbull Symposium, and internationally in these cancers, as • Exploring the psychological and rectal cancers. The establishment of the Survivorship Cleveland, USA, November 2008 – Trans-Tasman Radiation Oncology Group well as for pancreatic and anal cancers information needs of our patients Centre and Survivorship Research: (Speaker). (TROG) 20th Annual Meeting, Alice through the development of novel chemo- – Stereotactic radiation of hepatic lesions. including the development of This Australian-first initiative (led by Assoc. Springs, May 2008 (Speaker). radiotherapy regimens. – Concurrent radionuclide and systemic – Colorectal Cancer Conference: A survivorship research programs. Professor Michael Jefford) includes the – 10th Annual Scientific Meeting of therapies for metastatic neuroendocrine Multidisciplinary Approach, Peter We are also at the forefront of evaluation of (i) provision of general information about the Australasian Gastro-Intestinal RESEARCH PERSONNEL tumours. MacCallum Cancer Centre, Melbourne, intra-operative radiation therapy for locally ending treatment / life ahead (including a Vic, March 2008 (Speaker). Trials Group (AGITG), Sydney, NSW, Chair, GI Services advanced and recurrent rectal cancers. – Laparascopic upper oesophageal and DVD developed at Peter Mac and booklet September 2008 (Speaker). – Tripartite Colorectal Meeting, Boston, Dr Michael Michael These innovations are now being evaluated gastric surgery. developed in partnership with Cancer USA, June 2008 (Speaker). – Clinical Oncological Society of Australia (Medical Oncology) further through the national cooperative The GI service has also begun studies in Council Victoria), (ii) a 1hr nurse-led (COSA) Annual Scientific Meeting, – Victorian Annual General, Scientific Medical Oncologists trials groups, including the Australian supportive care research with a focus on end of treatment session (iii) a tailored Sydney, NSW, November 2008 (Invited and Fellowship Meeting, January 2008 Professor John Zalcberg OAM Gastrointestinal Tumour Trials Group patient information and their psychological survivorship care plan (SCP) for patient Speaker). (AGITG) and the Trans-Tasman Radiation needs at diagnosis and during therapy and GP (iv) as well as nurse-led telephone (Speaker). Assoc. Professor Michael Jefford Assoc. Professor Michael Jefford Oncology Group (TROG), with the GI as well as survivorship care planning and review and follow up clinic. Mr Craig Lynch Dr Alan Zimet – UICC World Cancer Congress, Geneva, Service clinicians leading these studies. nurse led follow-up clinics following the Phase III trial of short course – Tripartite Colorectal Meeting, Boston, Switzerland, August 2008 (Invited Surgical Oncologists completion of treatment. radiotherapy vs long course chemo- USA, June 2008 (Speaker). Colorectal Speaker). radiotherapy in patients with Assoc. Professor Alexander Heriot 2008 RESEARCH ACHIEVEMENTS – Colorectal Cancer Conference: A – 4th Biennial Cancer Survivorship resectable rectal cancer: Designed and Mr Craig Lynch Multidisciplinary Approach, Peter Research Conference, Atlanta, USA, The GI Service clinical and translational led by Assoc. Professor Sam Ngan, this Assoc. Professor John Mackay MacCallum Cancer Centre, Melbourne, June 2008 (Poster). research program continues to focus on randomized study ran through the AGITG Vic, March 2008 (Speaker). Upper GI the following areas. Professor Robert Thomas and TROG, supported by a National Health – Victorian Annual General, Scientific and Professor Bruce Mann – Colorectal Cancer Conference: A – Oesophageal cancer: Profiling tumours and Medical Research Council (NHMRC) Fellowship Meeting, 2008 (Speaker). Professor Robert Thomas, OAM project grant. The trial recruited more Multidisciplinary Approach, Melbourne, to allow for the choice of the most effective – 29th Annual Turnbull Symposium, Mr Cuong Duong than 300 patients across several sites in Vic, March 2008 (Session Chair and treatment and understanding patient Cleveland, USA, November 2008 Mr John Spillane Australasia, representing the largest rectal Speaker). outcomes. (Speaker). Hepatobiliary cancer study completed in the region. – Barrett’s oesophagus: Genetic Mr Simon Banting The trial arms represent two accepted Dr Michael Michael analysis of patients with a family history Mr Ben Thomson modes of preoperative therapy that until – Malaysian Upper GI Surgical Club of gastro-oesophageal reflux in Barrett’s now have not been directly compared in a Inaugural Meeting, Port Dixon, Malaysia, Radiation Oncologists oesophagus and adenocarcinoma [see randomised Phase III trial. The final results, May 2008 (Speaker). Assoc. Professor Trevor Leong also Surgical Oncology laboratory pg 28 ]. in terms of local recurrence, survival Dr Michael Michael Assoc. Professor Sam Ngan parameters and quality of life, have the

Peter MacCallum Cancer Centre – Research Report 2008 Tumour Streams & Clinical Trials/ Gastrointestinal 111 Tumour Streams & Clinical Trials/ Tumour Streams & Clinical Trials/ Gastrointestinal Gynae-Oncology

Professor John Zalcberg strategies to support adult survivors of The Gynaecology Oncology Service is a RESEARCH OVERVIEW • Phase II trial of adjuvant chemo-radiation – ASCO GI, Orlando, USA, January 2008 colorectal cancer’, 2008–09. multidisciplinary program with a research The Gynaecology Oncology Service followed by chemotherapy for patients (Invited Speaker). – Cancer Australia/Cancer Council focus directed at understanding and brings together expertise from the three with newly diagnosed endometrial – Roche Oncology China Forums, Beijing/ Australia: $596,625, ‘A randomised improving the management and treatment major Gynaecology Oncology Surgical carcinoma at high-risk of relapse. This Shanghai/Xiamen, China, May 2008 phase III trial of preoperative of gynae-oncology patients. units in a coherent multidisciplinary multi-centre investigator-initiated trial led (Invited Speaker). chemoradiotherapy versus preoperative clinical setting. Gynaecology oncologists, by Dr Mileshkin completed accrual in RESEARCH FOCUS 2008 and will be analyzed towards the – ASCO Annual Meeting, Chicago, USA, chemotherapy for resectable gastric medical oncologists, oncologic imaging Assessing and improving the trestment of: end of 2009. June 2008 (Invited Speaker). cancer’, 2008–10. radiologists, radiation oncologists, nuclear • Cervical cancer. physicians and pathologists continued to • Aprepitant, an anti-nausea medication, – SAGE Meeting, Barcelona, Spain, June – NHMRC: $443,100, ‘Predicting response work together at bi-monthly Tumour Panel with whole-abdominal radiotherapy 2008 (Invited Speaker). to chemoradiotherapy in patients with • Endometiral carcinoma. advanced rectal cancer’, 2008–11. meetings to devise the best treatment (WAR) for recurrent ovarian carcinoma: a – 10th World Congress on Gastrointestinal • Ovarian carcinoma. plan for every new patient referred to the feasibility and efficacy study. – AGITG and Merck-Serono, Australia: Cancer, Barcelona, Spain, June 2008 Service. This multidisciplinary approach $400,000, ‘THE DECO STUDY: RESEARCH PERSONNEL • A randomized controlled trial for women (Invited Speaker). incorporates diagnostic laparoscopy A randomised phase II trial of Chair, Gynae-oncology with relapsed ovarian cancer and a – Novartis Oncology Asia Pacific Summit, and histological and cytopathological weekly docetaxel (Taxotere®) Assoc. Professor Kailash Narayan BRCA 1 or 2 mutation – comparing Phuket, Thailand, July 2008 (Invited investigations, as well as Magnetic chemoradiotherapy +/- cetuximab (Radiation Oncology) standard treatment with liposomal Resonance Imaging (MRI) and Positron Speaker). (Erbitux®) in the treatment of localized doxorubicin chemotherapy to an oral Medical Oncologists Emission Tomography (PET) services. – Chevra Hatzolah, Melbourne, Vic, August resectable cancer of the oesophagus. PARP inhibitor. Dr Linda Mileshkin 2008 (Invited Speaker). Co-sponsored by AGITG and Merck- All types of gynaecologic cancer, including • A Feasibility Study of Carboplatinum Assoc. Professor Danny Rischin – World Congress on Gastrointestinal Serono, Australia’, 2008. patients with complex and uncommon plus Paclitaxel followed by radical Cancer: Asian Perspectives, Bangkok, – Roche (Australia): $400,000, ‘The GATE Gynae-Oncologist presentations, as well as those requiring pelvic radiotherapy for Uterine Serous Thailand, October 2008 (Invited Study: A multicentre randomised open Professor Michael Quinn palliative care, are managed and treated by Papillary Cancer. Speaker). label phase II trial of Tarceva in sequential Radiation Oncologists the Service. To further enhance the Service, Retrospective studies: preparation is underway to introduce a – 8th Princess Margaret Hospital combination with Gemcitabine compared Dr David Bernshaw • Taking part in a multi-institutional Colposcopic Service, which will offer a Conference, Toronto, Canada, October to Gemcitabine monotherapy as first line Dr Pearly Khaw (national) retrospective study comparing complete spectrum of management. 2008 (Invited Speaker). therapy in elderly or ECOG PS 2 patients pelvic radiotherapy vs extended Surgeons The Gynae-oncology Service utilises with advanced NSCLC’, 2008. field radiotherapy in node positive Mr. John Spillane Assoc. Professor David Allen state-of-the-art radiation therapy, including – Cancer Australia: $90,000, ‘Model for endometrial cancer. – Associations of Upper Gastrointestinal Assoc. Professor Tom Jobling Ultrasound and MRI image based bowel cancer peer support groups’, • The patterns of failure, outcome and Surgeons of the United Kingdom Nurse Coordinator 3D dosimetry. 2005–08. toxicity of locally advanced cervical Meeting, Liverpool, UK, September 2008 Ms Leanne Webb (Poster). – NHMRC Project Grant: $429,750, The service is actively involved in the cancer patients with positive common ‘Imaging functional changes during Brachytherapist Australian and New Zealand Gynaecology iliac or para-aortic nodes, treated PRIZES AND AWARDS molecularly targeted therapy in a Sylvia van Dyk Oncology Group (ANZGOG), a cooperative radically with extended field radiotherapy. clinical trials group. Assoc. Professor Sam Ngan new model of gastrointestinal stromal Social Worker • The loco-regional failure and toxicity in – Best Poster at Australia & New Zealand tumour’, 2006–08. Allison Hocking Major research studies undertaken by the locally advanced patients given either Joint Oncology Scientific Meeting, PUBLICATIONS AND PATENTS Gynae-oncology group include: lymph node boost or parametrial boost Christchurch, New Zealand depending on PET nodal status and not Prospective studies Publications are listed at the end of the parametrial invasion. GRANTS AND FUNDING report and include references 32, 47, 48, 49, 66, • PORTEC 3, a randomized controlled • Pattern of failure and toxicity in patients 83, 84, 86, 87, 89, 92, 136, 137, 159, 163, 164, 166, 179, 223, multi-institutional trial comparing – National Health and Medical Research treated with central pelvic radiotherapy in 231, 233, 283, 284, 303, 313, 339, 342. radiotherapy alone vs concurrent chemo- Council: $443,100, ‘Predicting response irradiation and adjuvant chemotherapy gynaecological cancer. to chemoradiotherapy in patients with in high risk endometrial cancer patients, • Patterns of failure in cervical carcinoma advanced rectal cancer’, 2008–11. was recently opened at Peter Mac, with assessed by post therapy positron – NHMRC Project Grant: $1,303,750, Dr Mileshkin as the Australian principal emission tomography. ‘Increasing appropriate screening for investigator for this international GCIG PUBLICATIONS AND PATENTS colorectal cancer patients and first study. Funding to run this study in degree relatives’, 2008–10. Australia was obtained from a National Publications are listed at the end of the – NHMRC Project Grant: $925,625, ‘Risk Health and Medical Research Council report and include references 210, 314. factors for gastro-oesophageal reflux (NHMRC) project grant. Peter Mac is disease & Barrett’s oesophagus in a also collaborating on an Australian-led prospective cohort study’, 2008–10. sub-study of patient preferences for – NHMRC Project Grant: $277,500, ‘In vivo chemotherapy. models for understanding the cellular • Prospective study to determine the and molecular pathogenesis of Barrett’s relationships between survival and oesophagus’, 2006–08. FIGO stage, tumour volume and corpus – Peter Mac Foundation: $74,672, invasion in cervical cancer. ‘Development and testing of novel Assoc. Professor Kailash Narayan

Peter MacCallum Cancer Centre – Research Report 2008 Tumour Streams & Clinical Trials/ Gynae-Oncology 113 Tumour Streams & Clinical Trials/ Haematology

We conduct a broad repertoire of clinical RESEARCH OVERVIEW – Ongoing Phase-I trial in patients with were obtained from trials exploring the GRANTS AND FUNDING Cells +/- Lenalidomide Maintenance in and translational research focused on In an ongoing effort to improve treatment, chronic lymphocytic leukemia of ABT263 addition of the monoclonal antibody – Peter MacCallum Foundation: $330,000, Multiple Myeloma, LITVACC’, 2008. patients with haematologic malignancies, care and patient outcomes, we have (a BH3-mimetic) in collaboration with against CD20, rituximab, to nucleoside ‘Immunology of novel therapies in – NCRIS: Capability 5 Project: $50,000, including studies into pathogenesis, pursued a broad and varied clinical Peter Mac’s Gene Regulation laboratory analogue combination therapy in both myeloma’, 2007–10; $343,000, Morris ‘A Phase I study Investigating the supportive care and the enhancement and translational research program, and colleagues at WEHI. previously untreated and relapsed chronic Grant ‘Immunotherapy for Myeloma’, tolerability, safety and biological of long-term quality of life. Our key which incorporates our own initiatives, – Ongoing Phase-I trial of a monoclonal lymphocytic leukemia. These studies 2005–08; Vaccari Grant: $540,000, parameters of an infusion of autologous focus is on conditions including multiple cooperative group trials – particularly antibody against the cell surface have led to the adoption of combined ‘Murine Models for Myeloma’, 2007–09. peripheral blood T lymphocytes myeloma, non-Hodgkin lymphoma, those of the Australasian Leukaemia receptor, CSL360, which has the capacity chemo-immunotherapy as standard for transduced with an anti-LewisY chimeric chronic lymphocytic leukaemia and the this disease. We are continuing to explore – Health Research Council of NZ: and Lymphoma Group (ALLG) – and to eradicate myeloid leukemia ‘stem $1,226,960, ‘Immunology of Cancer and receptor gene in patients with LewisY myelodysplastic syndromes. pharmaceutical industry studies. cells’ in laboratory animal studies. novel monoclonal antibody therapies: positive multiple myeloma’, 2008. Ocreluzimab, a humanised anti-CD20 Infective Disease’, 2005–10. – Studies into novel therapies for multiple – NCRIS: Capability 5 Project: $92,000, RESEARCH FOCUS The focus of our research is improving our antibody, and Lumilixumab, directed – Leukaemia and Lymphoma Society myeloma, including an international ‘Cell tracking of immune-regulatory cells’, understanding of disease pathogenesis, against CD23, added to standard chemo- (US): $1,000,000, ‘Anti-Lewis-Y chimeric • Novel therapies for multiple myeloma, Phase-III trial of the immuno-modulatory 2008–2009. improving treatments, enhancing immunotherapy for relapsed chronic receptor gene in patients with Lewis Y and their immunologic basis of activity. agent Lenalidomide in combination supportive care, and enhancing the lymphocytic leukemia and a novel CD20 positive multiple myeloma’, 2006–11. – NCRIS: Capability 5 Project: $68,000, • Early phase development of novel with melphalan and prednisolone, and long-term health status of patients with antibody (GA101) in combination with Genvax immunotherapy, 2008–09. therapeutics. a Phase I study of the combination – National Health and Medical Research haematologic malignancies. chemotherapy. Council (NHMRC) Project Grant: – NCRIS: Capability 5 Project: $50,000, • Enhancing the efficacy and safety of of the histone deacetylase inhibitor At every opportunity we seek to enhance $342,250, ‘A prospective single-arm trial Lipotek production, 2008–09. nucleoside analogue combination depsipeptide with the proteasome PRESENTATION HIGHLIGHTS translational research productivity and of involved-field radiotherapy for stage – Leukaemia Foundation of Australia: therapies in indolent lymphoproliferative inhibitor bortezomib. collaborate with laboratory-based research Professor Miles Prince I–II low-grade non-gastric marginal-zone $169,000, Haematology late-effects disorders. – Ongoing clinical trials with patients colleagues, particularly in the Tumour lymphoma’, 2007–11. nurse co-ordinator, 2008–11. with cutaneous lymphomas, exploring – Satellite Symposium at American • A state-wide referral centre for the Immunology Group, through the work the therapeutic potential of LBH589 Society of Hematology Annual Meeting, – CLL (Chronic Lymphocytic Leukemia) – Rotary Australia: $162,000, Design and management of cutaneous lymphomas of Assoc. Professor David Ritchie and (panobinostat) and depsipeptide in San Francisco, USA, December 2008 Global Research Foundation: testing of new combination therapies and investigation of novel therapies for Dr Simon Harrison in the Haematology collaboration with the Skin Lymphoma (Session Chairman and Speaker). US$300,000, 2006–08. for the treatment of leukemia and these diseases. and Immunology Translational Research Clinic at St Vincent’s Hospital, Melbourne. Assoc. Professor David Ritchie – Roche Australia: $180,000, Quality lymphoma) 2008–10. • A recognised centre of excellence Laboratory [see page 78]. Assurance Program Development Grant – Cancer Australia: $1,294,000, Support for for management of myelodysplastic Management of myelodysplastic – 11th Western Pacific Congress on to ALLG, 2006–08. cancer clinical trials program, 2008–10. syndromes and development of novel 2008 RESEARCH ACHIEVEMENTS syndromes and development of novel Chemotherapy and Infectious Diseases therapies (WPCCID), Taipei, Taiwan, December – NHMRC Enabling Grant: $1.5 million, – Peter MacCallum Foundation Project therapies. Early phase development of novel 2008 (Speaker). National Leukaemia and Lymphoma Grant: $50,000, ‘Treg in Lymphoma’, therapeutics The myelodysplastic syndromes (MDS) RESEARCH PERSONNEL are a highly prevalent, often fatal, group – Taiwan Haematologists Meeting, Taipei, Tissue Bank, 2006–10. 2008. This is a high-priority area of research Chair, Haematology Services of bone marrow stem-cell disorders Taiwan, January 2008 (Invited Speaker). – Leukemia and Lymphoma Society: and in 2008 included the following clinical – Victorian Cancer Agency Project Grant: Assoc. Professor John Seymour with no currently effective therapies. In US$600,000, ‘A Phase I study investigations: Assoc. Professor John Seymour $250,000, Developing a DC vaccine in 2008, trials continued to address the investigating the tolerability, safety and Consultant Haematologists – Visiting Professor, Universite Claude Myeloma, 2008–10. – Commencement of a Phase-I trial of burdensome clinical problems of anemia, biological parameters of an infusion Dr Dennis Carney Bernard, Lyon, France, September– – Australian Cancer Research Foundation a novel Jak-2 inhibitor (SB1518) in with the combination of Lenalidomide and of autologous peripheral blood T Dr Simon Harrison December 2008. (ACRF): $1,200,000, Establishment of Cell collaboration with the Walter and Eliza the haematopoietic cytokine stem-cell lymphocytes transduced with an Dr Henry Januszewicz and Molecular Therapies Laboratory at Hall Institute (WEHI). factor, and transfusional iron overload, – American Society of Hematology Annual anti-Lewis-Y chimeric receptor gene in Dr Melita Kenealy (Locum, July – Dec Royal Prince Alfred Hospital, NSW, 2008. with the oral iron chelating agent ICL670 Meeting, San Francisco, USA, December patients with Lewis Y positive multiple 2008) – Ongoing studies exploring oral and (Exjade). Earlier trials at Peter Mac helped 2008 (Session Chairman). myeloma’, 2005–08. – Victorian Cancer Agency, Clinical Stream: Professor Miles Prince intravenous administration of LBH589 establish that a new class of drugs, DNA – GELA Scientific Committee Meeting, $250,000, ‘Phase-III Study, Autologous Assoc. Professor David Ritchie (panobinostat - a potent histone de- – NHMRC Program Grant: $10,810,800, hypomethylating agents, can alter the Paris, France, 2008 (Speaker). Peripheral Stem Cell Transplant and Dr David Westerman acetylase inhibitor that may potentially ‘Immune Regulation, Effector function natural history of MDS through restoration Adjuvant Vaccination with Autologous Assoc. Professor Max Wolf restore the abnormal pattern of gene – European Mantle-cell Lymphoma and Human Therapy’, 2007–11. of normal gene expression patterns and Dendritic Cells +/- Lenalidomide expression in cancer). Network Meeting, Turin, Italy, February – Merck Serono: $11,440, ‘Analysis Cancer Council Victoria Fellow lead to improved survival of patients Maintenance in Multiple Myeloma’, 2008 (Speaker). of Victorian Cutaneous Lymphoma Dr Kirsten Herbert [Lancet Oncology 10:223, 2009]. A multi- 2008–2009. – German Low-grade Lymphoma Study database’, 2007–08. Research Fellows centre study coordinated through the ALLG – Novartis Pharmaceuticals: $270,000, Group, Munich, Germany 2008 (Speaker). – National Collaborative Research Dr Stefan Peinert is now aiming to further improve outcomes ‘Determining the effects of Panobinostat – 10th International Conference on Infrastructure Strategy (NCRIS), Dr Hang Quach through the use of the combination of on platelet production and survival and Malignant Lymphoma, Lugano, Capability 5 Project: $7.6 million ‘Cell Dr Ines Chamaki 5-azacitidne and the immuno-modulatory analysing the mechanisms of action of agent thalidomide, which has shown Switzerland, June 2008 (Speaker). Therapy capacity development in pan-HDAC inhibitor (local ref PLBH589_ Nurse Coordinators modest activity in MDS. – American Society of Clinical Oncology Australia’, 2007–12. JOHRI02)’, 2008–2010. Odette Blewitt Educational Session, Chicago, USA, – NCRIS: Capability 5 Project: $50,000, Nucleoside analogue PUBLICATIONS AND PATENTS Linda Clark May–June 2008 (Speaker). Maintenance of TGA license no. 149827, combination therapies in indolent Suzanne Eerhard 2008. Publications are listed at the end of the Trish Joyce lymphoproliferative disorders PRIZES AND AWARDS 3, 11, 12, 14, 25, – NCRIS: Capability 5 Project: $100,000, report and include references Sharna Moloney Peter Mac has a long history of trials 27, 28, 29, 40, 41, 42, 76, 77, 80, 95, 107, 108, 109, 110, 111, Dr Stefan Peinert ‘Phase-III Study Autologous Peripheral aiming to optimise therapeutic approaches 112, 127, 134, 135, 138, 143, 144, 176, 199, 205, 206, 207, 237, – Haematology Society of Australia and New Stem Cell Transplant and Adjuvant for many indolent lymphoproliferative 238, 242, 250, 252, 253, 254, 263, 297, 335. disorders. In 2008, very positive results Zealand Albert Baikie Medal for HSANZ Vaccination with Autologous Dendritic Assoc. Professor John Seymour Presidential Symposium presentation.

