Annual Report 2010 Coordinating Editor Kirsty Brunsden
Design and production Sue Dyer Design
Photos and figures Centre staff and Mark Fitz-Gerald
We gratefully acknowledge the support and valuable contribution to this publication of Heddy Zola, Anna Nitschke, Mark Goldsmith and Frank Stomski Contents
2 SA Pathology Executive Director’s Report 4 Centre for Cancer Biology Co-Directors’ Report
Laboratories 6 Acute Leukaemia Laboratory 8 Cell Growth and Differentiation Laboratory 10 Cell Signalling Laboratory 12 Cytokine Receptor Laboratory 14 Cytokine Research Laboratory 16 Haematology Clinical Research Unit 18 Hepatitis C Virus Research Laboratory 20 Leukaemia Biology Group 22 Leukaemia Unit 24 Lymphatic Development Laboratory 26 Mast Cell Laboratory 28 Melissa White Memorial Laboratory – Clinical and Research 30 Molecular Pathology Research Laboratory 32 Molecular Regulation Laboratory 34 Molecular Signalling Laboratory 36 Myeloma Research Laboratory 38 Vascular Biology and Cell Trafficking Laboratory
40 Publications 48 Major Awards 49 Research Staff and Students 51 Seminar Program 55 Invited Presentations 58 Grants and Fellowships Awarded 61 Financial Highlights 62 Organisational Chart 63 Our Supporters 64 How you can Support our World Class Research
1 centre for cancer biology annual report 2010 sa pathology Executive Director’s Report
Professor Ruth Salom THESE ARE genuinely exciting This is of great benefit to Executive Director SA Pathology times, as we move away from our South Australian patients conventional methods and and we know that they towards more targeted, appreciate this unique mix. cancer personalised and effective This vital interface must be is a leading cause of death and it is estimated treatments. But amidst all of continually strengthened that one in every two Australians will be diagnosed this progress and the tangible as we move forward and with cancer by the age of 85. Encouragingly however, improvements that I’m delighted that the increasingly benefit cancer Centre for Cancer Biology new research is leading to more effective patients, we need to remind has kept this very much in diagnostics, procedures and treatments, which have ourselves that there is a long mind when conducting its road ahead. For training program to prepare seen the survival rate for many common cancers breakthroughs to occur, we our scientific and medical increase by 30 per cent in the past two decades. need to galvanise the colleagues of the future. significant commitment of our cancer researchers in an I congratulate our environment that nurtures co-Directors Professor their capacity and their Angel Lopez and Professor interactions. We have been Sharad Kumar for their work very conscious of the power in leading the Centre, and of this formula since for both receiving significant establishing the Centre for recognition for their valuable Cancer Biology two years ago. contributions to research.
The Centre for Cancer Professor Angel Lopez Biology performs its research shared the highly-coveted within SA Pathology (which 2010 South Australian Scientist trades as IMVS Pathology), of the Year title in the annual alongside professional South Australian Science colleagues that provide quality Excellence Awards, and clinical diagnostic pathology received a 2010 South services. This dual activity of Australian of the Year award in SA Pathology is highly the Science category. conducive to excellence in both areas. On the one hand, For almost 25 years, Professor researchers benefit from easy Lopez’s research has focused access to well studied and on cytokines that regulate documented patient samples blood cell production and through our highly regarded function. The South Australian tissue bank collection and Scientist of the Year award pathology expertise. On the recognised many seminal other hand, the very cutting discoveries of Professor Lopez edge cancer research that is that have led to the better conducted next door provides understanding of the our pathologists with new functioning of cytokines and insights into cancer cytokine receptor networks in progression and therapies normal physiology and in well before they reach the diseases such as leukaemia medical press. and asthma.
2 centre for cancer biology annual report 2010 Opening of the Centre for Cancer Biology on April 16th 2009 by Professor Ian Frazer, inventor of the cervical cancer Professor Angel Lopez accepting the $3.5 million grant vaccine, and SA Health Minister John Hill from the ACRF to establish the South Australian Cancer Genome Facility
Professor Sharad Kumar won its long term commitment to “For breakthroughs to occur, we need to the prestigious Ranbaxy cancer research by substantial Research Award 2009 in financial support through galvanise the significant commitment of our Medical Sciences for his surpluses generated from cancer researchers in an environment that seminal contributions to the private pathology patient understanding of fees. The Centre for Cancer nurtures their capacity and their programmed cell death and Biology also had a strong year interactions”. the regulation of the protein in funding, winning many function by ubiquitination. personal fellowships and His group also made key attracting significant funding better patient outcomes. I extend my sincere thanks contributions to the from the NHMRC. The field of personalised and appreciation to the heads fundamental understanding medicine is certain to expand of each laboratory and the of developmental cell death, As is detailed in the rapidly in the near future as dedicated staff striving for caspase function and cancer Co-Directors’ Report, in we increasingly understand research excellence and biology. The work from his conjunction with researchers the way specific genes work better cancer patient care. laboratory on the Nedd4 from the University of with medicines. We are proud Above all, the story of the family of ubiquitin ligases and Adelaide, the Centre for to be at the forefront of this Centre for Cancer Biology apoptosis has led to many Cancer Biology successfully genetic research into is one of endurance, seminal discoveries impacting won a bid to establish the gastrointestinal, colon, expectation and hope for on the understanding of South Australian Cancer prostate, breast, ovarian, the cure of cancer. I, like the human diseases. Genomics Facility, and was neuronal and haematological researchers of the Centre, awarded $3.5 million by the malignancies. remain fully committed to During 2010, Professor Kumar Australian Cancer Research continue building on our was also awarded the highest Foundation, $1.05 million The success in winning achievements as one of level of National Health and from the South Australian financial support for the Australia’s leading cancer Medical Research Council Government and $525,000 South Australian Cancer research organisations. (NHMRC) Research from Cancer Council SA. Genomics Facility gives me Fellowship. These highly great pleasure for the added sought after fellowships This is the first time South reason that whilst medical provide the opportunity for Australia will have a facility research is a very competitive outstanding biomedical and of this capacity, with activity, we have demonstrated health researchers with equipment that can perform our awareness of the need proven track records that sophisticated analysis and a and benefits of meaningful place them in the top 5-10% team of senior scientists to collaborations. I am grateful of their fields, to perform analyse and apply findings. to the University of Adelaide, full-time research of major It will facilitate discovery and Flinders University and the importance in the medical innovation by our researchers University of South Australia and health arena. and help their translational in supporting our bid, and to efforts in developing better our Royal Adelaide Hospital As a non-profit organisation, diagnostics and more effective colleagues for their all of the work of the Centre anti-cancer drugs. enthusiastic participation. for Cancer Biology is funded Their collegiality and belief through internal support It is our hope that the in the greater good augur very from SA Pathology (trading research outcomes from the well for the successful future as IMVS Pathology) as well Cancer Genomics Facility will utilisation of this Facility. as grants and donations. contribute to the eventual SA Pathology, the South reality of personalised Australian Government’s medicine with fewer pathology service, has shown long-term side effects and
3 centre for cancer biology annual report 2010 centre for cancer biology Co-Directors’ Report
what is the centre for cancer biology about?
Professor Sharad Kumar Professor Angel Lopez THE CENTRE studies basic Similarly, fundamental studies Co-Director Co-Director mechanisms of cancer and into metastases, a major cause Centre for Cancer Biology Centre for Cancer Biology carries out translational of death in many cancers, by clinical research. Our six Associate Professor Gregory it has been major fundamental research Goodall and Dr Yeesim Khew- two years since the launch of the themes include stem cells, Goodall (published in Nature Centre for Cancer Biology. The vision to bring programmed cell death or Cell Biology), are revealing the together some of the best South Australian cancer apoptosis, metastasis, cancer molecular basis of the immunology, tumour epithelial-mesenchymal researchers under a single umbrella and governance, vascularisation, and cell transition. Thirdly, we aim to materialised into the formation of the Centre for signalling. These themes rapidly translate our encompass critical processes fundamental discoveries into Cancer Biology. In this, our inaugural Annual that affect the vast majority better clinical practice. Report, we would like to pay tribute to Professor of cancers irrespective of the Although this can take many Ruth Salom, Executive Director of SA Pathology, organ of origin. On the years, recent advances by translational front, our clinical Professor Timothy Hughes Professor Heddy Zola, and Health Minister John Hill, research focusses largely on and Associate Professor for their enthusiastic support, and to Professor leukaemia, lymphoma and Deborah White are already Ian Frazer, 2006 Australian of the Year, and a creator myeloma. improving the lives of patients with chronic myeloid of the HPV vaccine against cancer, who officially We are strong believers in leukaemia by understanding opened the Centre on April 16th 2009. They share innovation, and of the need drug resistance and with us the dream and the promise of the Centre for for fundamental discoveries to optimising their treatment fuel new ideas to alleviate options. Cancer Biology. human suffering. It is the understanding of basic and fundamental biological processes that plants the seeds of breakthroughs, with their translation ultimately leading to better cancer patient management. Secondly, we think that studying common denominators in cancer gives us a tremendous opportunity to impact on several cancers at once. For example, our studies on stem cells of endothelial, neuronal, lymphatic, mesenchymal, and hemopoietic origin are showing us the key requisites for normal stem cell behaviour and how this is subverted in cancer stem cells. This is critical information as we are targeting the cancer stem cell for long-lasting therapies.