Peter MacCallum Cancer Centre – Research Report 2008 Tumour Streams & Clinical Trials/ Haematology 115 Tumour Streams & Clinical Trials/ Head & Neck

The Head and Neck Service has a strong RESEARCH OVERVIEW Post-operative concurrent radiotherpay Beyondblue GRANTS AND FUNDING – Victorian Cancer Agency (VCA): $70,000, commitment to clinical research, based versus post-operative radiotherapy Ours is Australasia’s largest head and Prospective study into the prevalence of ‘Establishment of a Dietitian led clinic for in high-risk cutaneous squamous cell – National Health and Medical Research on the belief that good clinical research neck service – currently managing 70 per H&N cancer patients‘, 2008–09. carcinoma of the head and neck (POST depression, anxiety symptoms and overall Council (NHMRC) Project Grant: underpins excellence in patient care. cent of Victoria’s head and neck cancer study) psychosocial function of an Australian $500,125, ‘Predictive significance of – VCA Early Career Seed Grant: $60,000, population through a multidisciplinary head and neck cancer population: Part RESEARCH FOCUS [Assoc. Professor Sandro Porceddu, and tumour hypoxia in patients with head and ‘Molecular predictors of outcome after and holistic approach to patient care. Our A - Validation of the DASS21 and Part Assoc. Professor Danny Rischin] neck cancer treated on a randomised chemoradiation in Head and Neck • Improving clinical outcomes for head treatment recommendations are derived B - Psychosocial risk factors. 320 patients The aim of this study is to determine if trial’, 2006–08. Squamous Cell Carcinoma’, 2008–09. and neck (HandN) cancer patients. from evidence-based medicine and state- were accrued and data collection will be the addition of chemotherapy (weekly – National Institute of Health Grant: • Investigating novel head and neck of-the-art practice of cancer care. completed in Sept 2009. PUBLICATIONS AND PATENTS carboplatin) adds to the efficacy of post- $US1,970,346, ‘Defining Molecular cancer treatments with a focus on With a major commitment to clinical operative radiotherapy alone to improve Markers for Tumour Hypoxia’, 2006–11. Publications are listed at the end of the hypoxia. PRESENTATION HIGHLIGHTS report and include references 26, 53, 54, 55, 239. research, we initiate relevant clinical loco-regional control and disease free and – Cancer Council Multi-state Grant: • Minimising treatment side-effects with a Assoc. Professor June Corry studies through a process of actively overall survival. This is a multi-centre study $150,000, ‘Post-operative concurrent focus on Intensity-Modulated Radiation maintaining our database on all new under the auspices of the Trans Tasman – 1st Australia- Hong Kong Scientific chemo-radiotherapy versus post- Therapy (IMRT). cancer patients and regularly reviewing Radiation Oncology Group (TROG). The meeting of H&N Oncology, Hong Kong, operative radiotherapy in high-risk our treatment results. The service is China, November 2008 (Speaker). RESEARCH PERSONNEL aim is to accrue a total of 265 patients. cutaneous squamous cell carcinoma of currently working to improve activity in The study is accruing well with expected – 7th International Head & Neck the head and neck’, 2006–08. Chair, Head and Neck Services translational research studies and allied completion of patient accrual in 2010. Conference, San Francisco, USA, July Assoc. Professor June Corry (Radiation – Queensland Smart State Grant: health research activities. 2008 (Speaker). Oncology) A Phase I/II study of cetuximab, $324,000, ‘Post-operative concurrent 2008 RESEARCH ACHIEVEMENTS carboplatin and radiotherapy for – Royal Australian and New Zealand chemo-radiotherapy versus post- Medical Oncologists patients with Locally Advanced College of Radiologists (RANZCR) operative radiotherapy in high-risk Assoc. Professor Danny Rischin Gemcitabine and carboplatin induction Head and Neck Cancer (LAHNC). Australian Society for Microbiology cutaneous squamous cell carcinoma of Dr Ben Solomon chemotherapy followed by concurrent TROG 07.04 (ASM), Adelaide, SA, October 2008 the head and neck’, 2006–11. cisplatin and IMRT for locally Radiation Oncologists There is currently no standard treatment for (Speaker). advanced nasopharyngeal carcinoma – Beyond Blue: $90,000, ‘An investigation Professor Lester Peters patients with locally advanced head and – Australian and New Zealand Head [Assoc. Professor Danny Rischin, and of levels of psychological distress Dr Margaret Chua neck cancer (LAHNC) who are medically and Neck Society (ANZHNS) ASM, Assoc. Professor June Corry] (depression and anxiety) and unmet Dr Andrew Coleman unfit for cisplatin chemoradiation. The aim Melbourne, Vic, September 2008 This Phase II study aims to maintain needs amongst people diagnosed with Dr Leta D’Costa of this study is to assess the safety and (Presidential Address). head and neck cancer’, 2007–09. our excellent treatment results in this feasibility of combining radiotherapy and Surgical Oncologists – IG&ART (Image Guided and Adaptive – Merck: $350,000, ‘A Phase I/II study of uncommon cancer while reducing the carboplatin (chemotherapy) with a new Professor Andrew Sizeland RT) Consensus Forum, Melbourne, Vic, cetuximab, carboplatin and radiotherapy late toxicity of treatment. Specifically the drug called cetuximab in patients with Mr Felix Behan February 2008 (Invited Speaker). for patients with Locally Advanced Head induction chemotherapy regimen has LAHNC. If this regimen is proven to be safe Mr Stephen Kleid and Neck Cancer (LAHNC). TROG been altered to include a new drug in this and feasible, it will provide evidence for Assoc. Professor Danny Rischin Mr Sorway Chan 07.04’, 2007–11. disease (Gemcitabine) and carboplatin, to a randomised Phase III study comparing – 2nd Modelling of Tumour (MoT) Meeting, Mr David Wiesenfeld reduce the ototoxicity which was significant it with a carboplatin-containing regimen Adelaide, SA, May 2008 (Invited Dental Oncologist in our previous induction chemotherapy without cetuximab, e.g. the GORTEC Speaker). regimen. The use of IMRT is expected Dr John O’Grady regimen. The Phase 1 component of this – American Society of Clinical Oncology to significantly reduce the severity of study was completed in 2008 and the Annual Meeting, Chicago, USA, May Palliative Care xerostomia (chronic dry mouth). This Dr Odette Spruyt regimen was found to be safe and feasible 2008 (Invited Speaker). study completed accrual in 2008 and is - now accrual can commence in other ANZ – ANZHNS ASM, Melbourne, Vic, Radiation Therapist awaiting analysis. centres. The planned total patient accrual September 2008 (Invited Speaker). Ms Sue Walsham number is 60. – Hong Kong Head and Neck Society Radiotherapy Nurses Prospective Study of the feasibility and Annual Meeting, Hong Kong, China, Ms Robyn Lister efficacy of a Head and Neck Dietitian December 2008 (Invited Speaker). Bev Myer led clinic Dr Ben Solomon Speech Pathologists This clinic was established following the – ANZHNS ASM, Melbourne, Vic, Ms Louise Malcolm awarding of a Victoria Cancer Agency September 2008 (Invited Speaker). Nurse Manager (VCA) grant. The study aims to optimise Ms Tenille Lewin the provision of timely supportive care to head and neck cancer patients, and Nurse Coordinator equip these patients with knowledge and Ms Wendy Poon self care strategies in order to minimise Dietitian the physical and emotional impact of Ms Jenelle Loeliger nutritional problems and radiotherapy side effects. Once the background work was Social Worker completed (Feb-Aug 08) the clinic was Ms Rebecca McMillan established and patients recruited (Sept 08 onwards) and the results will then be Assoc. Professor June Corry analysed. Figure1: Head and Neck Intensity Modulated Radiation Therapy

Peter MacCallum Cancer Centre – Research Report 2008 Tumour Streams & Clinical Trials/ Head & Neck 117 Tumour Streams & Clinical Trials/ Lung

The Peter Mac Lung Service promotes RESEARCH OVERVIEW Radiotherapy technical studies The growth kinetics of therapy naïve PRESENTATION HIGHLIGHTS and facilitates clinical, translational and lung tumours according to 18F-FDG Our researchers are taking the lead in • Hybrid CT/PET assisted treatment Assoc. Professor David Ball supportive care research directed at planning. PET/CT Australia and globally with particular clinical – First European Lung Cancer Conference, improving outcomes for patients with lung This study analysed tumour progression studies, which evaluate new therapeutic • Monitoring tumour motion and insertion Geneva, Switzerland, April 2008 (Invited cancer and other thoracic malignancies. in 28 patients with therapy naïve non-small strategies for lung cancers. of fiducial markers into tumours using Speaker). EBUS. cell lung cancer (NSCLC) using serial RESEARCH FOCUS With a comprehensive multidisciplinary pre-treatment 18F-FDG PET/CT scans. – 9th International Lung Cancer Congress, • 4D CT for treatment planning and • Molecular imaging and prognostic evidence-based therapeutic program All patients were considered eligible for Koloa, Hawaii, USA, June 2008 (Invited monitoring changes during treatment. factors. for patients with lung and mediastinal radical treatment based on their initial Speaker). tumours, we maintain a strong focus on • Development of extracranial ‘stereotactic’ scan. The median inter-scan period was • Development of novel therapies for non- – The IASLC Lung Cancer Staging Project, identifying the psychosocial needs of (highly conformal image guided) 24 days (range 8-176 days). Disease small cell lung cancer. Hobart, Tas, July 2008 (Invited Speaker). patients and providing holistic care beyond radiotherapy for early lung cancer and progression (TNM stage) was reported – 2nd Australian Lung Cancer Conference, • Symptom palliation. medical requirements. pulmonary metastases. in 11 (39%) patients. Treatment intent Gold Coast, Qld, August 2008 (Invited • Psychosocial research. Evidence-based and investigational Palliation changed from radical to palliative in 8 Speaker). (29%) cases, including 5 (18%) patients RESEARCH PERSONNEL treatment of thoracic malignancies is • Brain irradiation (QUARTZ trial). – Chicago Multidisciplinary Symposium directed at improving outcomes for who developed distant metastatic disease. Chair, Lung Services Chemotherapy for advanced disease in Thoracic Oncology, Chicago, USA, Figure 1: An example of progression during patients with lung cancer and other The estimated probability of disease inter-scan interval (22 days) from Stage T4N3M0 • Phase I and II agents; participation in November 2008 (Speaker). Assoc. Professor David Ball (Radiation thoracic malignancies. progression, according to TNM staging, to T4N3M1. Sites of disease progression included Oncology) international Phase III trials. at 7, 14 and 28 days was 11%, 20% and – Engineering and Physical Sciences increasing size and intensity of 18F-FDG uptake Our treatment approach is based on in Medicine Conference (EPSM), in the primary lung lesion and mediastinal lymph Medical Oncologists Psychosocial research 37%, respectively. Of the 18 patients nodes as well as tumour involvement in a supra- research activities, including the following: Christchurch, NZ, November 2008 Dr Michael Michael • Randomised trial of providing patients who underwent both scans at Peter Mac, clavicular fossa node and hepatic metastases. (Speaker). Dr Linda Mileshkin Diagnostic techniques with pre-treatment information. there was a mean relative inter-scan increase of 19% in SUVmax (p=0.022), GRANTS AND FUNDING Dr Benjamin Solomon • Endobronchial ultrasound (EBUS). • Identification of unmet patient needs. Sarah Everitt 16% in SUVave (p=0.004) and 116% – Chicago Multidisciplinary Symposium – National Health and Medical Research Psychosocial Prognostic factors • Smoking cessation. in percentage injected dose (p=0.002) in Thoracic Oncology, Chicago, USA, Council (NHMRC) Project Grant: Assoc. Professor Penny Schofield • Molecular predictors of patterns of • Patient preferences for follow-up after in the primary gross tumour. Based on November 2008 (Speaker). $63,000, Palliative Care Priority Driven relapse and of long-term survival in Radiation Oncologists treatment. SUV settings individualised for each Research Grant, ‘QUARTZ – Quality of radiation hypersensitive individuals. Professor Tomas Kron Assoc. Professor Michael MacManus patient, the expected doubling time of the life after radiotherapy and/or steroids’, 2008 RESEARCH ACHIEVEMENTS – Engineering and Physical Sciences Dr Nikki Plumridge • Influence of PET SUV on survival. metabolically active primary tumour was 2007–09. Dr Matthew Seel Three prospective trials completed 66 days. Further, there was a 2.5% and in Medicine Conference (EPSM), • Significance of EPO receptors on lung – Victorian Cancer Agency Tumour Dr Greg Wheeler accrual during the year, two of which were 97.5% probability of this volume doubling Christchurch, NZ, November 2008 cancer cells. Stream Research Grant: $250,000, Dr Andrew Wirth conducted under the auspices of the in 51 days and 95 days, respectively. (Speaker). • Influence of tumour volume on survival. ‘A prospective study investigating the Trans Tasman Radiation Oncology Group These findings highlight the importance of Dr Linda Mileshkin Radiation Oncology Fellows impact of serial PET/CT scans on the Innovative surgical techniques (TROG) with significant Peter Mac input. initiating treatment in a timely manner to Dr Marie-Pierre Campeau (Montreal) – Australian Lung Cancer Conference, radiation therapy treatment of patients • VATS lobectomy. minimise the impact of tumour progression Dr Debbie Gregory (Cambridge) The first of these, TROG 9905 (PI David Surfers Paradise, Qld, August 2008 (Oral with lung cancer’, 2008–09. in patients with NSCLC (see Fig 1). Presentation). Dr Sinead Brennan (Dublin) Combined chemo-radiotherapy Ball), was a prospective observational – Cancer Australia: $40,000, ‘Patients with study designed to determine the Imaging Cellular Proliferation During – Western and Central Melbourne Thoracic Surgeons • Combination with biological agents. lung cancer and their carers – supporting prognostic influence of tumour volume Therapy: A Pilot Study Of Serial 18F-FLT- Integrated Cancer Service (WCMICS) Mr Naveed Alam Molecular imaging through novel information models’, in patients with non-small cell lung PET Scanning During Chemo-radiation Supportive Care Conference, Melbourne, Mr Phillip Antippa • Novel tracers to detect hypoxia (FAZA) 2008–09. cancer treated by non-surgical means. It For Non-Small Cell Lung Cancer Vic, October 2008 (Oral Presentation). Mr Gavin Wright and tumour proliferation during – Victorian Cancer Agency: Supportive accrued a total of 531 patients, and will Five patients with locally-advanced NSCLC treatment (FLT). – American Society of Clinical Oncology Care Fellowship - Supporting the patients Respiratory be presented at the World Conference on underwent radical chemo-RT (60 Gy (ASCO), Chicago, USA, May–June 2008 with advanced lung and breast cancer Dr Louis Irving Lung Cancer (WCLC) in San Francisco, in 6 weeks with concurrent carboplatin (Speaker). and their family: making a difference Dr Renee Manser August 2009. and paclitaxel), one baseline and two Belinda McInnes ($258,671): principal researcher, on-treatment 18F-3′-deoxy-3′-fluoro-l- Nurse Coordinator TROG 0307 (PI Michael Michael), was a 2008–09. thymidine (FLT) PET/CT scans. Baseline – 2nd Australian Lung Cancer Conference, Mary Duffy randomised phase II study of two different FLT and FDG abnormalities corresponded Gold Coast, Qld, August 2008 (Speaker). – Sylvia and Charles Viertel Clinical chemo-radiation regimens for palliation Molecular Imaging in all patients. FLT tumour uptake was Investigator’s Award: $60,000, ‘Proteomic of patients with locally advanced or Dr Benjamin Solomon Professor Rod Hicks observed on five of nine (55%) on- profiling of tumour interstitial fluid in Non- oligometastatic non-small cell lung cancer – Australian and New Zealand Head and treatment scans, on day 2, 8 and 29, but small cell lung cancer’, 2008. Structural Imaging unsuitable for radical treatment. It accrued Neck Society Meeting, Melbourne, Vic, not day 15. A ‘flare’ of FLT occurred in Dr Brooke Sawyer 80 patients and will also be presented at September 2008 (Invited Speaker). PUBLICATIONS AND PATENTS one primary tumour following 2 Gy (1.22 Physics the World Conference on Lung Cancer. x baseline). FLT tumour uptake reduced PRIZES AND AWARDS Publications are listed at the end of the Professor Tomas Kron report and include references 15, 16, 17, 78, 79, A randomised controlled trial of a novel (mean 0.58 x baseline) on the remaining Associate Professor David Ball psychosocial intervention to address the 158, 193, 214, 235, 268. Radiation Therapists eight on-treatment scans. FLT uptake in – Paula Pitt Award for Outstanding unmet needs of patients with lung cancer Yolanda Aarons irradiated bone marrow was reduced after Contribution, 2008. Sarah Everitt (PI P. Schofield) completed accrual and 2 Gy and absent after 10 Gy. This proof of Eric Nguyen has been accepted as an oral presentation concept study highlights the potential of for the WCLC. FLT as a marker of response and further Assoc. Professor David Ball studies are continuing.