4 centre for cancer biology annual report 2010 Left: Professor Angel Lopez being co-awarded South Australian Scientist of the Year in the 2010 South Australian Science Excellence Awards
Right: Professor Sharad Kumar receiving the Ranbaxy Research Award 2009 in Medical Sciences
how can we monitor how well the centre for cancer biology is doing?
SOME OF THE best key In setting up the Centre for Similarly, Dr Quenten Schwarz supplemented by generous performance indicators are Cancer Biology, we recognised recently arrived from grants from the SA the number of scientific that a key ingredient that University College, London, Government, and the Cancer manuscripts we publish and drives innovation is a critical and his hard work has already Council of SA. This will allow where we publish. The mass of highly motivated been rewarded with several us for the first time to study prestige and breadth of researchers working closely grants and also an NHMRC genetic changes in patients readership of the international together and aided by Career Development that contribute to their scientific journals is often state-of-the-art infrastructure. Fellowship. We recognise the cancer and their response measured as Impact Factor We have been very fortunate support of Professor Salom in to cancer drugs. We hope to (IF). We are very pleased to in the last two years with facilitating this recruitment. not only understand how say that the Centre for Cancer successes in grant funding We look forward to the some cancers arise and Biology has published that allowed us to grow, but imminent arrival of Dr progress but also bring closer approximately 200 manuscripts more so in recruiting highly Michael Samuel from the to reality the concept of in the last two years and a talented and energetic young Beatson Institute to energise personalised medicine. We great number have been in researchers. Dr Michele our studies on signal look forward to this new journals of high impact factor. Grimbaldeston’s arrival from transduction and skin cancer Facility to open and be fully For example, over 62% of our Professor Steven Galli’s Lab development. The ten operational by the end of manuscripts were published in at Stanford University to set Fellowships gained in 2009- this year. journals with an impact factor up her Mast Cell Laboratory 2010, several operationally- of >5, over 17% of articles were invigorated the Centre for funded scientists and the SA One of the most pleasing published in journals of Cancer Biology, and her three Pathology infrastructure are recent developments in the impact factor of >10, and 2.5% National Health and Medical underpinning our research Centre has been the strong in journals of impact factor of Research Council of Australia effort. This powerful mix has influx of students. These are more than 22. This indicates (NHMRC) grants and an provided strong leverage for the next generation of that the Centre for Cancer NHMRC Career Development attracting grants and funding scientists and medical doctors, Biology ranks among the top Fellowship attest to her from the NHMRC, the and our future colleagues. research organisations calibre. biotechnology sector, and We are very proud of our nationally. from several charitable strong postgraduate program foundations. in association with the three South Australian universities, As with every professional and are pleased with the scientific journal impact factor biomedical research number and level of
30 organisation, new technology scholarships obtained from and state-of-the-art many organisations. infrastructure are required to 25 make significant advances. We are confident that in its We are very pleased to report third year, the Centre for 20 that in the last two years the Cancer Biology will continue Centre for Cancer Biology to produce exciting new 15 has won major competitive discoveries through constant infrastructure funds. Of note striving for scientific is the support of $3.5 million excellence, further promoting 10 we received (in conjunction collaborative interactions
number of publications with the University of among our scientists, and 5 Adelaide researchers) from exploiting the opportunities the Australian Cancer that arise from new 0 Research Foundation to technological developments, set up the South Australian such as our new Cancer 0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-10 10-1111-1212-1313-14 14-1515-1616-1717-1818-19 =or>19 Cancer Genomic Facility, Genomics Facility.