Peter MacCallum Cancer Centre – Research Report 2008 Tumour Streams & Clinical Trials/ Lung 119 Tumour Streams & Clinical Trials/ Melanoma & Skin

Our group undertakes translational and Pathologists therapy for skin cancer continues to squamous cell carcinomas of the skin and Surgeons, Hong Kong, May 2008, National Institutes of Health (USA): clinical research in melanoma and non- Dr Bill Murray be the use of anti-=PDGFR therapy in dermatofibrosarcoma protuberans. This (Invited Speaker). US$702,418, ‘Defining Molecular Markers melanoma skin cancer with a focus on Dr Hugh Turner deramatofibrosarcoma protuberans, has required evaluation of target activation – Presentations of the keystone flap in of Hypoxia’, 2006–10. integrating research with multidisciplinary which the unit is hoping to apply to other in tissue samples using molecular Palliative Care overview of its reconstructive applications CCV: $1.2m, ‘Identification of novel breast care of patients with skin cancer. skin cancers. techniques and clinical trials to evaluate Dr Odette Spruyt from the head and neck to the lower limb cancer suppressor and chemotherapeutic novel therapeutics such as imatinib. with Phillip Pelliser, Bordeaux, France, drug sensitivity genes using shRNA- RESEARCH FOCUS Social Worker 2008 RESEARCH ACHIEVEMENTS The unit’s clinical trials activities also October 2008 (Speaker). mediated functional genomics screens’, Catherine Coppolino examine novel immunological strategies in • Role of radiotherapy in melanoma and Evaluation of radiotherapy in the – University of Hong Kong, Hong Kong, 2007–10. melanoma given the ongoing challenges in other skin cancers. Physicist management of patients with China, November 2008 (Invited Speaker). identifying effective cytotoxic agents in NHMRC Project Grant: $128,125 pa, • Evaluation of novel therapeutics in Dr Jim Hagekyriakou melanoma and Merkel cell carcinoma this disease. – International meeting of the Combined ‘Inhibition of CHK1 Kinase for Cancer melanoma. [M. Henderson, A. Hui and M. Seel] Melbourne Melanoma Project Officer Australian & Hong Kong Head and Neck Therapy’, 2008–10. • Integration of molecular analysis of Cristina Conessa Patients with regional nodal metastases PRESENTATION HIGHLIGHTS Society Meeting, Hong Kong, China, melanoma with clinical care. from melanoma are at risk of regional November 2008 (Speaker). Victorian Cancer Agency (VCA): $339,000, RESEARCH OVERVIEW Assoc. Professor Grant McArthur ‘The Melbourne Melanoma Project’, • Targeted therapies in skin cancer. recurrence following lymphadenectomy, Dr Odette Spruyt which can be associated with very – New Directions in Leukemia Research, 2008–09. The management of patients with skin – Indian Association of Palliative Care RESEARCH PERSONNEL significant morbidity and is a sign of Queensland, March 2008 (Speaker). cancer requires a highly integrated Conference, Kochi, India, February 2008 Novartis: $429,875, ‘Mutation screening high risk of distant disease (see Fig – Pfizer Oncology Forum, Melbourne, Vic, Chair, Melanoma and Skin Services, and multidisciplinary approach that provides a (Plenary Session Chair). for Melanoma and other malignancies’, Head Surgical Oncology framework for our research activities. 1). The unit has led a national study to April 2008 (Invited Speaker). 2007–08. Assoc. Professor David Speakman formally evaluate the role of radiotherapy – Australian and New Zealand Society Our researchers have uncovered a new – Association of Regulatory and Clinical Pfizer: $14.99m, ‘Peter MacCallum in the adjuvant setting following of Palliative Medicine (ANZSPM) AGM, Surgical Oncologist paradigm for molecular classification of Scientists (ARCS) of Australia & NZ, Pfizer Translational Oncology Research lymphadenectomy by randomising Darwin, NT, September 2008 (Speaker). Assoc. Professor Michael Henderson: melanoma, which could have profound Sydney, NSW, May 2008 (Speaker). Collaborative Hub (TORCH), 2008–10. patients to observation versus adjuvant – Refresher Course in Pain and Palliative (Deputy Director: Dept. of Surgical outcomes for those in advanced stages – AGITG Trials in Action Annual Scientific external beam radiotherapy. The study Medicine Trivandrum 15th to 17th Feb NHMRC Project Grant: $295,000, ‘A Oncology) of the disease, and we’ve taken a lead in Meeting, Sydney, NSW, May 2008 has completed accrual and results will 2008 (Course Speaker). randomised clinical trial of surgery versus national studies into radiotherapy use for (Speaker). Plastic Surgery be available during 2008. Radiotherapy – Teaching Grand Round, Mildura, Vic, May surgery plus adjuvant radiotherapy for particular melanomas. – Australian Society of Medical Research, Dr Simon Donahoe (Head) also plays a major role in the treatment 2009 (Speaker). regional control in patients with completely Mr Felix Behan Specifically, we’ve led a nation-wide study of Merkel cell carcinoma. The unit is Research Week, Monash Institute of resected macroscopic nodal metastatic – GP Seminar, Mildura, Vic, May 2008 Dr Miklos Pohl into the role of adjuvant radiotherapy in evaluating the role of combined modality Medical Research, Melbourne, Vic, June melanoma’, 2007–09. (Speaker). Mr Terry Wu the management of patients at high risk of therapies with cytotoxic chemotherapy 2008 (Invited Speaker). Mr Jeremy Wilson regional relapse after lymphadenectomy and the role of sentinel lymph node – International Melanoma Working Group, – Aboriginal Health Centre, Mildura, Vic, PUBLICATIONS AND PATENTS Florence, Italy, May 2008 (Speaker). May 2008 (Speaker). Radiation Oncologists for Stage III melanoma. Our work shows biopsy in planning the management of Publications are listed at the end of the Dr Matthew Seel (Acting Head) radiotherapy has a clear role in the these patients. – International Melanoma Working Group, PRIZES AND AWARDS report and include references 99, 180, 182, 240. management of patients with Merkel cell Dr Andrew Hui The Melbourne Melanoma Project Florida, USA, November 2008 (Speaker). carcinoma and continues to be a focus of Assoc. Professor Grant McArthur Dr Margaret Chua – World Meeting of Interdisciplinary our research activities. [G. McArthur, C. Conesa and D. Speakman] – Cancer Council Victoria, Sir Edward Melanoma Centres, Florida, USA, Nurse Co-ordinators Dunlop Clinical Research Fellowship: We’ve also driven the establishment Despite recent improvements in survival November 2008 (Speaker). Marianne Griffin of patients with many melanoma types, 2006–10. Elizabeth Le Hunt of the Melbourne Melanoma Project, – Royal Australian Chemical Institute mortality from melanoma has not – Medical Media Award for his tireless which will integrate routine molecular Annual Meeting, Couran Cove, Qld 2008 Administrative Assistant improved. The Melbourne Melanoma commitment to the media to honour the evaluation of patients’ melanomas (Plenary Lecture). Melissa Faulkner to patients’ clinical care, including Project (MMP) has established an dying wish of 26 year old Clare Oliver – – The University of Melbourne, Defence evaluation of novel therapeutics – for infrastructure to link collection of clinical that the message about the danger of Head and Neck Surgeon Mechanisms and Their Failure (510-310) example, targeted therapies to proteins and outcome data from melanoma sun bed tanning reach as many people Professor Andrew Sizeland The Principles of Chemotherapy Lecture mutated in melanoma and immunological patients with routine molecular evaluation as possible. Fellow Head and Neck, Surgery Series, May 2008 (Invited Lecturer). modulators. The paradigm of targeted of patients’ melanomas. Initial focus is – Melanoma Symposium, Peter MacCallum Dr Uri Peleg on the therapeutic targets BRAF and Dr Andrew Hui Cancer Centre, Melbourne, Vic, October Consultant KIT that link the project to the targeted – American Society for Therapeutic 2008 (Invited Speaker). therapies evaluation research that the Christian Kenfield Radiology and Oncology (ASTRO) Michael Henderson unit undertakes (see Fig 2). The project 50th Annual Meeting, Boston, USA, Registrar – Member of the Victorian Surgical requires collaboration between clinicians, September 2008 (Poster). Dr Navin Rudolph pathologists, molecular biologists, the Consultative Committee. Dr Kibula Kiyingi Mr. Felix Behan Victorian Cancer Biobank, Biogrid Australia GRANTS AND FUNDING Medical Oncologists and major Melbourne melanoma services. – French Society for Surgery of the Hand, Assoc. Professor Grant McArthur (Head) Paris, France, December 2008, (Invited Cancer Council Victoria (CCV) Sir Edward Targeted therapies for skin cancers Dr Marisa Grossi Speaker). Dunlop Clinical Research Fellowship: [G. McArthur] Dr Ben Brady – Malaysian Society of Plastic & $140,000 pa, 2006–10. The development of targeted therapies for Reconstructive Surgery, Malaysia, March Fellows, Medical Oncology National Health and Medical Research cancer has revolutionised the therapeutic 2008, (Invited Speaker). Dr Bianca Devitt Council (NHMRC) Project Grant: $166,708 approach in patients with cancer. The Dr Carmel Pezzaro – Combined meeting of the RACS and the pa, ‘Predicting Outcomes of Treatment in Melanoma and Skin Service has been Hong Kong Society of Reconstructive Head and Neck Cancer’, 2006–08. Assoc. Professor David Speakman evaluating inhibitors of protein kinases in

Peter MacCallum Cancer Centre – Research Report 2008 Tumour Streams & Clinical Trials/ Melanoma & Skin 121 Tumour Streams & Clinical Trials/ Tumour Streams & Clinical Trials/ Neuro-Oncology Paediatrics & Late Effects

The Neuro-Oncology Service is a RESEARCH OVERVIEW MAJOR RESEARCH STUDIES We are part of developments in a number RESEARCH OVERVIEW – Randomised controlled study assessing multidisciplinary program with a research We’ve expanded services and made • Low grade glioma study – EORTC/ of institutional, national and international Our primary research aim is participation whether self-selected recorded focus directed at understanding and significant international alliances to TROG. clinical and translation trials into the in the Children’s Oncology Group music reduces anxiety of patients improving the outcomes of clinical further enhance our highly specialised, treatment and clinical outcomes of children Cooperative trials (in conjunction with the undergoing their first radiotherapy treatment of brain tumours.. • Hypofractionated radiotherapy for with cancer. treatment. [Research collaboration with multidisciplinary unit, which provides elderly patients with high grade glioma Royal Children’s Hospital) and the St Jude assessment and management for patients Meduoblastoma consortium in the SJMB03 Radiotherapy staff at Peter Mac and the RESEARCH FOCUS incorporating functional imaging (under RESEARCH FOCUS University of Melbourne.] with tumours of the central nervous development) – TROG. study, as outlined below. Understanding and improving the system, or with neurological complications • Understanding and improving the – Life threatening cancer across the • Phase II study of temozolomide and In late effects, we are developing outcomes associated with: of cancer. treatment of children with cancer. lifespan: Examining the relevance of guidelines and protocols that will, over the caelyx for newly diagnosed glioblastoma music to patients and their companions. • Neuro-oncology radiation. We’ve grown beyond radiotherapy to • Cooperative research into childhood next few years, result in the development multiforme – Victorian Cooperative This research entails a series of projects include a medical oncology component, brain tumours. of research protocols. We are also • Medical oncology. Oncology Group (VCOG) Neuro- supported by a NHMRC post doctoral in an effort to meet growing demand, • Effects of supportive care on developing an important network of • Low and high grade glioma studies. oncology Group. palliative care fellowship. [Includes and we’ve continued with an active radiotherapy treatment in children. supportive care projects to investigate the • Clinical studies into treatments for newly • Cilengitide for subjects with newly involvement with Caritas Christi Hospice, radiosurgery service. • Physical and psychology health of the effects of the process of radiotherapy on diagnosed glioblastoma multiforme. diagnosed glioblastoma multiforme and St Vincent’s Health.] ‘survivors’ attending the clinic. children. These include music therapy, We remain the choice for complex neuro- methylated MGMT. – Resounding Attachment: A lyric analysis RESEARCH PERSONNEL information books and video creation. oncology radiation for the Royal Melbourne • Gene promoter – a multicentre, RESEARCH PERSONNEL of cancer inpatients’ song writing for their Chair, Neuro-Oncology Services Hospital, and continue strong links with the open-label, controlled Phase III study, Chair, Paediatrics & Late Effects Services 2007 RESEARCH ACHIEVEMENTS children. [Research collaboration with Mr Damien Tange (Surgical Oncology) Trans-Tasman Radiation Oncology Group testing cilengitide in combination with Dr Greg Wheeler (Radiation Oncologist) Peter Mac Social Work, Music Therapy (TROG). More recently, we joined with the standard treatment (temozolomide with SJMB03: Treatment of patients with Medical Oncologist at the Royal Melbourne Hospital, and the European Organisation for Research and Radiation Oncologist newly diagnosed medulloblastoma, Dr Ross Jennens concomitant radiation therapy, followed University of Windsor, Canada.] Treatment of Cancer (EORTC). Dr Mary Dwyer supratentorial primitive by temozolomide maintenance therapy) – Connecting with music: Effects of a song Radiation Oncologists neuroectodermal tumour (PNET), versus standard treatment alone (under Radiation Therapist creation group for adolescent and young Dr Claire Phillips or atypical teratoid rhabdoid development) – EORTC/RMH. Mr David Willis adult (AYA) cancer patients. [onTrac@ Dr Gail Ryan tumuor (ATRT)

Nurse Coordinator The Paediatric and Late Effects Service PeterMac Victorian Adolescent and Neurologist Ms Natalie Goroncy is participating in the SJMB03 study, with Young Adult Cancer Service research Dr Mark Farragher Ms Priscilla Gates St Jude Children’s Hospital, which has study.] Dr Richard Stark Ms Suzie Taylor seen progress made in the treatment PRESENTATION HIGHLIGHTS Neuro-Radiologist of childhood brain tumours known as Music Therapist Dr Catherine Mandel medulloblastomas and supratentorial Priscilla Gates Assoc. Professor Clare O’Callaghan PNETs. This study is investigating the – LFA Lymphoma support group, LFA Box Nurse Pip Barry genetic makeup of tumours related to Hill, August 2008 (Speaker). Sandra Wilson treatment outcomes and cognitive effects – Cancer Council of Victoria, August 2008 of treatments. (Speaker). Supportive Care projects: – Epworth Freemasons, September 2008 – Effects of music therapy CD creation (Speaker). on paediatric patients’ first radiotherapy – Traralgon Cancer Centre, September treatment. Masters research thesis 2008 (Speaker). (under examination). [Principle – LFA Support Services National Supervisor: Dr O’Callaghan.] Conference, October 2008 (Speaker). – Effects of music therapy on oncologic – Price Waterhouse Coopers Seminar, staff bystanders: A substantive October 2008 (Speaker). grounded theory. GRANTS AND FUNDING – The Leukaemia Foundation Seed Grant: Creation of a Specialist Clinical Nurse Coordinator in Haematological Maliganancy Late Effects – 3 years funding. – Peter Mac Foundation Grant: $6553, ’New Children’s Radiation Therapy Information Book’, 2008. PUBLICATIONS AND PATENTS Publications are listed at the end of the report and include references 19, 216.

Dr Greg Wheeler

Peter MacCallum Cancer Centre – Research Report 2008 Tumour Streams & Clinical Trials/ Paediatrics & Late Effects 123 Tumour Streams & Clinical Trials/ Sarcoma

The Sarcoma unit provides access to RESEARCH OVERVIEW Study Group (ASSG). Led by Assoc. infrastructure and protocols developed – Annual Seminar Day, Israeli Society Meeting MOGA/FRO/NZSO/NZACS, leading treatments through an active With basic research activities driven Professor David Thomas, it is a national by kConFab for case ascertainment, of Pediatric Hematology/Oncology, Christchurch, New Zealand, August clinical trials program, and supports basic from the laboratories of Professor Peter cooperative aiming to facilitate access to biospecimen collection and processing, Jerusalem, Israel, November 2008 2008. and translational research programs in Choong at St Vincent’s Hospital, and leading treatments through translational and coordination of the management team. (Invited Speaker). osteosarcoma and liposarcoma, and and clinical research. First formed with GRANTS AND FUNDING the Sarcoma Genomics and Genetics Radiation therapy clinical studies – Connective Tissue Oncology Society adolescent and young adult cancer. laboratory of Assoc. Professor David grant funding from Cancer Australia, underway annual meeting, London, UK, November – Cancer Australia: $220,000, Australian Thomas at Peter Mac, our teams are the group’s chief aim is to develop and Led by Dr Julie Chu including: a pilot study 2008 (Invited Speaker). Sarcoma Study Group, 2008. RESEARCH FOCUS coordinate cohesive clinical trials and basic focused on the identification of basic and of 4-D CT based radiotherapy for solitary – Davidoff Cancer Centre Seminar series, – Cancer Australia: $40,000, ‘ICT-based research while still focusing on community • To develop a leadership role nationally translational aspects of osteosarcoma liver lesions; a randomised phase II trial Tel Aviv, Israel, November 2008 (Invited communication in AYA with cancer’, education and patient advocacy of and internationally in the development and liposarcoma, and a broad-based of weekly docetaxel chemoradiotherapy Speaker). 2008. of a vibrant, innovative clinical molecular profiling of sarcoma. sarcomas. Ongoing efforts by Dr Whyte +/- cetuximab in the treatment of localised – Australian Health and Medical Research – Cancer Australia: $40,000, ‘Using research program based on basic and (CEO, ASSG) and Assoc. Professor David resectable cancer of the oesophagus); We’ve led a number of international Conference, Brisbane, Qld, November Emerging Technologies to Improve translational science. Thomas (chair, ASSG) have secured and the pattern of utilisation of radiation collaborative trials, including an innovative 2008 (Invited Speaker). Supportive Care for Young Adults Living additional funding from Cancer Australia therapy in soft tissue sarcomas in the adult • To further strengthen our active research Phase II international multi-institutional with Cancer’, 2007–08. and philanthropic groups to further the population in Australia. Dr Jayesh Desai into adolescent and young adult cancers, study in giant cell tumour of bone; a group’s research efforts. – Hong Kong Oncology Society Forum. – Cancer Australia Grant: $362,702, osteosarcoma, liposarcoma, clinical trials hypoxic imaging study in soft-tissue PRESENTATION HIGHLIGHTS Hong Kong, China, April 2008 (Invited ‘Support for cancer clinical trials of targeted therapeutics. sarcoma, and an analysis of outcomes 2008 RESEARCH ACHIEVEMENTS Speaker). program’, 2008. in adolescent and young adult sarcomas Professor Peter Choong RESEARCH PERSONNEL Denosumab treatment of giant cell – Cancer Australia: $95,000, ‘Building in Australia. – John Mitchell Crouch Oration. Royal – Canberra Hospital: Medical Oncology tumour of bone Cancer Support Groups: A facilitated Chair Australasian College of Surgeons Annual Rounds, Canberra, ACT, July 2008 The Choong group explores molecular Peter Mac is leading an international peer support and education based Professor Peter Choong Scientific Meeting, Hong Kong, May (Invited Speaker). mechanisms for regulating the growth and open-label Phase II study of the new support group for adolescent and young Consultants 2008, (Invited Speaker). – Peter MacCallum Cancer Centre Grand progression of sarcoma: drug denosumab which has shown adults living with cancer,’ 2007–08. Assoc. Professor Guy Toner Rounds, July 2008 (Invited Speaker). substantial improvements in patients with – 13th Hong Kong Medical Forum. Hong Assoc. Professor Sam Ngan • The efficacy of DZ-13 dnazyme for – Cancer Council Multi-State Grant - bone cancer. Giant cell tumour (GCT) Kong, May, 2008, (Invited Speaker). – Annual Meeting of the Korean GIST Study Mr Gerard Powell targeting sarcoma – an in vivo and in $246,378, ‘Support for cancer clinical of bone is a rare, aggressive benign – 11th Breast Care Nurse Conference. Group, Seoul, South Korea, September Assoc. Professor David Thomas vitro model. trials program’, 2008–10. tumour that is associated with significant Melbourne, Vic, February, 2008, (Invited 2008 (Speaker). Dr Jayesh Desai – Department of Health and Ageing (DHA): • Developing a novel delivery system skeletal morbidity and can be lethal. Speaker). – Australian Sarcoma Group Annual Dr Sarat Chander $297,000, ‘Palliative Care in AYA with for anti-sarcoma therapy based on GCT is rich in RANKL, a key mediator of Meeting, Melbourne, Vic, October 2008 Dr Julie Chu Assoc. Professor Sam Ngan cancer’, 2007–09. nanotechnology. (Invited Speaker). osteoclast formation, function and survival, – Royal Australian and New Zealand Fellows • The importance of PEDF in preventing – DHA: $380,000, ‘Improving Palliative suggesting a potential therapeutic effect College of Radiologists Annual Scientific – Inaugural LCCI Workshop, Melbourne, Dr Ken Khamly growth and metastasis in osteosarcoma. Care Services to Adolescents and Young on tumour growth from denosumab, a Meeting, Adelaide, SA, October 2008 Vic, May 2008 (Invited Speaker). Dr Hannes Rudiger fully human monoclonal antibody against Adults Living with Cancer’, 2007–08. • Developing a new in vivo model of (Speaker). Dr Kenneth Khamly Nurse Consultant chondrosarcoma. RANKL. Adult patients with resectable – Merck & Co - $50,000 grant plus or unresectable GCT participated in this – Royal Australian and New Zealand – Connective Tissue Oncology Society $54,000-$60,000 for provision of Marianne Griffin The Thomas group is focused on the international study of denosumab. The College of Radiologists 2008 Annual (CTOS) 14th Annual Meeting, London, aprepitant, ‘Aprepitant for germ cell molecular switches that propel bone Australian Sarcoma Study Group impact of the subcutaneous administration Scientific Meeting, Adelaide SA, October UK, November 2008 (Speaker). chemotherapy’, 2008–09. and soft tissue cells down the pathway Dr Sally Whyte, Executive Officer of denosumab 120 mg on tumour 2008 (Speaker). of cancer formation – specifically the PRIZES AND AWARDS – NHMRC project grant: $340,500, Dr Mandy Ballinger, Study Manager response showed significant improvement Assoc. Professor David Thomas identification and characterisation of ‘Identification of amplified oncogenes in in their GCT of bone after 25 weeks in 87% Professor Peter Choong a novel tumour suppressor gene in – 29th Lorne Genome Conference, Lorne liposarcoma’, 2008–10. of patients. [J Clin Oncol 26: 2008 (May 20 – Royal Australian College of Surgeons osteosarcoma, Wif1. Vic, February 2008 (Invited Speaker). – Pfizer Investigator Initiated Research suppl; abstr 10500)]. (RACS) John Mitchell Crouch Fellowship – AMGEN Oncology Symposium, Sydney, Grant: $293,000, ‘Neoadjuvant sunitinib We’ve also taken a national leadership (2008). Hypoxic imaging of sarcomas NSW, February 2008 (Invited Speaker). and radiotherapy in soft-tissue sarcoma’, role in establishing the Australian Sarcoma Assoc. Professor David Thomas This study utilised 18F-azamycin – European Society of Medical Oncology/ 2007–09. arabinoside and PET to image hypoxia CONTICANET Faculty Meeting, Milan, – Victorian Cancer Agency Clinician – Philanthropic support, $500,000, in patients with sarcoma undergoing Italy, May 2008 (Invited Speaker and Scientist Fellowship, 2008–10. ‘Rainbow’s for Kate Australian Sarcoma pre-operative radiotherapy. A very high Session Chair). – Queensland Cancer Council Sam Kindred Study’, 2008–11. incidence of PET-detectable hypoxia in – American Society of Clinical Oncology Sciacca Travelling Fellow. – RACS John Mitchell Crouch Fellowship: primary sarcomas (46%) was revealed, annual meeting, Chicago, USA, June – Associate Professor with title of Principal $82000, ‘The multidisciplinary which has adverse clinical significance. 2008 (Speaker). Research Fellow, University of Melbourne management of sarcoma’, 2008. Patients with hypoxia are more likely to – Queensland Cancer Council Sam – 2008 Victorian Public Healthcare Awards: – Liddy Shriver Foundation, USA: $64,000, demonstrate resistance to radiotherapy, or Sciacca Lecture, Brisbane, Qld, August Highly Commended Premiers Award for ‘PEDF: A potential therapeutic agent for early relapse. 2008 (Invited Speaker). Excellence in Improving Cancer Care in osteosarcoma’, 2008. The Australian Sarcoma Kindred Study Victoria. – Molecular Biology and Therapeutics of PUBLICATIONS AND PATENTS (ASK) Musculoskeletal Oncology, Salt Lake – Chair, Inaugural COSA AYA Steering This world-first prospective familial cancer City, USA, September 2008 (Invited Committee. Publications are listed at the end of the study in adult-onset sarcoma will use the report and include references. 1, 19, 22, 30, 46, Speaker and Session Moderator). Assoc. Professor Sam Ngan existing research nurse network located 50, 60, 61, 62, 63, 64, 65, 67, 83, 162, 216, 281. – GEIS Annual Meeting, Madrid, Spain, – Best Poster Award, Australia & New Professor Peter Choong at major treatment centres and will employ November 2008 (Invited Speaker). Zealand Joint Oncology Scientific

Peter MacCallum Cancer Centre – Research Report 2008 Tumour Streams & Clinical Trials/ Sarcoma 125 Tumour Streams & Clinical Trials/ Uro-Oncology

Our Uro-oncology Service aims to provide RESEARCH OVERVIEW nurse led phone follow up program. The PRIZES AND AWARDS – NBCF: $96,243, ‘Providing tailored PUBLICATIONS AND PATENTS Victorians with the best multidisciplinary nurse led phone follow up clinic, while preparatory information about radiation Our service provides comprehensive care, Assoc. Professor Michael Jefford Publications are listed at the end of the care in an academic setting, conducting staffed by senior nursing staff works in therapy for women with early breast 93, 189, 266, 267, ranging from diagnosis, management – Principal Fellow with the title Associate report and include references. clinical and technical research directed at close collaboration with hospital medical cancer: a feasibility study’, 2008–09. 269, 300, 326, 327. and treatment of prostate, bladder, Professor from July 2008, University of improving patient outcomes. staff as well as the patient’s general kidney, and testicular and rarer urological Melbourne. – Cancer Council Victoria Multi-State malignancies. practitioner. If found to be effective the Research Grant: $217,500, ‘The effects RESEARCH FOCUS nurse led follow up clinic has significant GRANTS AND FUNDING of chemotherapy on cognitive function in We continue our commitment to clinical potential benefits in terms of patient • Multidisciplinary care. – National Health and Medical Research patients with testicular cancer’, 2006–08. research with a particular focus on prostate connivance and reduction of costs to • Nursing interventions and supportive Council (NHMRC) Project Grant: – Cancer Australia Grant: $362,702, cancer, and an increasingly strong focus hospital system care on technical research in image guided $621,600, ‘A clinical trial to determine the Support for cancer clinical trials program, • Image guided and adaptive radiotherapy. and adaptive radiotherapy for urological PRESENTATION HIGHLIGHTS optimal timing of androgen deprivation 2008. malignancies, such a prostate and bladder in relapsed or non-curable prostate – Merck & Co Pharmaceutical Industry • Testicular cancer. Professor Gillian Duchesne cancers. Other work includes supportive cancer’, 2005–08. Grant: $50,000 (plus $54,000-$60,000 – ASCO-ASTRO-SUO Genitourinary RESEARCH PERSONNEL care and psychological research with – NHMRC Project Grant: $2,390,500, aprepitant provision), ‘Investigator Cancer Symposium, San Francisco, Head increasing links to supportive care ‘Value of androgen deprivation and initiated trial: Aprepitant for germ cell USA, February 2008 (International Invited Dr Farshad Foroudi (Radiation Oncologist) and psychiatry; and technical surgical bisphosphonate therapy in patients chemotherapy’, 2008–09. Faculty). innovations with increasing use of treated by radiotherapy for localised Radiation Oncologists – Cancer Council Multi-State Grant: laparoscopic surgery. Various research – USANZ Annual Scientific Meeting, Hong prostate cancer’, 2007–11. Dr Patrick Bowden $246,378, ‘Accelerated first line studies and clinical trials are active, Kong, China, February 2008 (Invited Dr Sarat Chander – Multistate Cancer Council Project Grant: chemotherapy for advanced germ cell predominantly in the areas of prostate, Speaker). Professor Gillian Duchesne $480,000, ‘A phase III trial comparing tumours’, 2008–10. bladder and renal tumours. Dr Farshad Foroudi – South Australian Urology Group, adjuvant versus salvage radiotherapy – Cancer Australia Grant: $197,078.20, Adelaide, SA, April 2008 . Dr Michael Lim Joon Nurse Led Care of Prostate Cancer for high risk patients post radical Support for the merger of the ANZ Dr Keen Hun Tai Patients – RANZCR Annual Scientific Meeting, prostatectomy’, 2008–10. Germ Cell Trials Group (ANZGCTG) and Dr Scott Williams In a series of ethics approved evaluations Adelaide, SA, October 2008. – National Breast Cancer Foundation the Australian Prostate and Urogential (NBCF): $352,114, ‘Can a peer support Cancer Group (APUG), 2008–09. Urologists there has been development of nurse Dr Keen Hun Tai program for cancer gene mutation Assoc. Professor Laurence Cleeve led care for patients receiving prostate – Victorian Urologic Oncology Group carriers reduce distress? A randomised Mr Jeremy Goad cancer radiotherapy. Mary Leahy our (VUOG) Meeting, Melbourne, Vic, June nurse co-ordinator completed a study of 2008 (Convenor). controlled trial’, 2008–11. Medical Oncologists nurse led care of Prostate Cancer patients – Trans-Tasman Radiation Oncology – Cancer Australia: $40,000, ‘Patients with Assoc. Professor Michael Jefford while undergoing radiation therapy. She Group (TROG) Prostate Research lung cancer and their carers: providing Assoc. Professor Guy Toner presented this at the Urological Nurses Meeting, Sydney, NSW, November 2008 support through novel information Association Annual Meeting in Hong Kong Nurse Co-ordinator (Speaker). models’, 2008–09. Ms Mary Leahy winning the prize for best study. This study – Peter Mac Foundation Grant: $74,672, has been followed by a study evaluating Research Radiation Therapists Development and testing of novel nurse led care in patients who have Ms Rebecca Owen strategies to support adult survivors of completed radiation treatment and are Mr Jacky Wong colorectal cancer’, 2008–09. undergoing follow up. Clinical Research Fellow The ethics approved evaluation of nurse Dr Alison Stillie led phone follow up of patients treated Medical Physicists curatively for low and intermediate risk Mr Joseph Pillainayagam prostate cancers is completing accrual. Mr Christopher Fox The study is comparing standard medical Assoc. Professor Annette Haworth consultation follow up with an innovative Clinical Nurse Specialist Ms Kath Schubach Radiologist Dr Colin Styles

Dr Farshad Foroudi

Peter MacCallum Cancer Centre – Research Report 2008 Tumour Streams & Clinical Trials/ Uro-Oncology 127 Tumour Streams & Clinical Trials/ Centre for Biostatistics & Clinical Trials (BaCT)

We provide statistical and data Sophie Katsabanis diagnostic trials and treatment planning presentations, serving on hospital scientific Tumour volume as an independent PRIZES AND AWARDS management support for clinical and Kate Richards studies. It is the trial centre for the review committees and quality assurance prognostic factor in patients with Alan Herschtal laboratory research undertaken at Peter Vicky Walcher Australasian Leukaemia and Lymphoma activities. inoperable non-small cell lung cancer – Varian Award, Best Radiation Therapy Mac, and via cooperative oncology Group (ALLG) and the Australasian (TROG 9905) Administration Development of a new method Presentation, EPSM Conference, groups, including multicentre national and Sarcoma Study Group (ASSG), and This multicentre prospective observational Ditas Sioco for prostate radiotherapy margin November 2008. international clinical trials. for many of the trials conducted by the study was undertaken to investigate Julie Umek calculation Trans-Tasman Radiation Oncology Group the hypothesis that tumour volume is a Cattram Nguyen In collaboration with Peter Mac RESEARCH FOCUS Australian Leukaemia & Lymphoma (TROG). BaCT has extensive experience prognostic factor independent of T and N – The Biostatistics Collaboration of radiotherapists, physicists and urologists, Group(ALLG) in designing computer databases for stages in patients with NSCLC treated by Australia Pfizer Annual Award for • Provision of high quality biostatistical BaCT considered van Herk’s recipe for Business Manager both clinical studies and administrative definitive radiotherapy. 513 patients were Excellence. and data management support to radiotherapy margin - the current standard researchers at Peter Mac and to David Ridler purposes. accrued to the study. While the hypothesis method by which radiotherapy margins are was not substantiated, an observed GRANTS AND FUNDING cooperative oncology groups. Operations Manager With 32 staff, BaCT covers biostatistics, determined in clinical practice - and how it plateauing of the relationship of tumour – Cancer Australia: $238,624, for the • Collaboration in clinical trials, including Delaine Smith information technology, data management, might be refined in a clinical setting. volume to survival suggests that tumour Cancer Clinical Trials Development Unit, Phase I trials, translational research trial coordination, business and Protocol Development Coordinator Applying van Herk’s recipe to real datasets size alone should not influence treatment 2008–09. programs and supportive care. administration, and staff hold specific Dr Megan Sanders of patient motion, the study found it intent. See also Lung Services [pg 118]. expertise in design, conduct, analysis – Victorian Cancer Agency: $498,000, • Biostatistical and clinical trial resulted in serious inaccuracies in the Administration & Events Officer and interpretation of cancer clinical trials Adjuvant radiotherapy in patients with ‘Infrastructure support, staff professional methodological research. computed margin—under-margining by Dilu Uduwela and retrospective studies. They are also completely resected nodal metastatic development and training’, 2008. up to 40%. Some of the characteristics RESEARCH PERSONNEL experienced in the analysis of other clinical malignant melanoma (TROG 0201) RESEARCH OVERVIEW of patient motion responsible for these and laboratory research data. Six staff also After lymphadenectomy, patients were Director shortcomings have been identified. Since 1971, BaCT has provided statistical work as Peter Mac site study coordinators. randomised to radiotherapy or observation. Dr Dina Neiger Analysis of the real patient data showed and data management services for This is the first randomised study of Clinical Trials Program Manager that the breach of van Herk’s assumptions all divisions of Peter Mac. It provides 2008 RESEARCH ACHIEVEMENTS adjuvant radiotherapy (RT) for regional Marianne Hundling has an impact on the required margin. randomisation services and trial centre control in patients with completely resected In 2008 BaCT was engaged in 169 This analysis goes some of the way in Manager Business & IT support for multicentre national and nodal metastatic malignant melanoma scientific projects. The BaCT Trial Centre explaining the observed discrepancy Graeme Bird international clinical trials, as well as but at significant risk of further regional collaborated in 106 trials in different stages between theory and reality. Future research study coordination for trials conducted relapse, with 250 patients randomised from Biostatisticians of development, 669 new patients were will study the nature of patient motion at Peter Mac. 22 centres in Australia, New Zealand, Brazil Assoc. Professor Richard Fisher registered on 41 open trials managed by during treatment in order to bridge the and the Netherlands. This study showed Gaelle Dutu In 2008, BaCT supported 54 Peter Mac BaCT, 18 new trials were in development remaining gap. Alan Herschtal trials (mainly in collaborative group or and 28 trials had patients in follow-up. A that adjuvant RT improves regional control Dr Alvin Milner academic settings) with 22 trials open further 19 trials are undergoing analysis Extension of the minimisation in these patients although a survival to accrual and 32 trials with active follow and write-up. BaCT is the central or algorithm difference was not demonstrated. Further IT regional trial centre for international trials The minimisation algorithm is used follow-up will assess quality of life and Jenny Beresford (Program Analyst/ up only. For these trials, more than 100 patients were recruited during the year, and involving investigators and patients from for assigning treatments to patients toxicity in these patients. Biostatistician) the USA, Canada, Europe, South America, in randomised trials so as to achieve Linas Silva (Program Analyst) more than 2260 were on active follow up. The 2008 trials are part of a centre currently South Africa, Singapore and New Zealand. similar distributions of tumour and patient characteristics across treatment arms. The Trial Centre Data Managers supporting 106 Phase I to III trials involving In addition to clinical trials, BaCT extension developed by BaCT researchers, Dr Ruth Columbus over 4150 patients. was involved in 63 other types of Richard Fisher and Jenny Beresford, Linda Cowan scientific projects as well as a range BaCT holds expertise in all phases allows continuous and ordinal variables to Joanne Dean of other activities, such as creation of of clinical trials as well as specialist be used without the need to convert these Dr Juliana Di Iulio prospective databases, surveys, in-house Dr Bereha Khodr to categorical variables. This extension Dr Narmatha Kuru results in better balance of factors between Poppy Kypreos treatment arms. The work has been Ania Matera presented in statistical and clinical trials Bev McClure scientific forums and will be submitted Sarah McInnes for publication. Dr Teresa Morgan Cattram Nguyen Christine Russell Janani Sivasuthan Janey Stone Marijana Vanevski Dr Glen Wiesner Study Coordinators Deborah Cruickshank Lisa Demosthenous Left to right, Front Row (seated): Teresa Morgan, Poppy Kypreos, Narmatha Kuru, Juliana Di Iulio, David Melanie Evans Ridler. Next Row, L-R: Ruth Columbus, Delaine Smith, Bev McClure, Dilu Uduwela, Glen Wiesner, Dina Neiger, Marianne Hundling, Cattram Nguyen. Back Row, L-R: Alan Herschtal, Bereha Khodr, Julie Umek, Sarah McInnes, Marijana Vanevski, Gaelle Dutu, Dittas Sioco, Graeme Bird, Richard Fisher.

Peter MacCallum Cancer Centre – Research Report 2008 Tumour Streams & Clinical Trials/ Centre for Biostatistics & Clinical Trials(BACT) 129 Tumour Streams & Clinical Trials/ Clinical Trials Unit

Our unit is involved in the coordination, Ethics Project Coordinator that coordinate trial activity – Peter Mac liaison, management and education of Sarah Bascomb staff take a leadership role in many of clinical trials to both internal and external Ali Robertson these trials. bodies, with a focus on Phase I, II, and III trials. RESEARCH OVERVIEW 2008 RESEARCH ACHIEVEMENTS The Clinical Trials Unit (CTU) has continued The CTU was engaged in more than 100 RESEARCH FOCUS: to grow to meet demand – with more than active clinical trials, including the following. • Coordinating clinical trials, including 100 active clinical trials and more than 150 • Early phase development of novel Phase I, II, III and IV studies within the active clinical research projects currently therapeutics (LBH589) clinical services, translational research underway within the clinical services and programs, and supportive care. supportive care departments at Peter Mac. • Phase I studies of Thalaza, ABT263, CSL360, PLX4032 and, PF02341066 • Providing ongoing education and Starting out as a small group of nurses, • Phase II REVLITE study in Multiple support to study participants. the unit has grown over an eight year Myeloma • Coordinating the care of patients period into a diverse group of research participating in clinical trials. This assistants, data managers and nurses, • Phase II Revlimid in MDS involves assisting in the administration with further expansion set for the coming • Phase III PORTEC study in Ovarian of study drugs, patient monitoring and 12 months with six study coordinators Cancer the collection of trial-specific biological currently housed within BaCT to be added • Phase II IMRT study, and a Phase I/ samples. to the team. The move will facilitate a more II study of cetuximab, carboplatin and • Liaising with trial sponsors (including comprehensive, cohesive and integrated radiotherapy: TROG 07.04. study coordination and local data cooperative groups and drug • Phase II trial of docetaxel + cisplatin +/- management service for the organisation. companies) to ensure drug trials are cetuximab with radiotherapy in patients conducted in a professional and The entire team functions under with resectable oesophageal cancer. ethical manner. the auspices of the Department of Haematology and Medical Oncology, PRESENTATION HIGHLIGHTS RESEARCH PERSONNEL coordinating more than 100 national Sharyn Meadows Unit Manager and international clinical trials. Research – 35th Clinical Oncological Society of Cate O’Kane is multidisciplinary, involving clinicians, Australia (COSA) Annual Scientific Associate Unit Managers physicists, radiation therapists, research Meeting, Sydney, NSW, November 2008 Allison Lamb nurses, research assistants, allied health (Poster). Di Saward practitioners, pharmacists, data managers and statisticians. PRIZES AND AWARDS Research Nurses Andrea Buckewell Our clinical research program covers Di Seward Glenda Burke prevention, diagnosis and management – Masters in Nursing. Jill Davison and extends from early to advanced Michelle De Bock stages of disease. It includes investigations Michelle Gough of novel treatments or new approaches in Rosetta Hart medical oncology, haematology, radiation Jo Hawking oncology and surgery, imaging and Karena Hanlon treatment planning, and pain control. Madeline Israelsohn National and international clinical trials Kate Khamly often involve external cooperative groups Sharyn Meadows Amanda Marshall Allison Rocher Carmela Rooney Sam Ruell Cath Sully Research Assistants Jaclyn Bartlett Tenille Gaylard Nicole Roylance Clinical Trial Nurse Specialist Rebecca Doherty Administrative Assistant Val Saunders Image Richard Young, Research Assistant, Allison Lamb Translational Research Laboratory

Peter MacCallum Cancer Centre – Research Report 2008 Tumour Streams & Clinical Trials/ Clinical Trials Unit 131 Core Technologies/

Victorian Centre for Functional Core technologies are the Genomics 134 backbone of research, providing Microarray Next Generation DNA Sequencing 135 the equipment and expertise Bioinformatics 137 needed to facilitate research and Flow Cytometry 138 Media & Laboratory Services 139 identify, import and develop new Microscopy 140 technologies. Tissue Bank 142

A revolution in the scale of scientific approach has occurred recently. Genome-scale high throughput technologies now exist that harness the power of RNA interference to identify the contribution of individual genes to disease states. Its an exciting and challenging time to utilise such technology to identify targets for therapy’.

Dr Kaylene Simpson Manager, Victorian Centre for Functional Genomics

Peter MacCallum Cancer Centre – Research Report 2008 Core Technologies/ 133 Core Technologies/ Core Technologies/ Victorian Centre for Functional Genomics Microarray Next Generation DNA Sequencing

The Victorian Centre for Functional 2008 ACHIEVEMENTS reagents against the whole human and The Microarray Core at Peter Mac provides OVERVIEW project requirements, as well as complete Genomics (VCFG) provides researchers • The VCFG was officially opened on 21st mouse genomes. state-of-the-art facilities and expertise in The purchase of cutting edge technology Affymetrix microarray services to both with the ability to analyse gene function May 2008, by The Hon Gavin Jennings the use of microarrays and other high- bolstered our capabilities, and further set internal and external researchers. using high throughput approaches. PRESENTATION HIGHLIGHTS throughput technologies to facilitate MLC, Minister for Innovation. apart our genomics facility as a centre for Microarray services are offered on a fee- Vikki Marshall genetic/genomics related cancer research. • Standard Operating procedures for all excellence in cancer genetics research. for-service basis. We continuously survey RESEARCH PERSONNEL – Next-Generation Sequencing Data technical aspects of the RNA interference the genomics technology arena for new Head Analysis, Rhode Island Convention RESEARCH PERSONNEL In 2008, we conducted an intensive platform were established and genomics related technologies, tools and Vikki Marshall (January-September) Centre, Providence, USA, September Head evaluation of next generation DNA disseminated to screeners. products, and facilitate their introduction Dr Kaylene Simpson (October-December) 2008 (Delegate). Vikki Marshall sequencing platforms, and the hardware • By the end of the year, the VCFG had was purchased with generous grant to Peter Mac so that our research remains Research Assistant completed multiple rounds of viral Dr Kaylene Simpson Senior Research Assistant funding from Peter Mac. The Illumina internationally competitive. Katrina Falkenberg – Human Genome Organisation (HUGO) Rebecca Driessen Genome Analyser IIx platform was production for all 80,000 available 2008 ACHIEVEMENTS constructs. High Content Screening Workshop, Research Assistants procured, with installation set to occur OVERVIEW Singapore, November 2008. In 2008, more than 1,000 Affymetrix • An information flyer detailing the Katherine Ellis in 2009. Our centre offers unprecedented access to microarrays were processed through capabilities of the facility was created The VCFG hosted the following scientists: Katrina Falkenberg Co-managed by the head of the Microarray genetic information data covering the entire the facility. Of these, 650 were high and distributed to local research Core facility, the next generation DNA human genome with small customised Dr Frank Whitney, Panomics, January density arrays including some all-exon institutes. sequencing and microarray core facilities gene collections. Open to Australian 2008. (gene expression) and Single Nucleotide • The VCFG is a member of the recently will combine to form the Molecular medical researchers, we provide expertise Dr Devin Leake, ThermoFisher Scientific, Polymorphism (SNP) arrays, and the formed Bio21 cluster platform technology Genomics facility. in the use of high throughput technologies February 2008. remaining 370 were whole transcript gene for evaluation of gene function, and network. The move will add to existing state-of- expression arrays (Affymetrix Gene 1.0ST Professor John Wilkins, Manitoba Centre unparalleled access to RNAi interference • The VCFG collaborates with researchers the-art facilities and expertise in the use array). This number of cancer samples for Proteomics and Systems Biology, gene knockdown technology. at the Walter and Eliza Hall Institute, of microarrays and other high-throughput processed via microarray technology Canada, February 2008. the Diamantina Institute and Institute of technologies for cancer genomics. reflects the continuing utility of microarrays The platform is built on an Open Molecular Biology, Queensland and is as a relatively low cost, efficient tool for BioSystems lentiviral-based short hairpin PUBLICATIONS AND PATENTS Our facility currently offers access primarily a member of Open BioSystems Open studying genomic lesions in cancer. micro-RNAi (shRNAmir) vector backbone, to the Affymetrix microarray platform Access Program (OAP). Publications are listed at the end of the which enables the shRNA sequences to be report and includes reference 271. but also supports other microarray The Microarray Core facility also undertook expressed in viral particles. This strategy • In October, Associate Professor Ricky platforms including Agilent which is a full microarray services on several larger is broadly applicable to human cell lines Johnstone was awarded $150,000 from For further details, please visit the two-colour/dual laser system. Our facility projects for internal users of various as well as primary cells, and enables the Victorian Cancer Agency to offset the Core Facilities pages of the Research also encompassed management of the Cancer programs in 2008, including a either short or long term gene knockdown. cost of whole genome screens, to enable website: Victorian Centre for Functional Genomics project of more than 100 Affymetrix Exon The ability to assess the function of each enhanced access to the technology. http://www.petermac.org/Research/ (VCFG) from its beginnings in March 2006 arrays commissioned by the DNA Repair gene in the human genome will allow • In November, researchers involved in VictorianCentreforFunctionalGenomics to September 2008, when Dr Kaylene Laboratory for a study to determine the researchers to discover genes that the Facility were awarded $2,500,000 Simpson assumed the role of VCFG facility gene regulation of radio-sensitivity in play critical roles in disease states, such from the Australian Cancer Research manager [see pg 134]. cancer patients. Another large project as cancer. Foundation (ACRF) to establish the commenced involved a large study of Microarray services offered by the ACRF Cancer Genomics Program. more than 100 ovarian cancer cell lines Microarray Core include access to all The funding, to commence in 2009, looking for regulators of drug sensitivity. microarray instrumentation and robotic will enable the purchase of the robotic liquid handling, protocol development, We introduced the QuBit, a small infrastructure, high throughput imaging provision of reagents for new fluorimeter, as a core instrument for equipment and small interfering RNA methodologies, and for the purposes of accurate quantitation of nucleic acid cost efficiency and catering to smaller (DNA or RNA) for samples which have

Left to right: Daniel Thomas, Katrina Gouranamis, Dr Kaylene Simpson. Left to right: VBikki Marshall, Aidan Flynn.

Peter MacCallum Cancer Centre – Research Report 2008 Core Technologies/ Microarray Next Generation DNA Sequencing 135 Core Technologies/ Core Technologies/ Microarray Next Generation DNA Sequencing Bioinformatics

scarce amounts of DNA/RNA, below was selected as the most appropriate – Dr Darryl Irwin and Mr. Jeff Bryant, The Bioinformatics Core at Peter Mac OVERVIEW most up-to-date commercial and open- the limits of sensitivity of the NanoDrop platform for the study of several aspects Sequencom Inc., Brisbane (Workshop), works together with the research institute With increasing demand for microarray source software to analyse any kind of spectrophotometer. We have applied of cancer genomics. Models of cost September 2008. to complement the latest biological and second generation sequencing data microarray data produced at Peter Mac. for funding to enable us to accurately recovery were established and projects – Dr Peter Campbell, Wellcome Trust technologies and the latest developments produced at Peter Mac, our bioinformatics Expert advice on the use of the software quantitate DNA/RNA on a larger scale plans cemented in advance of the delivery Sanger Institute (Special Seminar), in bioinformatics by applying novel and team has become pivotal to the success of is readily available. General advice is (96-well and 384-well fluorescent readers), of the Illumina Genome Analyser in 2009. November 2008. established analysis methods to the many projects – with our team supporting provided through presentations and following increasing recognition of the Attendance at international conferences biological data, with the ultimate goal of training sessions for the bioinformatics – Dr Hazelle Lam, Fluidigm Inc., November more than 10 labs across 25 projects in huge importance of accurate nucleic related to NGS and international uncovering the mechanics of cancer. software that is available on bioinformatics 2008. 2008 alone. quantitation for experimental success in exchanges particularly with the Wellcome work stations, and specific questions are genomics technologies. Trust Sanger Centre were a highlight of – Mr Dominic Herring, Technical & RESEARCH PERSONNEL Our Bioinformatics Core provides an attended to on a one-to-one basis with 2008 and facilitated Peter Mac’s entry into Business Development Manager, Biotek essential core technology platform for analysts. We also acquired a new Bio-RAD Acting Manager the cutting-edge technology arena that Instruments Inc. (Workshop), November researchers, ensuring clear statistical DNA Tetrad 2 thermocycler for in vitro Gian Sberna is underpinned by Next Generation DNA 2008. objectives, and a budgeted time and cost 2008 ACHIEVEMENTS amplification of DNA, made possible Bioinformaticians Sequencing. of the analysis when grants are submitted. by a generous donation (See Grants & 2008 GRANTS AND FUNDING Jason Li Over the year, the core has actively stayed Our analysts work closely with up-to-date in the field of bioinformatics Funding). Internal funds were used to PRESENTATION HIGHLIGHTS – Peter Mac Foundation Tax Appeal: Jason Ellul experimental scientists and clinicians to through efforts in three areas: 1) procure a new laboratory grade, glass $870,000, Establishment of the Next Vikki Marshall ensure that the biological assumptions maintaining competence by researching, door fridge for the safe and secure storage Generation DNA Sequencing Facility. of expensive microarrays and reagents for – 20th Annual Lorne Cancer Conference, and translational relevance of the studies understanding and applying latest – Victorian Cancer Agency (VCA) Platform researchers. Lorne, Vic, February 2008 (Poster). are fully considered when building and algorithmic developments, 2) purchasing Technology Capacity Building Grant: and providing support and access to – Bio-21 Cluster Scientific Advisory Cluster analysing the models of the biological The MCF at Peter Mac is part of the $150,000, ‘Enhanced access to whole leading-edge analysis software packages Meeting, The University of Melbourne, systems. Analytical support is provided on Victorian Microarray Technology genome RNA interference screens such as Partek and Ingenuity, 3) setting Parkville, Vic, August 2008 (Invited demand. Consortium, a partnership with the through the Victorian Centre for up collaboration with leading external Speaker). Data produced at Peter Mac include Department of Primary Industries (DPI) Functional Genomics’, 2007–08. bioinformatics groups — such as at the comparative genomic hybridisation, SNP and the Australian Genome Research – Peter MacCallum Cancer Centre – Victorian State Government via Walter and Eliza Hall Institute in Melbourne array, gene expression, second generation Facility (AGRF). Importantly, the Microarray Workshop Symposium, Wilson’s Department of Industry, Innovation and — for authoritative advice and access to sequencing and other high-throughput Core Facility at Peter Mac is a node Promontory, Vic, October 2008 Regional Development: $127,468 in high-performance computing facilities. technologies produced primarily by member of the Australasian Microarray (Delegate). funding installments received following Through these efforts the Bioinformatics Affymetrix, Illumina, Agilent, Applied and Associated Technologies Association – Next-Generation Sequencing Data successful attainment of performance core continued to maintain top quality Biosystems and OpenBioSystems. Data (AMATA). In 2008, the Head of the Peter Analysis, Rhode Island Convention milestones, 2007–08. resources and provided valuable services sources include in vitro and in vivo model Mac Microarray Core Facility was elected Centre, Providence, USA, September to many Peter Mac research laboratories – The Estate of Elsie May Barton: $40,000, systems, as well as biospecimens derived to the AMATA committee and will convene 2008 (Delegate). during 2008. the AMATA 2010 Annual Conference in for the purchase of a new Bio-Rad ‘Tetrad from large-scale clinical studies. The – Australasian Microarray and Associated Hobart, Australia. 2’ DNA Engine peltier thermocycler, for Victorian Centre for Functional Genomics For further details, please visit the Technologies Association (AMATA) DNA amplification, 2008. group, located within the Peter Mac Core Facilities service pages of the Ongoing education for Peter Mac Annual Conference, Dunedin, New For further details, please visit the research group, is providing the capacity Research website: researchers on both microarray and Zealand, November 2008 (Delegate and Core Facilities service pages of the to perform functional genomics screens http://www.petermac.org/Research/ functional genomics is provided through Election to AMATA Committee). Research website: using lentiviral whole-genome shRNAmir- Bioinformatics technology related seminars hosted by the Technology Seminars Hosted: http://www.petermac.org/Research/ based libraries. MCF. Regular updates and rapid uptake of In 2008, the Microarray Core hosted Microarray The core also provides workstations new methodologies occurred through 2008 genomics technology-related seminars by with specialty user-friendly software Next Generation DNA Sequencing the following presenters: for biologists. The facility provides the (NGS): – Dr Frank Witney, President/CEO, Considerable effort in 2008 was directed Panomics, USA (sponsored by toward the establishment of a Next GeneWorks), January 2008. Generation DNA Sequencing (NGS) Facility at Peter Mac, which is managed under the – Dr Oliver Vasilebski (Millennium Science) umbrella of the Microarray Core Facility. A technical presentation – The ‘Cyto’ highlight of 2008 was the announcement protocol, an abbreviated Affymetrix SNP by the Peter Mac Foundation in July 6.0 Protocol, June 2008. 2008 of generous funding support from – Dr Oliver Vasilebski (Millennium Science)- multiple donors for the procurement of Quality Metrics for Gene/Exon and SNP a Next Generation DNA Sequencing 6.0 Arrays, June 2008. platform (hardware), following an intensive – Dr Mike Payne, Applied BioSystems, Tax Appeal. We would like to take this August 2008. opportunity to acknowledge and thank our – Dr Daixing Zhou, Head of Sequencing donors for their generous support. Technology (Asia), Illumina Inc., August A comprehensive evaluation of available 2008. NGS platforms was undertaken and the Left to right: Jason Li, Jason Ellul. Genome Analyser II from Illumina (USA)

Peter MacCallum Cancer Centre – Research Report 2008 Core Technologies/ Bioinformatics 137 Core Technologies/ Core Technologies/ Flow Cytometry Media & Laboratory Services

The Peter Mac Flow Cytometry and Cell OVERVIEW Services overview The Media and Laboratory Services OVERVIEW Sorting Core provides researchers with Our chief function is providing researchers The service provided by the FACS Core provides an essential service to the As a key support service made up of two state-of-the-art equipment and expertise with a high level, integrated service that Facility is to give researchers access to Research Division, serving the needs working departments – the media kitchen in all aspects of flow cytometry and cell includes multi-parameter flow cytometric and support with, modern Cytometric of Peter Mac laboratory researchers in and laboratory services – we provide sorting for the analysis and separation of analysis; fully supported fluorescent technologies, that enable them to supplying high quality liquid and solid researchers with high quality liquid and cell populations stained with fluorescent activated cell sorting (FACS); training and conduct their work. The Facility provides media and sterile laboratory ware in a cost solid media, and sterile laboratory ware compounds. education on all aspects of cytometry; a professional consultation and technical efficient manner under strict quality control. in a cost-efficient manner under strict reliable and comprehensive system for assistance with samples, appropriate quality control. RESEARCH PERSONNEL RESEARCH PERSONNEL management, storage and archival of instrumentation, data analysis capabilities, Our media kitchen maintains a cost- Core Head flow cytometry data; and the development and assistance with data interpretation. Head effective, consistent and reliable store of Ralph Rossi of new cytometry analysis and FACS Lara Sekhon The major areas of support are: commonly used sterile media and buffers Research Assistant approaches. Media Kitchen Technicians • sorting samples that are brought to the for the Research Division and Pathology Daud Duhur Menka Kyriakou Flow cytometry is a powerful technique facility Department. The facility supports the for the analysis of individual cells within Helen Braun needs of individual research groups, • technical assistance with protocols complex populations. It is used in both Laboratory Services Technicians which may have specific media or buffer • advice on instrumentation research and clinical settings and in the Emily Breninger stock maintained for them. Media kitchen translation of knowledge from the research • data interpretation Elzbieta Gajewska staff can also supply specific non-stock setting to the clinical area (translational • education, tutorials Graham Heffernan requests on demand. The facility steam- research), where it has become invaluable Suh-youn Ko sterilises all Research Division liquids and Capabilities and Activities: as a resource for both cell identification Menka Kyriakou retrovirus linen and maintains the X-ray This facility is heavily used by most and isolation. Belinda Whitby developer and water ultra filtration unit on Peter Mac Research staff. The type of level 2. Capabilities work ranges from simple screening and The FACS Core at Peter Mac incorporates sorting of transfected cells, complex Laboratory services provides a convenient six instruments: two cell sorters (both multiparameter analysis and sorting, cell and consistent system of cleaning, Vantage SE Divas), an LSR2, a Canto, function assays, etc. There is a strong sterilising and returning reusable laboratory aCant2 and an Automacs magnetic cell demand for sorting with an emphasis on items to the Research Division across all sorter. Both of the Diva sorters have been low frequency populations. Education research laboratories and the Pathology configured to have maximum flexibility in and training are viewed as an important Department. Both dry heat and steam the scope of work they can perform. One component of the facility and as such sterilisers are used. We also maintain the analyser, the LSR2, is capable of more tutorials and “one to one” advice are given research linen stock and organise cleaning complex analysis (and has a plate reader) on a regularly basis. of personalised gowns for the research whilst the other analysers do somewhat division. The services of the facility are utilised in simpler work. The Automacs Magnetic cell many of the projects undertaken at Peter For further details: http:// separator (Miltenyi Biotech, Germany) is an Mac. The output contributes to a large www.petermac.org/Research/ adjunct to the other sorters. This instrument variety of innovative research projects, MediaandLaboratoryServices allows the separation of magnetically dedicated to advancing the understanding labelled cells. This technology is ideal for of how cancer occurs and how it can be quick separations where very high purity is prevented or treated. not required. As the biological sciences become increasingly technologically dependant it is important to have sufficient technology to allow researchers to conduct their work in a competitive manner with other leading institutes. The Flow Cytometry facility is well positioned at the present to do this. For further details, please visit the Core Facilities service pages of the Research website: http://www.petermac.org/Research/ FlowCytometry

Left to right: Daud Duhur, Ralph Rossi. Left to right: Lara Sekhon, Suh-Youn Koh, Graham Heffernan, Menka Kyriakou, Elzbieta Gajewsaka.

Peter MacCallum Cancer Centre – Research Report 2008 Core Technologies/ Media & Laboratory Services 139 Core Technologies/ Microscopy

Our Microscopy Core is a world-class OVERVIEW live cell work), one spinning disc confocal, Australian Cancer Research Foundation PRESENTATION HIGHLIGHTS PUBLICATIONS AND PATENTS facility, providing sophisticated microscopy six wide-field microscopes, a transmission grant and was immediately popular after Our forward approach to new technology Sarah Ellis Publications are listed at the end of the equipment and software, which is electron microscope (TEM), a laser capture being commissioned in 2007. After a few 187, 276, 323. has positioned us as a global facility of – CRC for Cancer Therapeutics: Faculty of report and includes reference supported by leading technical expertise to microscope, and digital recording and months, both live cell microscopes were excellence, encompassing all aspects Pharmacy and Pharmaceutical Sciences facilitate research integral to a wide range analytical software for each microscope. fully booked and in very heavy demand. For further details, please visit the of biological optical and electron 3rd Annual Postgraduate Research of cancer research projects. Three of the microscopes are dedicated Core Facilities pages of the Research microscopy. Our renown locally has A spinning disc confocal microscope Symposium, Melbourne, Vic, September to the capture of live cell data through website: also led to collaborations with leading differs from the existing microscope 2008 (Speaker). RESEARCH PERSONNEL the addition of gas-controlled, heated http://www.petermac.org/Research/ medical research institutes and universities systems by delivering very small doses of environmental chambers, motorised – Microscopy and Microanalysis Microscopy Core Head throughout Australia. light to the live cells for imaging. Images Sarah Ellis stages, and specialist objectives. Conference, Albuquerque, USA, August First developed in 1999 with the merger are captured with a highly sensitive camera 2008 (Speaker). Research Assistants A vast array of ancillary equipment required capable of single photon collection. Light of existing electron microscopy/histology – International Society for Experimental Stephen Asquith for the processing of tissues and cells is potentially toxic to cells so the spinning and optical microscopy facilities, we Hematology Annual Scientific Meeting, Judy Borg for both optical and electron microscopy disc confocal will permit imaging of live began expansion in 2001 to include laser Boston, USA, July 2008 (Speaker). Karin Sedelies capture microscopy. Since then, we have is also provided for histological work cells over very long periods of time and – Guest speaker to medical laboratory Dhanya Menon continued to expand our capabilities with including a tissue processor, embedding increases the scope of imaging within technical students at La Trobe University Basia Przbylowski new equipment funded by competitive centre, auto-stainer, coverslipper, rotary the microscopy core. The spinning disc (Invited Speaker). Darlene Deo grants. Today, we are recognised as a microtomes, and immunostainer. We confocal will be installed in the second half world-class facility in biological optical and also provide EM, high pressure freezer, of 2009. – Monash Live Cell Imaging course, ultramicrotomes with cryoattachments, electron microscopy. Also purchased in 2008 was the powerful Clayton, Vic, December 2008 (Invited freeze substitution system, and Speaker). Our objectives are two-fold: to provide software ‘IMARIS’ for analysis of images immunostainer for electron microscopy In 2008, the Microscopy Core hosted the researchers with sophisticated microscopy captured with the live cell microscopes grids. following workshops and seminars: equipment and software to facilitate and confocals. This software assists research; and to educate, train and We aim to maintain our reputation and to researchers to quantify their images – ‘Imaris’ analytical software. continue to meet the current and future including analysis of tracking and supervise researchers utilising the facility. – ‘Volocity’ analytical software. Our staff are extensively skilled in aspects needs of researchers by continually measurement of cellular features including: – Immunohistochemistry enhancement of tissue processing for subsequent updating our equipment and extending our shape changes, division, death etc. through tyramide signal amplification. analysis, using either optical or electron knowledge base. Equipment evaluated during the year microscopy – and our team advises included electron multiplying cooled – Inaugural imaging. 2008 ACHIEVEMENTS charge coupled device (EMCCD) cameras, researchers on imaging and sample – ‘Imaris’ image analysis. processing, and hosts regular workshops. The purchase of a spinning disc confocal a high throughput image analysis system, Organising regular trials and evaluations was a highlight for the Microscopy Core an Olympus OV1000 for imaging live GRANTS AND FUNDING animals, and the ‘Volocity’ analytical of newly developed microscopes facility in 2008. Demand for sophisticated – Australian Microscopy and Microanalysis software. and software also ensures Peter Mac state-of-the-art microscopes to image Research Facility Travel and Access researchers have access to the latest live cells over extended periods of time The microscopy core also organized a Grant: $3,480, ’Analysis of the technology. has increased dramatically since the 3-day workshop with international guest, relationship between blood vessels, Microscopy Core purchased its first live bone and transplanted hemopoietic stem Currently the facility houses microscopes Mike Wussow, to train researchers in the cell microscope system in 2004 — but use of ‘Imaris’ software for image analysis cells (HSC) in situ’, 2008. and equipment to suit a wide range after two years this microscope system of experimental protocols and design, and held its inaugural imaging workshop was unable to keep up with growing at Peter Mac with sponsorship from including three confocal laser scanning demand. A live cell confocal microscope microscopes (one of which is dedicated to Invitrogen, and Fluorescence Applications was purchased with the help of an in Biotechnology and Life Sciences (FABLS) group.

Left to right: Stephen Asquith, Dhanya Menon, Karin Sedelies, Christina Tucci, Matthew Reardon, Leah Adolphe. Absent: Sarah Ellis, Judy Borg. Sarah Ellis

Peter MacCallum Cancer Centre – Research Report 2008 Core Technologies/ Microscopy 141 Core Technologies/ Tissue Bank

The Tissue Bank at Peter Mac is a core RESEARCH OVERVIEW 2008 RESEARCH ACHIEVEMENTS PRESENTATION HIGHLIGHTS facility and member of the Victorian Cancer As one of Australia’s leading facilities Our collaboration with the Victorian Cancer Samantha Cauberg Biobank, which provides researchers with of its kind, our ability to meet demand Biobank has been more widely advertised – Australasian Biospecimen Network (ABN) ethically collected, high quality human for readily available human material has this year with the commencement of 6th Annual Conference, Sydney, NSW, tissue. been pivotal in Peter Mac researchers central operations and the Cancer Council November 2008 (Poster and Speaker). securing major grants from funding Victoria coordinating all new researcher RESEARCH PERSONNEL bodies including the National Health and applications and invoicing for specimens GRANTS AND FUNDING Head Medical Research Council (NHMRC) and collected after 1st October 2006. This – Australasian Biospecimen Network, Samantha Cauberg international funding agencies such as the collaboration has provided us with our Oncology Enabling Grant: $1.75 million, Senior Research Assistant US Department of Defense. fourth round of funding this year. Our 2004–09. participation in the NHMRC Enabling Rhonda Mawal Our approach has been to liaise closely – Victorian Cancer Biobank: Department Grant-funded Australasian Biospecimen with researchers at Peter Mac to determine of Innovation, Industry and Regional Research Assistants Network-Oncology group continues to the exact specifications of human material Development (DIIRD) and participant Kent Huynh mature and the Peter Mac Tissue Bank has required. Since first launching in 1998, organisation funding (≈$400,000 for Donna Popov gained a higher national profile through we’ve collected biospecimens from more 2008). Lauren Turner this association. Staffing levels have than 10,000 donors and supported 75 Leanne Bowes increased in a year that has seen a change For further details, please visit the research projects and 20 clinical trials. in department head and the recruitment of Core Facilities pages of the Research Data Manager The breadth of collection across nine of Samara Rosenblum four very capable and valued staff. website: the 10 major tumour streams, as well as http://www.petermac.org/Research/ Resource Enhancement Scientist rare tumour types, sets us apart from other The Tissue Research Management TissueBank Kylie Scott tissue banks across Australia. Committee (TRMC) is the scientific arm of the Peter Mac Human Research Ethics Another useful link is the Victorian The storage and preservation protocols, Committee and is coordinated through Cancer Biobank website: and sound management practices the Tissue Bank. Eleven meetings have http://www.viccancerbiobank.org.au established from the very first collection, been held in 2008 with 11 new internal and meant that in 2008 the Peter Mac tissue two new external applications considered bank collection remained of highest quality along with 17 amendments. Thirty-two – for use in a wide variety of analyses, with projects and/or clinical trials have sourced individual samples having up to seven tissue or services from the Tissue Bank in years of follow up data associated with 2008. Over 2,000 individual biospecimens them. have been processed and stored in the The Tissue Bank is open to all researchers Peter Mac Tissue Bank as either part of who have the required Human Research the Latrobe Valley Mesothelioma collection Ethics Committee (HREC) approval. or biospecimens collected from Peter Access to samples collected after 1st Mac, the St Vincent’s group of hospitals, October 2006 is via the Victorian Cancer Cabrini, Freemasons-Epworth and Box Hill Biobank. This one application enables Hospitals in 2008. access to tissues collected at Peter Mac and our three other collaborating banks.

Left to right: Sam Cauberg, Anita Matusan, Leanne Bowes, Samara Rosenblum, Rhonda Mawal, Paul Pinto Correia, Jeremy Hoglin.

Peter MacCallum Cancer Centre – Research Report 2008 Core Technologies/ Tissue Bank 143 Education & Learning/

Encouraging and training research scientists of the future.

‘The Peter MacCallum Cancer Centre is a leader in cancer research. I wanted to combine my interest in Immunology and apply it to cancer, one of the largest health burdens worldwide. The Cancer Immunology Program at Peter Mac facilitated this interest’.

Christopher Chan PhD Student, Cellular Immunity Laboratory, & Leukaemia Foundation Scholar, & Winner Of The Nicole Lundie Undergraduate Student Prize In 2008

Peter MacCallum Cancer Centre – Research Report 2008 Education & Learning/ 145 Education & Learning/

PETER MAC 2008 RESEARCH SEMINAR SERIES

DATE SPEAKER INSTITUTE TITLE Feb-11 Prof. Norbert Perrimon Harvard Medical School Genome-wide RNAi screening in Drosophila cells: Methods and Applications Feb-18 Dr. Philipp Kaldis Institute of Molecular and Cell Cell Cycle regulation by Rb, Cdk2, and Cdk4 Biology, Singapore Feb-21 Dr. Mark Shackleton University of Michigan Melanoma stem cells - big needles in small haystacks? Education of future research scientists Seminar Programs is a priority at Peter Mac. The research Peter Mac scientists are given ongoing Mar-13 Dr. Stephen Ting University of Montreal Tracking Self-Renewal in Hematopoeitic Stem Cells education program strives to support access to the latest research data with Mar-20 Assoc. Prof. Ian Campbell Peter MacCallum Cancer Centre Somatic Alterations in Tumor Stroma: Genetic, Epigenetic, or the teaching and learning needs of our seminar program, which aims to build Both? all scientists and clinicians involved in knowledge and improve professional Mar-26 Assoc. Prof. Michael McKay Peter MacCallum Cancer Centre Towards biologically-driven cancer radiotherapy research at Peter Mac. development at all levels. Apr-03 Dr. Alex Dobrovic Peter MacCallum Cancer Centre Molecular Pathology gets SMART EDUCATION FOCUS The weekly research seminar series brings Apr-07 Dr. Yixian Zheng Carnegie Institution of Washington Assembly of the mitotic spindle matrix, a template for coupling together cutting edge cancer science with and Howard Hughes Medical Institute cell division and cell fate choices? • Encouraging and training research a range of Peter Mac and guest speakers. scientists and clinician-scientists of the Apr-24 Dr. Melanie Pritchard Monash University Functional characterisation of genes involved in the Staff and students also participate in neurophenotypes of Down syndrome future. weekly laboratory meetings and research • A destination of excellence for hub seminars – which provide a forum for May-01 Dr. Adam Cole University of Melbourne Identification of novel protein kinase substrates using the KESTREL technique postgraduate education in Australia. discussion with broad expert audiences, • Wide-ranging research opportunities. and opportunities to build presentation May-08 Prof. Joe Trapani Peter MacCallum Cancer Centre Perforin As global leaders using state-of-the-art skills and breadth of knowledge. May-15 Prof. Yvonne Paterson University of Pennsylvania School of Targeting tolerogenic breast tumour antigens with recombinant Medicine Listeria monocytogenes facilities, we’re driving significant studies in In 2008, the Topics in Cancer seminars basic and translational research that show continued as a postgraduate lecture series, May-22 Assoc. Prof. Greg Goodall Institute of Medical and Veterinary Regulation of epithelial to mesenchymal transition by microRNAs Science, Adelaide and its implications for tumour metastasis promise for groundbreaking improvements providing a platform for students and in cancer diagnosis, treatment and care. scientists to expand their understanding May-29 Prof. Malcolm Sim Monash University Cancer cluster investigations: experience from the ABC Toowong Breast cancer cluster Postdoctoral scientists and postgraduate of key aspects of cancer research by PhD and MD students make a major studying key research papers and Jun-05 Prof. Robert Saint Australian National University Breaking up is hard to do: genetic and molecular approaches to understanding cell division contribution to Peter Mac’s global discussing the development of associated reputation – these outstanding, motivated research directions. Jun-12 Dr. Ian Smyth Monash University The skin you’re in: using mouse genetics to understand epidermal development and enthusiastic individuals are a key part of our internationally renowned research Jun-19 Prof. Robert Parton Institute for Molecular Bioscience New insights into the formation and function of caveolae teams. Jun-26 Assoc. Prof. Sally The Victor Chang Cardiac Research Notch signalling and embryo segmentation: exploring the Dunwoodie Institute mechanism and its relevance to human congenital malformation The education program is supported by fulltime Education and Communications Jul-03 Dr. David Thomas Peter MacCallum Cancer Centre A smorgasbord of sarcoma research at Peter Mac Officer Dr Caroline Owen, who coordinates Jul-10 Dr. Heather Verkade Monash University Analysing early cell movements in the zebrafish embryo all aspects of student and staff education Jul-17 Prof. Robert Lewis Monash University Imaging and Radiotherapy with Synchrotron X-rays: The Road to and career activities across the research Clinical Relevance division, and liaises with affiliated universities and research institutes. Jul-31 Prof. Geoff McFadden University of Melbourne The relict chloroplast of malaria parasites: origin, function & therapeutic potential Aug-07 Assoc. Prof. Carol Wicking Institute for Molecular Bioscience Hedgehog signalling in the limb - implications for development and disease Aug-14 Dr. Paul Gregorevic Baker IDI Heart & Diabetes Institute Using gene transfer technology to study muscle diseases Aug-21 Dr. Patrick Humbert Peter MacCallum Cancer Centre Understanding the function of cell polarity regulators in Development and Cancer Aug-28 Assoc. Prof. Robert Ramsay Peter MacCallum Cancer Centre Intestinal stem cells and disease Sep-04 Dr. Sarah Russell Peter MacCallum Cancer Centre Polarity and asymmetric cell division in lymphocytes Sep-11 Dr. Carl Walkley St Vincent’s Institute Cell Cycle Regulation and Cancer Sep-18 Dr. Helena Richardson Peter MacCallum Cancer Centre Modelling Cancer in Drosophila Sep-24 Prof. Bernhard Lüscher Institute for Biochemistry and Control of cell proliferation by the MYC/MAX/MAD network Molecular Biology, Germany

Image Oct-02 Dr. Enrique Martin-Blanco Instituto de Biologia Molecular de Mechanisms regulating cell proliferation and invasiveness during Dr Caroline Owen, Barcelona (CSIC), Spain morphogenesis Education & Communications Coordinator. Oct-23 Assoc. Prof. Robin Anderson Peter MacCallum Cancer Centre Genes that regulate breast cancer metastasis

Peter MacCallum Cancer Centre – Research Report 2008 Education & Learning/ 147 Education & Learning/

2008 POSTGRADUATE SEMINAR SERIES: TOPICS IN CANCER cell recognition of cancer. Dr D. Andrews, Rantshilane, K, Detection of occult Lindawati, M, The assessment of Professor M. Smyth,. LF Scholarship disseminating tumour cells and tumour locoregional failure and toxicity in DNA in early stage operable breast cancer. locoregionally advanced cervical cancer Bachelor Of Science (Honours) (La DATE TOPIC SPEAKER Assoc. Professor A. Dobrovic. patients treated with radical radiotherapy Trobe University) and given a boost if PET-node positive. Aug-05 Coding Sequences of Human Breast and Colorectal Prof. Ian Campbell, Peter MacCallum Cancer Centre Thashneem, E, Investigating the Cancers Cheasley, D. Investigations of Myb target Assoc. Professor K. Narayan. genes in stem/progenitor cell populations. developmental function of c-Myb Aug-12 Apoptosis and Cytochrome c Dr Nigel Waterhouse, Peter MacCallum Cancer Centre Assoc. Professor R. Ramsay. employing Zebra fish as a model system. Melati, T, Pap smear at the time of Aug-26 Tumour Angiogenesis Assoc. Prof. Steven Stacker, Ludwig Institute for Cancer Assoc. Professor R. Ramsay. colposcopy: is it useful? Assoc. Professor Research Bachelor of Science (Honours) (RMIT) D. Allen. Advanced Medical Science (AMS) Sept-09 Cell Cycle Control Dr Patrick Humbert, Peter MacCallum Cancer Centre Wang, H. Identification of genetic modifiers of Nutlin-3a sensitivity in Liposarcoma. (Universitas Indonesia) Patra, J, The role of cohesin in radiation Sept-30 The rise and rise of molecularly targeted cancer Assoc. Prof. David Thomas, Peter MacCallum Cancer Centre Assoc. Professor D. Thomas. Anton, J, Amplification of PI 3-kinase response and cancer. Assoc. Professor M. therapeutics and Akt genes in human cancers. Assoc. McKay. Advanced Medical Science (AMS) Oct-21 Identification of tumour suppression genes in flies Dr Kieran Harvey, Peter MacCallum Cancer Centre Professor W. Phillips. Triyuniati, H, Prognostic significance of (The University of Melbourne) Nov-18 Discovering human oncogenes in the sone age Prof. Joe Sambrook, Peter MacCallum Cancer Centre histological features in endometrial cancer. Corcoran, B, Investigating the activity of a Lestari, CN, DNA repair status of Assoc. Professor K. Narayan. novel PI3 kinase inhibitor in a model of B radiosensitive cancer patients. Assoc. cell lymphoma. Dr C. Cullinane. Professor M. McKay. STUDENT TRAINING PROGRAM CLASS OF 2008 Assoc. Professor R. Ramsay, Assoc. Professor T. Mantamadiotis, CCIA, Student teaching and learning are key Doctor Of Philosophy (The University Students In Progress activities in the Research Division, and Of Melbourne) Peter Mac. the attraction of high-quality students to Baran, K, The mechanisms by which Williams, L, Identifying tumour suppressor PhD in Progress undertake Doctor of Philosophy (PhD), Cathepsin B is able to protect cytotoxic genes on chromosome 22 in breast, Akcora, D Pathways regulating asymmetric cell division and binary cell lineage fate in the intestine. Dr J. Malaterre, Assoc. Professor Doctor of Medicine (MD) and Bachelor T lymphocytes from perforins toxicity. ovarian and colorectal cancer. Assoc. R. Ramsay, Ministry of National Education, Republic ofTurkey. of Science Honours programs in our Professor J. Trapani, Dr I. Voskoboinik, Professor I. Campbell, Dr R. Anderson, Alsop, K Genotypic and Molecular Analysis of Ovarian Cancer. Prof. D. Bowtell, Dr G. Mitchell, CCV. laboratories continues as a priority. In 2008, NHMRC. CCV. we welcomed nine new Honours students, Amos, S Enhancing lymphocyte trafficking for adoptive T-cell therapies. Dr M. Kershaw, CCV. Dworkin, S, The role of the transcription MSC (The University Of Melbourne) 14 new PhD students and two MD students Anthony, D Biological function of Granzyme M. Prof. M. Smyth, Prof. J. Trapani, MRS. to our team, maintaining our graduate factors CREB and c-MYB in brain Bojdazieva, J, Functional analysis of Discs Bearfoot, J Identification of microRNA genes involved in breast and ovarian tumourigenesis. Assoc. Professor I. Campbell, Assoc. Prof. student numbers at approximately 70. homeostasis and disease. Assoc. Large 5. Dr P. Humbert, Dr S. Russell, APA. Professor T. Mantamadiotis, Assoc. W. Phillips, Assoc. Prof. A. Dobrovic, MRS. The Research Division is home to Professor R. Ramsay, Peter Mac. Bachelor Of Science (Honours) (The Bidwell, B Endothelial and epithelial genes expressed in breast cancer metastasis. Assoc. Prof. R. Pearson, Assoc. Prof. R. Anderson, approximately 70 honours and post- University of Melbourne) Dr B. Parker, APA. graduate students. In addition, in 2008 Ellis, L, Mechanisms of action of Histone Chilcott, E. Functional genome-wide RNAi Deacetylose Inhibitors. Assoc. Professor R. Blashki, D Prospective Isolation and Characterisation of Candidate Mesenchymal Stem Cells from Multiple Adult Mouse Tissues, Dr P. we mentored 28 undergraduate students screens to investigate the mechanisms Kaur, Prof. P. Simmons, MRS. Johnstone, Dr M. Hulett, ANU. (local and international) associated of drug sensitivity and breast cancer Bolden, J Investigating Anti-Tumour Activities of Histone Deacetylase Inhibitors. Assoc. Prof. R. Johnstone, CRIS. with the following programs: Advanced Etemadmoghadam, D, Genome-wide development. Assoc. Professor R. Hannan. Medical Science (AMS), Summer Vacation Bolitho, P Immune surveillance of B cell lymphoma. Prof. M. Smyth, Prof. D. Godfrey, CRIS. microarray analysis of CAN copy number Chin, K. Preclinical evaluation of DNA Research Studentships, undergraduate Bruhn, M Role of SGK3 in tumourigenisis. Dr K. Sheppard, Assoc. Prof. R. Hannan, FUSRS. variation in ovarian cancer. Professor D. ligands labelled with Auger-electron work experience internships, and Bowtell, MRS. emitters. Dr T. Karagiannis, Assoc. Burrows, A The contribution of stromal caveolin-1 to breast cancer metastasis. Assoc. Professor R. Anderson, NHMRC. undergraduate projects undertaken in our Jastrzebski, K, Role of S6k in the Professor R. Martin. laboratories. The research team also offers Bywater, M Regulation of ribosome biogenesis during lymphomagenesis. Assoc. Prof. G. McArthur, Assoc. Prof. R. Hannan, NHMRC. regulation of rRNA gene transcription, opportunities to TAFE and secondary Copin, A. Identification and Cao, Y BMP4 – a metatstasis suppressor gene in breast cancer. Assoc. Prof. R. Anderson, Dr B. Eckhardt, MRS. ribosome biogenesis and cellular growth. school students to undertake short-term characterisation of oncogenes in Assoc. Professor R. Hannan, Assoc. Carpenteri, S Pathways regulating asymmetric cell division and binary cell lineage fate in the intestine. Assoc.Professor R. Ramsay, Dr P. work placements in the laboratories. liposarcoma. Assoc. Professor D. Thomas. Darcy, LaTrobe. Professor R. Pearson, APA. The comprehensive student program Pelzer, R. Radiosensitisation and Carter, R Integrin ß3 as a therapeutic target for breast cancer metastasis to bone. Assoc. Prof. R. Anderson, Dr N Pouliot, NBCF. Loi, S, The application of gene expression includes mentor programs, dedicated topoisomerase inhibition by DNA binding profiling to clinical breast cancer research. Chan, J Growth control by the AkT protein kinase: implications for cancer. Assoc. Prof. R. Pearson, Assoc. Prof. R. Hannan, MGS. student scientific review committees, onsite ligands. Dr T. Karagiannis, Assoc. Assoc. Professor G. McArthur, NBCF. Professor R. Martin. Chee, L Differentiation therapy of acute myeloid leukaemia: combining RAR-Agonists and G-CSF. Assoc. Prof. G. McArthur, Dr P. workshops and seminars, and community Humbert, CSL. and outreach opportunities. Poon, C, In vivo analysis of cooperative Roczo, S. The role of human Lgl1 in apical- tumourigenesis between Src and RasACT Chong, L Investigating Olt-4 in skin. Dr P. Kaur, Dr H. Schluter, Peter Mac. Our postgraduate PhD and MD, Honours basal polarity and cancer. Dr P. Humbert. in Drosophila. Dr H. Richardson, Dr P. Do, H Genetic and epigenetic mechanisms determining responses to therapy in non-small cell lung cancer. Assoc. Prof. A. and AMS students contribute significantly Humbert and Dr T. Brumby, MRS. Schlosser, T. The role of cell polarity Dobrovic, Prof. S. Fox, Peter Mac. to the success of Peter Mac. We warmly regulator human inscuteable in cancer. Dr congratulate the following students who Wall, M, The role of growth control in the Ellis, S In situ protein and molecular characterisation of the hemopoietic stem cell niche. Dr S. Nilsson, Dr I. Bertoncello, Peter P. Humbert. Mac/ASCC/CASS. successfully completed their studies at differentiation of normal and leukaemic Peter Mac in 2008. myeloid cells. Assoc. Professor G. Bachelor of Science (Honours) Elsum, I The Role of Scribble in oncogenic signalling and tumourigenesis. Dr P. Humbert, Dr H. Richardson, CCV. McArthur, CCV. (Monash University) Fleming, N Investigation of PTHrP in breast cancer. Dr D. Thomas, Dr R. Anderson, NBCF. Chan, C. The role of DNAx-Accessory Williams, B, Characterisation and immune Frew, A Combination therapeutics targeting the TRAIL receptor pathway. Prof. M. Smyth, Assoc. Prof. R. Johnstone, CRIS. Molecule 1 (DNAM-1) in Natural Killer (NK) targeting of nuclear oncogenes in cancer.

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PhD in Progress (Continued) MSc in Progress (Swinburne University of Technology) Galea, R The role of the Scribble/Discs Lager polarity complex in development and tumourigenisis. Dr P. Humbert, Dr H. Richardson, Shimoni, R Measuring Scribble and betaPIX interaction by Raster Image Correlation Spectroscopy (RICS). Dr S. Russell, Prof. Min Gu. APA.

George, J Integrated analysis of distinct molecular profiles of tumour data.. Prof. D. Bowtell, Assoc. Prof. G. Smyth, APA. MPhil In Progress (The University of Melbourne) Grusche, F Characterisation of genes that potentially function downstream of Ras and Scribble in Drosophila tumour model. Dr H. Arthur, H Molecular and biological characterisation of interferon mediated signal transduction pathways and genes that respond to Richardson, Dr K. Harvey, Dr T. Brumby, MIRS. interferon. Assoc. Prof. R Johnstone, MRS. Hare, L Investigating the role of PIK3CA mutations in colorectal cancer. Assoc. Prof. W. Phillips, APA. Chia, J Investigating the molecular basis of perforin dysfunction that leads to atypical Haemophagocytic Lymphohistiocytosis Hung, S The contribution of S6k/ribosome biogenesis axis to the process of cell transformation and tumour growth. Assoc. Prof. R. (HLH) or other primary pathologies. Prof. J. Trapani, Dr I. Voskoboinik, Peter Mac. Hannan, Assoc. Prof. R. Pearson, MRS. Huang, K Epigenetic mechanisms in benign and malignant breast cancer. Prof. S. Fox, Assoc. Prof. A. Dobrovic, MRS. Huynh, D CSF-1/c-fms signalling in intestinal biology and cancer. Assoc. Prof. R. Ramsay, LaTrobe. Khoo, P Investigation of pathways that act downstream of scribble and Rho GEF2 in cooperation with oncogenic RAS in a Advanced Medical Science (AMS) In Progress (The University of Melbourne) Drosophila cancer model. Dr H. Richardson , Dr P. Humbert/Dr T. Brumby, MRS. Chung, Michael Genetic and epigenetics of chronic lymphocytic leukemia. Assoc. Prof. A. Dobrovic. Kusuma, N Targeting of Laminin-10 in breast cancer metastasis. Dr R. Anderson, Dr N. Pouliot, NHMRC. Cochrane-Davis, S A Hypothetical Mechanism for Oesophageal Columnar Metaplasia. Assoc. Prof. W. Phillips. Lee, R Biochemical analysis of AKT3 specific signal transduction. Dr R. Pearson, Assoc. Professor R. Hannan, APA. Fielding, K Inducing Immunogenic Cell Death in Multiple Myeloma Cell Lines. Dr P. Neeson, Assoc. Prof. D. Ritchie. Lin, J Effects of ribosomal protein hypomorphs on cell growth and proliferation in Drosophila melangaster. Assoc. Professor R. Hannan, Assoc. Prof. R. Pearson and Dr L. Quinn, APA. Yao, Henry Investigating the basis of a gemcitabine-mediated ‘flare’ in 3’-deoxy-3’-fluorothymidine uptake into PC3 tumour cells. Dr C. Cullinane. Mellor, D Genetic and epigenetic determinants of response to therapy. Prof. S. Fox, Assoc. Professor A. Dobrovic. Messina, N Role of STAT1 in Interferon Signalling and Immunity. Assoc. Prof. R. Johnstone, Dr C. Clarke, CRIS. Scholarships to Support Training students at Peter Mac, and is judged in reflects the high calibre of research that Miao, YR The role of Myb in mammogenesis and breast cancer. Assoc. Prof. R. Ramsay, Assoc. Prof. R. Anderson, MRS. consideration of the international impact continues to be conducted at Peter Mac. ANU: ANU Research Scholarship Newbold, A Mechanisms of histone deacetylase inhibitors. Assoc. Prof. R. Johnstone, NHMRC. of the basic, translational or clinical cancer The Research Division is very grateful to APA: Australian Postgraduate Award research. Accompanying this prestigious Professor Lester Peters and the Peter Mac Orlowski, C The role of epithelial stem cells and progenitor cells in homeostasis and carcinogenesis.. Dr P. Kaur, Dr H. Schluter, Peter Mac. ASCC: ASCC Postgraduate Scholarship medal is a plaque and a prize of $1,500. Foundation for again supporting this award. Pasam, A Mechanisms and role of polarity proteins in T cells. Dr S. Russell, Dr P. Humbert, MRS. CASS: CASS Foundation Scholarship In 2008, the medal was awarded to Dr Sebastian Dworkin from the Differentiation Pegram, H Gene modification of multiple leukocytes for cancer immunotherapy. Dr P. Darcy, Dr M. Kershaw, MRS. CCV: Cancer Council Victoria Scholarship and Transcription Laboratory in the Pham, K Investigating polarity proteins in thymocytes - a potential role in asymetric cell division?. Dr S. Russell, Prof. M. Gu, NHMRC. CRIS: Cancer Research Institute Scholarship Research Division. Sebastian received Qiu, W Cellular, molectular and genetic characterisation of breast and ovarian cancer associated fibroblasts (CAFS). Assoc. Prof. I. CSL: CSL Postgraduate Scholarship this award based on the research Campbell, Dr I. Haviv, NHMRC. EGIPS: Egyptian Government International he conducted for his PhD under the Ramakrishna, M Identification of novel ovarian cancer genes using a cross-platform, integrative genomics approach. Assoc. Professor I. Postgraduate Scholarship supervision of Assoc. Professor Rob Campbell, Dr K. Gorringe, MRS. FUSRS: Flinders University Student Research Ramsay and Assoc Professor Theo Saad, M Biological characterisation of human phosphatidylinositide 3-kinase Mutations. Assoc. Professor W. Phillips, Rosenthal, Scholarship Mantamaditotis, where he explored the EGIPS, NHMRC. LaTrobe: La Trobe University Postgraduate action of the CREB transcription factor on neural homeostasis. Sacirbegovic, F The role of polarity proteins in T cell function. Dr S. Russell, Dr P. Humbert, MRS. Scholarship Shortt, J Therapeutic inhibition of the phosphatidylinositol-3 kinase/mammalian target of rapamycin pathway in Myc driven models LF: Leukaemia Foundation Scholarship Using the zebrafish as a model system, of B-cell neoplasia. Assoc. Prof. Ricky Johnstone, Assoc. Prof. Grant McArthur. LF. MGS: Monash Graduate Scholarship Sebastian discovered a key role for CREB in regulating neural progenitor Sinha, A Control of organ size during development and disease. Dr K. Harvey, Dr C. Milton. MIRS: Melbourne International Research Scholarship cell proliferation and survival in both Susanto, O Signalling pathways in cytotoxic lymphocyte-induced cell death. Dr N. Waterhouse, Prof. J. Trapani, CRIS. systems as well as performing the most MRS: Melbourne Research Scholarship Thompson, E Genome-wide allele-specific copy number analysis to identify genes involved in breast cancer predisposition. Assoc. comprehensive documentation of CREB Dr Seb Dworkin Professor I Campbell, Assoc. Prof. P. Waring and Dr A. Holloway, NBCF. NBCF: National Breast Cancer Foundation expression during brain development in the Scholarship Turkel, N Characterisation of a novel drosophila oncogene. Dr H. Richardson, Dr T. Brumby, Peter Mac. fish. As CREB has been subject to intense 2008 NICOLE LUNDIE NHMRC: NHMRC Dora Lush Postgraduate Pharmaceutical Industry interest in the Wiegmans, A The biomolecular actions of HDAC inhibitors. Assoc. Prof. R. Johnstone, NHMRC. UNDERGRADUATE STUDENT PRIZE Scholarship context of various psychosis, Sebastian’s Withana, N Contribution of tumour derived cysteine cathepsins to breast cancer metastasis to bone. Assoc. Prof. R Anderson, Dr. B. Peter Mac: Peter Mac Research Laboratory discoveries have direct implications for the The Nicole Lundie Undergraduate Parker, NHMRC. Funding use of drugs that target CREB action. In Student Prize is awarded annually to the Wong, C Inhibition of Siah ubiquitin ligase in breast cancer. Dr A. Moeller, Prof. D. Bowtell, CCV. Rosenthal: D.B. Rosenthal Postgraduate addition, constitutive activation of CREB most outstanding Honours student who Scholarship has undertaken their research project at Wood, P Molecular analysis and therapeutic targeting of the PI3K/AKT/mTOR pathway in paediatric neuroblastoma. Assoc. Prof. G. has been associated with a range of McArthur, Assoc. Prof. D. Ashley, MRS. human malignancies, particularly in the Peter Mac. 2008 PETER MAC POSTGRADUATE context of very difficult to manage brain The 2008 prize was awarded to RESEARCH MEDAL cancers such as glioblastoma multiforma. Doctor of Medicine in Progress (The University of Melbourne) Christopher Chan who was based in the In 1999, to mark the 50th anniversary In congratulating Sebastian on his research Cellular Immunity Laboratory under the Handolias, D Molecular analysis of the PI3K pathway in epithelial ovarian cancer. Assoc. Prof. G. McArthur, MRS. of Peter Mac, the Research Division achievements, we would also like to supervision of Dr Daniel Andrews and established the Peter MacCallum Cancer Khamly, K Tumour hypoxia and response to preoperative radiotherapy in soft-tissue sarcomas. Assoc. Prof. D. Thomas. acknowledge the research achievements Professor Mark Smyth while undertaking Centre Postgraduate Research Medal. Yan, M The impact of the tumour microenvironment on breast cancer prognosis and treatment. Assoc. Prof. A. Dobrovic, Prof. S. of the other applicants. The competitive his Honours research project. This prize This award aims to promote excellence Fox, NHMRC. nature of the medal selection process capped a productive and stellar year for in cancer research by PhD and MD

Peter MacCallum Cancer Centre – Research Report 2008 Education & Learning/ 151 Education & Learning/

Chris, who was awarded a Leukaemia relating to postdoctoral positions, finding project supported by government funding – Diagnostic tests: Protein Concentration secondary schools. This program will Foundation Honours Scholarship, and funding, and scientific writing for theses, from the Australian School Innovation in Assay as a diagnostics tool. continue in 2009. published two research papers based on CVs and publications. Science, Technology and Mathematics The students gained valuable practical Careers in Biotechnology his Honours research. (ASISTM) program. experience and insight into scientific We would like to acknowledge the In June 2008, Peter Mac joined with the research. The interactions with the This award is sponsored by the Lions sponsorship of our industry supporters The project brought scientific research to Bio21 Institute to present a “Careers in teachers and the students provided a Club of Geelong Breakfast, donations for this retreat in 2008: Australian Animal life by providing opportunities for students Biotechnology” program. Held during valuable and rewarding professional made in memory of Nicole Lundie, and the Care Systems, Sapphire Bioscience, Pfizer to engage in real world science through Careers Week, this morning program development opportunity for our Peter Research Division at Peter Mac. The award Animal Health, CSL, Bioline (Australia) and the dissemination of online information was attended by 55 teachers representing Mac researchers. honours the memory of Nicole Lundie DKSH Australia. and resources from Peter Mac that 42 Melbourne public and private who was a summer, Honours and PhD complemented VELS and VCE principles. We would like to take this opportunity to secondary schools. PETER MAC POSTDOCTORAL student at Peter Mac before she passed Teachers from the cluster schools worked acknowledge the generous support of PROGRAM Career and research overviews were away during the first year of her PhD, and with students and scientists at Peter Mac MGGS in supporting the development presented by Professor Carl Schiesser is made in memory of her exceptional Postdoctoral researchers undertaking to develop learning materials. All learning and running of this summer school, and Dr Nathan Godde and Faruk Sacirbegovic. (Bio21 Institute), Dr Sally Gras (Bio21 academic achievements and her passion, research at Peter Mac have the opportunity materials were produced by a select group the staff of MGGS, Ruyton Girls’ School, Institute) and Dr Kieran Harvey (Peter drive and commitment to science. PETER MAC POSTGRADUATE to work with Australia’s top cancer of science teachers from Melbourne Girls Camberwell Grammar and Shelford Girls’ Grammar, Ruyton Girls, Shelford Girls Mac). Attendees then participated in a The Research Division takes this RESEARCH STUDENT SOCIETY research scientists, in facilities designed Grammar for their hard work throughout Grammar and Camberwell Grammar. As discussion panel, facilitated by Dr Stella opportunity to thank the Lundie family and to encourage interaction and collaboration this project. The Research Division has an active a result, flexible, powerful, dynamic and Clark (The Bio21 Cluster), with panelists the Lions Club of Geelong Breakfast for locally and overseas. Postgraduate Student Society. This is a interactive online learning materials were Following the great success of pilot Dr Andy Hill (Bio21 Institute), Dr Thomas their ongoing support of this award. student-run organization that coordinates Postdoctoral research is a vital part of developed and made widely available for summer school, MGGS and Peter Mac Naderer (Bio21 Institute), Dr Sumone social and educational events for research both the researcher’s career path and aim to again combine to organize the Chakravarti (The University of Melbourne) 2008 HAROLD MITCHELL TRAVEL teachers and students to access. students throughout the year. Peter Mac’s overall research success. The 2nd Summer School to take place in and Assoc. Professor Rob Ramsay (Peter FELLOWSHIPS postdoctoral experience is a time when This project was a great success and January 2010. Mac). This was a very successful program, The main goal of the Student Society is The Harold Mitchell Travel Fellowship the early-career scientists develop their concluded in 2008 with the implementation providing an important opportunity for to provide a welcoming and comfortable VCE Biology Lecture Series program at Peter Mac recognizes two scientific and technical skills and gain of the planned Summer School, launching secondary school teachers to develop environment for students during their outstanding young researchers by experience in other skills needed for a of the website (www.animatedscience. Launched in 2008, this lecture series a better understanding of the breadth undergraduate and/or postgraduate awarding them travel support to provide professional career. com.au), and an ongoing lecture series. complemented the VCE Biology of biotechnology careers and future studies at Peter Mac. In this regard the opportunities to develop and build on their curriculum, and provided an opportunity opportunities for their students. This event student society not only supports scientific Our postdoctoral scientists play a crucial Animated Science Summer School career pathways. The Selection Committee for students to revise these topics and to was coordinated by the Inner Melbourne achievement at Peter Mac but also builds a role in facilitating the student education In January 2008, 38 gifted students from is faced with a very competitive process, understand them in the context of cancer VET Cluster. strong social and interactive network. program, undertaking roles as mentors 12 Victorian public and private secondary considering applications from excellent research. and scientific committee members that schools attended an intensive four-day students and postdoctoral researchers. It The Student Society also coordinates provide opportunities for them to support summer school hosted by Melbourne – “Signalling molecules and drug design” is a great reflection on research at Peter onsite academic workshops and seminars the next generation of scientists while Girls Grammar School (MGGS). The (Professor David Bowtell); Mac that there are so many talented young that support graduate study, as well as also furthering their own experiences program introduced high achieving senior scientists at work in our laboratories. the annual student retreat. The retreat – “A view to a kill – apoptosis and cell as supervisors. secondary students to exciting ideas and serves as a forum for undergraduate death” (Dr Nigel Waterhouse); The 2008 Travel Fellowships were awarded concepts in a wide range of scientific and postgraduate students to discuss Postdoctoral scientists are also at the – “Differentiation and Transcription” (Assoc. as follows: areas. Throughout the summer school, scientific ideas, career opportunities forefront of Peter Mac outreach activities, Professor Rob Ramsay). the students heard presentations from – The Post Graduate Fellowship was and professional skills, as well as participating in workshops and seminars 10 key scientists, and worked with nine These lectures were held at Peter Mac, awarded to Faruk Sacirbegovic in the allowing students to interact in a relaxed to build new research and education links research scientists in the MGGS science and were attended by students from Immune Signalling Laboratory. With this environment. with school and community groups. In a range of Victorian public and private award, Faruk undertook and extensive 2008 many of our postdoctoral scientists laboratories. Students also spent a day In April 2008, the students organized tour of eight laboratories and two took leadership roles in the development touring the Peter Mac research laboratories and coordinated the student retreat in conferences, giving research seminars at and presentation of workshops and to experience ‘real science in action’. Blairgowrie. The students participated all locations during his travels. seminars for our school outreach activities: Postdoctoral and postgraduate in two days of workshops and seminar Animated Science and VCE Biology researchers worked with the science – The Post Doctoral Fellowship was discussions on topics related to the Lectures. Our early career scientists teachers to develop the intensive science awarded to Dr Nathan Godde in the Cell research process, and career issues. also participated in school presentations program: Cycle and Cancer Genetics Laboratory. We sincerely thank the panel of guest associated with National Science Week Nathan used this award to travel to speakers who very generously gave their – Microscopy and breast cancer: and Careers Week, and visited schools Japan for a conference and collaborative time to talk to the students: developing microscopy and analysis and community groups for presentations discussions with Japanese researchers, skills, preparing and studying histology – Dr Sue Chantler, Pfizer Animal Health about their research. and to attend a short course on samples; experimental models of human cancer in – Dr Michael Wilson, CSL SCHOOL OUTREACH ACTIVITIES: – Embryonic patterning in Drosophila the USA. – Professor Annabelle Duncan, SCIENCE IN SCHOOLS melanogaster; in gene expression We thank the Harold Mitchell Foundation Biosciences Research Centre, La Trobe and mutations on embryological for their generous ongoing support of this University. Animated Science: Bringing scientific research to life development; program. Assoc. Professor Rob Ramsay, Dr Chris In 2007-08, Peter Mac scientists combined – Genomics: investigating Genetic testing Clarke and Dr Kieran Harvey from the Outreach activity science in schools student and postdoctoral participants: Dr Maya Kansara, Dr Belinda with teachers from a cluster of four and profiling through Gel Electrophoresis Parker, Dr Nico Grzeschik, Dr Kylie Gorringe, Felix Grusche, Jennifer Bearfoot, Andrea Newbold, Research Division also led discussions secondary schools to participate in a and web-based genetic analysis; Dr Chris Clark and Dr Andreas Moeller.

Peter MacCallum Cancer Centre – Research Report 2008 Education & Learning/ 153 Ethical Conduct of Research/

Peter Mac fosters a research environment of intellectual honesty, integrity, and scholarly and scientific rigour.

Peter MacCallum Cancer Centre – Research Report 2008 Ethical Conduct of Research/ 155 Ethical Conduct of Research/

TERMS OF REFERENCE, GUIDELINES Guidelines on Ethical Conduct in Human Committee and the Tissue Research projects were approved administratively or Policy issues AND GOVERNANCE Research (National Statement). This Management Committee with respect by executive process. Policies, guidelines and other initiatives requires attention to: to scientific merit, statistical validity and The Peter MacCallum Cancer Centre During 2008, the Expedited Review concerning numerous matters were other technical issues when considering Ethics Committee is formally recognised – the integrity of researchers and the Committee considered 41 proposals, considered, adopted or revised by the proposed research. as a Human Research Ethics Committee research enterprise of which 21 would otherwise have been Ethics Committee. These matters included as described by the National Health and Committee processes, use of patient data, – the principle of respect for people The Committee also maintains a sub- reviewed by the full Ethics Committee. All Medical Research Council (NHMRC). and research involving human tissue. (requiring informed consent) Committee called the Expedited Review of these projects were approved. In addition to reviewing and approving Committee, which is authorised to review – the principle of beneficence (requiring Education ETHICAL CONDUCT OF ANIMAL human research activity at Peter Mac, the low-risk research, quality activities and researchers to act in accordance with RESEARCH Committee generates policies, which the clinical audits requiring review. Many of the The Ethics Committee held two in- research participants’ welfare) board may adopt, and provides advice research projects undergoing review by service training programs for research The NHMRC has developed the Australian to Peter Mac on institutional policy and – the principle that the dignity of research this Committee are survey-based. and clinical staff on ethical issues during Code for the Responsible Conduct of other issues as requested by the Board participants takes precedence over any 2008. ‘Grand Rounds’ were held in March Research, which is designed to ensure that of Directors or the Executive. It is also benefits to knowledge that might accrue Project approval and September 2008 on ‘Case Studies research is conducted ethically and with engaged in educational programming from research During 2008, the Ethics Committee of Research Projects After They Are integrity. for hospital staff and the public and is considered 65 applications for new Completed: Findings, Outcomes, Benefits – the principle that there should be a fair In accordance with these guidelines, the available to staff as a forum for discussion research after preliminary approval by the to the Community?’ and ‘Discrimination distribution of the benefits and burdens Peter Mac Animal Ethics Committee (AEC) of ethical matters generally. of research Clinical Research Committee or Tissue and Privacy Issues in Human Genetics’ Research Management Committee (56) respectively. takes an important role in overseeing the The specific roles and responsibilities – the principle that the risks to a research or via the Mutual Acceptance Program or ethical conduct of any work involving the As part of their own further education, of the Ethics Committee are: participant should be in proportion to the Recognised Prior Review Scheme (9). The use of animals for scientific purposes. members of the Ethics Committee – To review and, as appropriate, approve benefits. Ethics Committee approved all of these attended several external seminars on As described by the NHMRC, the primary or reject research projects submitted by research projects; however most of the MEMBERSHIP, PROJECT REVIEW AND health care, research and/or ethics. role of the AEC is to ensure that the use of affiliated or non-affiliated researchers for OTHER MATTERS projects were approved subject to the animals is justified, provides for the welfare consideration by the Committee and any submission of a response to requested Finally, the Peter Mac Ethics Coordinator, of those animals, and incorporates the The membership of the Ethics Committee changes or amendments to these changes or queries by the Committee. Jeremy Kenner, continued his work with principles of ‘replacement, reduction and as at December 2008 was: – To consider and monitor ethical issues Four projects were not approved initially, the DHS, Cancer Trials Australia and other refinement’: related to the conduct of research Board members: Canon Alan Nichols but no projects were rejected outright by state and national groups with respect to – The replacement of animals with other projects approved by the Committee (Chair), Prof. Peter Sheldrake. the Committee in 2008. streamlining multicentre ethics review and methods – To consider and monitor ethical issues a variety of legal/insurance processes. Community members: Ms Anne Holmes Of the research projects formally approved – The reduction in the number of animals related to patient care, as necessary (lay woman), Dr Kate Jones, Ms Catharine by the Committee during 2008, 37 were Collaborative relationships used – To establish, maintain and monitor McKean, Dr Grant Moss (lay man), Ms clinical trials, 11 were other clinical During 2008, Peter Mac continued its – The refinement of techniques used to necessary sub-Committees and Mary Rydberg, Mr Tyson Wodak (lawyer). research projects (including non-clinical affiliation with Cancer Trials Australia (CTA). reduce the adverse impact on animals. trial supportive care research projects), six administrative processes for the review Centre staff: Mr Craig Bennett (Chief The Ethics Committee also continued were laboratory research projects, and 14 The AEC conforms to the NHMRC of matters submitted for the Committee’s Executive Officer) or Mr Shane Ryan its participation in the CTA’s Mutual consideration were other categories of research projects. Acceptance Program. This program Australian Code of Practice for the Care (Manager, Surgical Oncology), the Rev. and Use of Animals for Scientific Purposes. – To consider issues referred by the Board involves the delegation of full review by one David Dawes (minister of religion and Of the clinical trials submitted for In conforming to the code, the AEC works of Directors and, where appropriate, ethics Committee to an ethics Committee Head, Pastoral Care Department), A/ consideration, approximately 46% are to ensure the ethical and humane care of provide advice to the Board, especially of one of the other partner institutions, Prof. David Ritchie (clinician, Division of commercially sponsored, 24% are any animals used for scientific purposes, on policy issues with ethical implications Haematology and Medical Oncology sponsored by a cooperative research and an agreement by the ‘accepting’ ethics Committee(s) to formally endorse and aims to promote the wellbeing of – To provide a forum in which staff, patient representative and Chair, Clinical Research group and 30% are investigator-initiated the approval of the ‘primary’ reviewing animals and minimise their experience of and carer concerns regarding ethical Committee), Ms Tessa Jones (Allied Health and conducted only at Peter Mac. Committee, barring serious disagreement pain or distress. issues in research can be considered representative), A/Prof. Wayne Phillips The Committee welcomed the diversity regarding substantive issues. and investigated (Chair, Tissue Research Management For further information, visit: http:// of the research presented to it for www.nhmrc.gov.au/guidelines/animal_ – To promote a deeper understanding of Committee and Research Division The Committee also continued to extend consideration. guidelines.htm ethical issues within Peter Mac through representative), Mr Stephen Thomas the principle of mutual recognition to The Committee also considered and educational activities. (Nursing representative), Dr Scott Williams include a program unique to Peter Mac (clinician, Radiation Oncology Division approved 86 amendments to previously entitled ‘Recognised Prior Review’, The Ethics Committee is a Committee of representative) and Mr Jeremy Kenner approved projects. These amendments developed in 2007, which serves to permit the Peter Mac board and reports to the (Ethics Coordinator). included changes to protocols or the unilateral recognition of the prior board each month. consent forms, the withdrawal of a trial The Committee continued to operate using approval of other major research sites. drug because of adverse effects, the For greater linkage into the governance of a consensus model, rather than by voting. This scheme is premised on the idea that closure of a study because of insufficient Peter Mac, some members of the Ethics This model requires that lay members dozens of other Committees in Australia recruitment, the expansion of a participant Committee are on the Board’s Community of the Committee understand, and be in have sufficient experience and expertise group to include other disease categories, Advisory Committee. agreement with, proposed research before to review multicentre cancer research and and additional tests related to the is another step in the direction of more When considering proposed research, it proceeds. original project plan. A number of other expeditious review of research in Australia. the Committee adopts and follows the The Committee continued to rely heavily amendments to previously approved principles articulated in the NHMRC on the advice of the Clinical Research

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Building and Creating Commercial Relationships.

‘Cancer radiotherapy is ‘core business’ at Peter Mac and more generally, a major public health activity, and a commensurate research effort is required to improve this treatment modality. A specific goal is to develop new drugs to ameliorate the damage to normal tissues that often accompanies radiotherapy treatment’.

Assoc. Professor Roger Martin Head, Molecular Radiation Laboratory

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Commercialisation is a crucial arm of Peter A COMMERCIALISATION SUCCESS These commercial contracts have provided Victorian Prostate Cancer Research The Co-operative Research Centre for ongoing commitment to ensure that such Mac’s drug discovery and translational STORY: THE DEVELOPMENT OF AN Peter Mac with the opportunity to work with Consortium Membership Biomedical Imaging Development policies and practices continue to be research strategy. Our approach is to INNOVATIVE CANCER TREATMENT an Australian company to help realize the Peter Mac formally became a member of The Co-operative Research Centre for relevant and supportive of the strategic build on existing commercial relationships, TECHNOLOGY enormous therapeutic potentialities of the the Victorian Prostate Cancer Research Biomedical Imaging Development (CRC), directions taken by Peter Mac in the whether in Australia or overseas, and Following the execution of contracts in research undertaken on radioprotector Consortium (VPCRC) which also of which Peter Mac is a member, entered commercialisation of its research. create new partnerships in key drug October 2007 with Peter MacCallum compounds. The funding of the research includes the Ludwig Institute for Cancer its third year of operation in mid-2008 with PATENTS development areas of the world. Cancer Centre, the biotechnology and program also provides the potential for Research, The University of Melbourne, all the outcomes, outputs and milestones other avenues of research inquiry that may We start by carefully evaluating how medical devices company, Sirtex Medical Monash University, Melbourne Health, for the radiopharmaceutical and detector • During 2008 Peter Mac considered broaden application of the technology relationships will add value to our Limited (SRX), obtained exclusive licence TissuePath Pty. Ltd. and the VPCRC Ltd. research programs met or on track. The six disclosures of putative inventions, and which in turn may help consolidate process of discovery and then aim to rights to an innovative cancer treatment (the Consortium management company). CRC Review Panel (commissioned by the filed one Australian provisional patent research collaborative opportunities establish structures and mechanisms technology based on radioprotector The principal aim of the Consortium is Commonwealth Government) endorsed application and four international with other groups both in Australia and that will effectively enable the successful compounds. to establish a series of collaborations the achievements so far made by the CRC applications. overseas. [www.sirtex.com] [See pg 58] that will span the therapeutic and and in particular, commended the quality transfer of innovative technologies to the Radioprotector compounds provide a • Peter Mac now has fourteen patent pharmaceutical and biotechnology sectors diagnostic development systems, without of the policy and practice documentation families under active management means of protecting healthy tissue from 2008 Achievements the necessity of investing in physical produced by the CRC’s Commercialisation – with the ultimate goal of benefitting the the harmful effects of exposure to ionising and approximately 85% of the patent The following provides a sample of the infrastructure or capital development. The Committee for the proper identification, Australian cancer community. radiation, potentially providing significant prosecution costs are met through a range of commercialisation activities VPCRC charter, in part, promotes prostate evaluation and protection of new benefits to cancer patients receiving range of agreements settled with various The Board of Directors and the Research undertaken by Peter Mac and endorsed by cancer research that will result in the intellectual property developed by the treatment by conventional external beam corporate partners and licensees. Advisory Committee remain committed the Research Advisory Committee. pursuit of drug development opportunities CRC. Issues of governance, management to developing any opportunities and radiotherapy. in the treatment of prostate cancer. and collaborative organizational structures initiatives that emerge from our research The Sirtex-Peter Mac contracts provided BioGrid Australia were also considered in detail by the Collaborative establishment of image and clinical areas that might lend continuing support for research throughout During 2008 negotiations were underway Review Panel. Cytometrics Pty. Ltd. themselves to technology transfer and 2008-09, led by Dr Roger Martin, Head of to finalise Peter Mac’s participation in a In collaboration with Swinburne University Definition of research relationship with commercialisation. The commercialisation the Molecular Radiation Biology program range of agreements for the establishment of Technology (per Swinburne Ventures Swinburne University of Technology team co-ordinate the commercialisation at Peter Mac, to develop improved lead of BioGrid Australia, a reconfiguration Ltd.) and the Israeli-based Technion In late 2008 the Research Advisory effort of Peter Mac and work closely with radioprotector compounds. The licence and restructuring of the Molecular Research & Development Foundation Ltd., Committee endorsed the proposal for all major management streams within granted to Sirtex will run for a minimum Medicine Informatics Model Consortium. Peter Mac joined in the establishment of the Director of Research to develop the organisation in developing these term of 10 years to develop and market This collaboration aims to link database Image Cytometrics Pty. Ltd. The primary an appropriate Research / Academic opportunities and capitalising on their products based on radioprotector genomic information with clinical patient aim of this “start-up” company is to Exchange Memorandum of Understanding potential. technology developed by Peter Mac. information, allowing researchers to better understand how an individual’s genomic maximise the commercial prospects with Swinburne University of Technology, PERSONNEL It is anticipated that the radioprotector characteristics affect the way in which they of a novel methodology for performing to capture the respective research and compounds developed under these automated analysis of live cells. The academic aims of the parties. The final Director of Commercialisation, respond to a disease and to its various contracts may form the active component company is a venture-based enterprise agreement enunciates the purposes, Associate Director of Research potential treatments. It is anticipated that of products such as topically applied the collaboration will yield commercially and has initiated the preparation of principles and processes by which the Mr Jerry de la Harpe creams, aerosols, suppositories or valuable intellectual property. A limited business and marketing plans. The parties will most effectively collaborate for Manager, Intellectual Property & systemic administration prior to radiation liability, services company (BioGrid company’s interim Board of Management both research and academic purposes, Development treatment or exposure, in order to reduce Australia Ltd.) will now manage this is working closely with external consultants including the taking of commercial Dr Shari Lofthouse the effects of radiation on healthy tissue. incorporated joint venture which comprises in moving the company and project to its initiatives to explore novel therapeutics and a number of Victoria’s major hospitals, next stage of development. diagnostics for the treatment of cancer. Executive Assistant The technology is primarily aimed at providing a benefit to patients undergoing as well as certain interstate healthcare Ms Jade Tran Development of Peter Mac Perforin Board Review of Peter Mac external beam radiation treatment for organisations. Project Commercialisation Policy cancers of the breast, head and neck, Healthscope Ltd. Sub-Licensing A significant Research Project Agreement Allowing for Peter Mac’s continuing interest and prostate. Agreement was finalised with Monash University as in adopting models and mechanisms in A Sub-Licence Agreement was negotiated a means to further develop the Centre’s effectively transferring novel technology and finalised by Circadian Technologies Perforin Project, the primary aim of which and know-how to the industrial sector, Ltd. (a licensee of Peter Mac) and is to develop novel therapeutic agents the Peter Mac Board reviewed and Peter Mac, with Healthscope Ltd., (a for treating a range of immune-based in some instances, refined a number pathology-based company) providing pathologies, including graft rejection of extant Centre policies relating to: for Healthscope to licence a diagnostic and graft vs host disease. Auckland “Commercialisation by a Separate technology covered by internationally UniServices is the Centre’s key research Company – Allocation and Apportionment filed patent applications, relating to the collaborator on this exciting project and of Equity”; the “Board Nominee to an further development of a diagnostic test is working closely with Peter Mac in Outside Organisation or Company”; for cancer of unknown primaries. The Sub- exploring its commercial potentialities. the “Intellectual Property Policy”; and, Licence is limited to certain territories and This collaboration will provide a conduit “Distribution of IP Income Guidelines”. A will be of particular value and importance in sourcing other co-investors with the new policy was also enacted: “Guidelines to the Centre’s continuing commercial objective of progressing the research to a for Publication by Peter Mac Staff and development of this technology. clinical trial stage. Students in Research Sponsorship and [See pg 27] Collaborations”. The refresh of these Jerry de la Harpe policies is an example of the Board’s

Peter MacCallum Cancer Centre – Research Report 2008 Intellectual Property & Commercialisation/ 161 2008 Publications and Patents/

1. Akiyama, T., C. R. Dass and P. F. Choong (2008). and BRCA2 mutation carriers.” American Journal of dendritic cells loaded with allogeneic tumour 36. Breast Cancer Family Registry, Kathleen 51. Coquet, J. M., S. Chakravarti, K. Kyparissoudis, 66. Davey, K., A. G. Heriot, J. Mackay, E. Drummond, “Novel therapeutic strategy for osteosarcoma of Human Genetics 82(4): 937-48. lysate to metastatic melanoma patients.” Journal Cuningham Foundation Consortium For Research F. W. McNab, L. A. Pitt, B. S. McKenzie, S. P. A. Hogg, S. Ngan, A. D. Milner and R. J. Hicks targeting osteoclast differentiation, bone- 10. Aranda, S. (2008). “Designing nursing of Immunotherapy 31(1): 101-12. Into Familial Breast Cancer and Ontario Cancer Berzins, M. J. Smyth and D. I. Godfrey (2008). (2008). “The impact of 18-fluorodeoxyglucose resorbing activity, and apoptosis pathway.” interventions.” Collegian 15(1): 19-25. 26. Bibby, J. R., S. M. Cotton, A. Perry and J. F. Corry Genetics Network (2008). “Smoking and risk of “Diverse cytokine production by NKT cell subsets positron emission tomography-computed Molecular Cancer Therapeutics 7(11): 3461-9. (2008). “Voice outcomes after radiotherapy breast cancer in carriers of mutations in BRCA1 and identification of an IL-17-producing CD4- tomography on the staging and management of 11. Arulogun, S., H. M. Prince, P. Gambell, S. Lade, or BRCA2 aged less than 50 years.” Breast NK1.1- NKT cell population.” Proceedings of the primary rectal cancer.” Diseases of the Colon and 2. Anagnostopoulos, T., M. Pertesi, I. G. Ryan, E. Eaton and C. McCormack (2008). treatment for early glottic cancer: Assessment Konstantopoulou, S. Armaou, S. Kamakari, using multidimensional tools.” Head and Neck Cancer Research and Treatment 109(1): 67-75 National Academy of Sciences U S A 105(32): Rectum 51(7): 997-1003. “Extracorporeal photopheresis for the treatment 11287-92. G. Nasioulas, A. Athanasiou, A. Dobrovic, M. of Sezary syndrome using a novel treatment 30(5): 600-10. 37. Brumby, A. M. and H. E. Richardson (2008). 67. Davis, H., F. Vetere, S. Ashkanasy, G. Dyson, A. Young, D. Goldgar, G. Fountzilas and D. protocol.” Journal of the American Academy of 27. Bishton, M. J., R. J. Hicks, H. M. Prince, D. Modelling cancer in Drosophila. Encyclopedia of 52. Coquet, J. M., S. Chakravarti, M. J. Smyth and P. Schofield, K. Thompson, G. Withers and D. Yannoukakos (2008). “G1738R is a BRCA1 Dermatology 59(4): 589-95. S. Ritchie, M. Wolf and J. F. Seymour (2008). Life Sciences. Winchester, John Wiley & Sons Ltd. D. I. Godfrey (2008). “Cutting edge: IL-21 is not Thomas (2008). Towards social connection for founder mutation in Greek breast/ovarian cancer “Claimed association of absolute lymphocyte 38. Campbell, I. G., W. Qiu, K. Polyak and I. Haviv essential for Th17 differentiation or experimental young people with cancer. OZCHI Proceedings of patients: evaluation of its pathogenicity and 12. Arulogun, S. O., H. M. Prince, J. Ng, S. Lade, G. autoimmune encephalomyelitis.” Journal of the 20th Australasian Conference on Computer- F. Ryan, O. Blewitt and C. McCormack (2008). count with therapeutic efficacy of radio- (2008). “Breast-cancer stromal cells with inferences on its genealogical history.” Breast immunotherapy in patients with indolent TP53 mutations.” The New England Journal of Immunology 180(11): 7097-101. Human Interaction: Designing for Habitus and Cancer Research and Treatment 110(2): 377-385 “Long-term outcomes of patients with advanced- Habitat Carins, Australia 287: 319-322. stage cutaneous T-cell lymphoma and large cell lymphoma cannot be verified in an independent Medicine 358(15): 1634-5; author reply 1636. 53. Corry, J., L. Peters, R. Fisher, A. Macann, M. 3. Andrew, K. A., H. M. Simkins, S. Witzel, R. Perret, transformation.” Blood 112(8): 3082-7. data set.” Leukemia 22(12): 2259-60; author reply 39. Candiloro, I. L., T. Mikeska, P. Hokland and Jackson, B. McClure and D. Rischin (2008). 68. Dawson, S. J., N. M. Conus, G. C. Toner, J. M. J. Hudson, I. F. Hermans, D. S. Ritchie, J. Yang 2260-1. A. Dobrovic (2008). “Rapid analysis of “N2-N3 neck nodal control without planned Raleigh, R. J. Hicks, G. McArthur and D. Rischin and F. Ronchese (2008). “Dendritic cells treated 13. Ashley, D. M., C. D. Riffkin, M. M. Lovric, T. neck dissection for clinical/radiologic complete (2008). “Sustained clinical responses to tyrosine Mikeska, A. Dobrovic, J. A. Maxwell, H. S. 28. Bishton, M. J., R. J. Hicks, D. A. Westerman, heterogeneously methylated DNA using digital with lipopolysaccharide up-regulate serine M. H. Prince, M. Wolf and J. F. Seymour (2008). methylation-sensitive high resolution melting: responders-Results of Trans Tasman Radiation kinase inhibitor sunitinib in thyroid carcinoma.” protease inhibitor 6 and remain sensitive to killing Friedman, K. J. Drummond, A. H. Kaye, H. K. Oncology Group Study 98.02.” Head and Neck Anticancer Drugs 19(5): 547-52. Gan, T. G. Johns and C. J. Hawkins (2008). “In “A prospective study of the separate predictive application to the CDKN2B (p15) gene.” by cytotoxic T lymphocytes in vivo.” Journal of capabilities of 18[F]-FDG-PET and molecular Epigenetics Chromatin 1(1): 7. 30(6): 737-42. 69. Dawson, S. J., M. A. Price, M. A. Jenkins, J. M. Immunology 181(12): 8356-8362. vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or response in patients with relapsed indolent 40. Carney, D. (2008). “Peripheral blood 54. Corry, J., W. Poon, N. McPhee, A. D. Milner, McKinley, P. N. Butow, S. A. McLachlan, G. J. 4. Andrews, D. M., C. E. Andoniou, P. Fleming, M. chemotherapy drugs.” British Journal of Cancer non-Hodgkin’s lymphoma following treatment lymphocytosis--what is the threshold for further D. Cruickshank, S. V. Porceddu, D. Rischin Lindeman, P. Weideman, M. L. Friedlander, J. J. Smyth and M. A. 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Peter MacCallum Cancer Centre – Research Report 2008 2008 Publications and Patents/ 169 2008 Publications and Patents/

“Demonstration of inflammation-induced cancer of serous and endometrioid ovarian cancer linked period.” Anaesthesia and Intensive Care 36(3): 332. Wojdacz, T. K., A. Dobrovic and L. L. Hansen “Gene expression analysis in absence epilepsy and cancer immunoediting during primary to clinical outcome.” Clinical Cancer Research 308-23. (2008). “Methylation-sensitive high-resolution using a monozygotic twin design.” Epilepsia tumourigenesis.” Proceedings of the National 14(16): 5198-208. 321. Westerman, D. and S. Juneja (2008). “Re: melting.” Nature Protocols 3(12): 1903-8. 49(9):1546-54. Academy of Sciences U S A 105(2): 652-6. 308. Trapani, J. A. and P. I. Bird (2008). “A renaissance Essential thrombocythemia in young individuals: 333. Wojdacz, T. K., L. L. Hansen and A. Dobrovic 345. LaMontagne, A. D., C. E. Hunter, D. Vallance, A. 295. Takano, E. A., G. Mitchell, S. B. Fox and A. in understanding the multiple and diverse frequency and risk factors for vascular events and (2008). “A new approach to primer design for the J. Holloway (2008). Asbestos disease in Australia: Dobrovic (2008). “Rapid detection of carriers functions of granzymes?” Immunity 29(5): 665-7. evolution to myelofibrosis in 126 patients. Alvarez- control of PCR bias in methylation studies.” BMC looking forward and looking back. New Solutions with BRCA1 and BRCA2 mutations using high 309. Tremblay, A., L. Sheeran and S. K. Aranda (2008). Larran A et al.” Leukemia 22(4): 864-5; author Research Notes 1: doi: 10.1186/1756-0500-1-54 18(3):361-73. resolution melting analysis.” BMC Cancer 8: 59. “Psychoeducational interventions to alleviate hot reply 865-7. (3 pages). 346. Buck DP, P. M. Abeysinghe, C. Cullinane, A. I. Day, 296. Takeda, K., Y. Kojima, K. Ikejima, K. Harada, S. flashes: a systematic review.” Menopause 15(1): 322. Westwood, J. A., W. K. Murray, M. Trivett, A. Shin, 334. Wong, E. M., A. A. Tesoriero, G. M. Pupo, J. G. Collins, M. M. Harding (2008). “Inclusion Yamashina, K. Okumura, T. Aoyama, S. Frese, 193-202. P. Neeson, D. P. MacGregor, N. M. Haynes, J. kConFab, ABCFS, M. R. McCredie, G. G. Giles, complexes of the antitumour metallocenes Cp(2) H. Ikeda, N. M. Haynes, E. Cretney, H. Yagita, 310. Troke, P., K. Aguirrebengoa, C. Arteaga, D. Ellis, A. Trapani, P. Mayura-Guru, S. Fox, S. Peinert, J. L. Hopper, G. J. Mann, D. E. Goldgar and M. MCl(2) (M = Mo, Ti) with cucurbit[n]urils.” Dalton N. Sueyoshi, N. Sato, Y. Nakanuma and M. J. C. H. Heath, I. Lutsar, M. Rovira, Q. Nguyen, D. Honemann, H. M. Prince, D. Ritchie, A. M. C. Southey (2008). “Is MSH2 a breast cancer Transactions 7(17):2328-34. Smyth (2008). “Death receptor 5 mediated- Scott, F. E. Smyth, M. J. Smyth, P. K. Darcy and susceptibility gene?” Familial Cancer 7(2): 151-5. M. Slavin and S. C. Chen (2008). “Treatment kConFab - Kathleen Cuningham apoptosis contributes to cholestatic liver of Scedosporiosis with Voriconazole: Clinical M. H. Kershaw (2008). “Absence of retroviral 335. Worth, L. J., J. Black, J. F. Seymour, K. A. disease.” Proceedings of the National Academy Experience with 107 Patients.” Antimicrobial vector-mediated transformation of gene-modified Thursky and M. A. Slavin (2008). “Surveillance Foundation Consortium for Research into of Sciences U S A 105(31): 10895-900. Agents and Chemotherapy 52(5): 1743-50. T cells after long-term engraftment in mice.” Gene for catheter-associated bloodstream infection in Familial Breast Cancer 297. Tam, C. S. and J. F. Seymour (2008). Therapy 15(14): 1056-66. hematology units: quantifying the characteristics 311. Turner, M. L., E. D. Hawkins and P. D. Hodgkin AOCS - Australian Ovarian Cancer Study “Fludarabine.” Encyclopedia of Cancer (2nd (2008). “Quantitative regulation of B cell 323. Wilanowski, T., J. Caddy, S. B. Ting, N. R. Hislop, of a practical case definition.” Infection Control edition). M. Schwab. Berlin, Springer-Verlag: division destiny by signal strength.” Journal of L. Cerruti, A. Auden, L. L. Zhao, S. Asquith, S. and Hospital Epidemiology 29(4): 358-60. Group 1137-39. Immunology 181(1): 374-82. Ellis, R. Sinclair, J. M. Cunningham and S. M. 336. Worth, L. J., J. Black and M. A. Slavin (2008). Jane (2008). “Perturbed desmosomal cadherin 298. Tan, A. Y., D. A. Westerman, D. A. Carney, J. F. 312. Vali, M., J. A. Vossen, M. Buijs, J. M. Engles, E. “Reply to Graham and Olver.” Infection Control Seymour, S. Juneja and A. Dobrovic (2008). expression in grainy head-like 1-null mice.” The and Hospital Epidemiology 29(10): 986-7. Liapi, V. P. Ventura, A. Khwaja, O. Acha-Ngwodo, EMBO Journal 27(6): 886-97. “Detection of NPM1 exon 12 mutations and FLT3 G. Shanmugasundaram, L. Syed, R. L. Wahl 337. Worth, L. J., C. C. Blyth, D. L. Booth, D. 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