5 centre for cancer biology annual report 2010 Acute Leukaemia Laboratory Associate Professor Richard D’Andrea PhD Dr Ian Lewis MBBS, PhD, FRACP, FRCPA
aberrant cytokine receptor signalling occurs frequently in myeloproliferative neoplasms (MPN) key discoveries in 2009-2010 and acute myeloid leukaemia (AML), and modes of gm-csf receptor JAK2 and SFK, and acting identification of key downstream events provides an signalling synergistically in the mature approach for the development of targeted therapies GM-CSF promotes growth, liganded receptor complex. with reduced toxicity (Perugini et al, Leukemia 2009). survival, differentiation and a novel determinant of activation of normal myeloid response in aml MPN occurs as a result of We are also utilising cells, and plays an important role changes acquired in the molecular and proteomic in myeloid leukaemias. The GM- In 2009 (Leukemia 23: 729-738, haemopoietic stem cell approaches to identify factors CSF receptor (GMR) shares a 2009), we identified the stress- compartment, which induce that contribute to the β induced tumour suppressor gene aberrant growth factor therapeutic response and signalling subunit, c, with IL-3 and IL-5 receptors, and has Growth Arrest and DNA Damage responses and over- relapsed disease in AML inducible 45α (GADD45A) as a production of mature myeloid (Powell et al, Blood 2009 and recently been shown to act via down-regulated gene in AML, and erythroid cells. Kok et al, Leukemia 2010). formation of a unique and showed that silencing of Through molecular and dodecameric receptor complex. GADD45A contributes to the Our major focus is to genetic cohort studies of We have used two activated βc understand the mechanisms patients with MPN, we aim to mutants that display distinct growth, survival and blocked underlying normal blood cell understand the nature of the signalling capacity and have a differentiation typical of AML growth and differentiation, changes that are associated differential requirement for the cells. Recently, we discovered and the changes associated with disease initiation, long- specific GM-CSF receptor α- that GADD45A is associated with with the initiation and term maintenance of disease, subunit (GMRα), to dissect the promoter hyper-methylation progression of leukaemia. and disease progression in and silencing in a significant We are using novel systems these patients (see Butcher signalling pathways associated with GM-CSF response. proportion of patient AML to dissect signalling pathways et al, BJH in press). samples. that control cytokine-induced In a recent paper (Blood 115: cell survival, proliferation, Finally, we are investigating 3346-3353, 2010), we relate the Analysis of clinical outcome data differentiation and self- new approaches to monitor non-overlapping nature of shows that hyper-methylation renewal (Perugini et al, Blood disease and classify AML signalling by these two activated in the proximal promoter of 2010). patients using novel markers mutants to the structure of the GADD45A defines a sub-class of and bioassays (Patil et al, Bone unique GM-CSF receptor complex, Marrow Transplant 2010 and AML (>30% of patients) with and propose alternative modes Al Mawali et al, AM J Clin a particularly poor outcome Pathol 2009). of receptor activation, despite intensive chemotherapy. differentially dependent on Importantly, we show that in
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1 Ian Lewis 6 Nick Li 2 Diana Salerno 7 Teresa Sadras 3 Sonya Diakiw 8 Michelle Perugini 4 Richard D’Andrea 9 Grant Engler normal karyotype AML (NK-AML) approach, we have discovered 5 Anna Brown this is predictive of outcome, a small molecule that shows independent of other key selective toxicity in MLL- prognostic mutations such as leukaemia and kills leukaemia those in FLT3. Our analysis of a stem cells in vitro while sparing small transplant cohort suggests normal stem cells. that AML patients with this methylation mark respond poorly Whilst the precise mechanism to haemopoietic stem cell of action in MLL-LSCs remains to transplantation (HSCT), be determined, our data suggests therefore, we hypothesise that that targeting mitochondrial GADD45A hypermethylation metabolic function and the confers chemo-resistance in LSC amino acid deprivation response and is associated with high risk may be particularly effective in of relapse in AML patients. this AML subtype, which is associated with a poor prognosis treatment of aml with mll on standard chemotherapy. translocations MLL is an epigenetic modulator located on 11q23 that when fused to binding partners has the Outcomes for the community unique ability to confer stem cell >> Haemopoietic stem cell transplantation is an important renewal properties to committed salvage option for some leukaemic patients, however, progenitors. A recent body of it is associated with a few problems. Our new data on work suggests there are intrinsic the GADD45A gene helps subclassify some leukaemias differences between MLL- leukaemic stem cells and normal and define patients that may or may not benefit from haematopoietic stem cells that transplantation. This work impacts on cancer can be therapeutically exploited. classification and treatment and is important for To this end, using a novel in silico leukaemic patients for whom selection of treatment bioinformatic drug screening options is critical.
7 centre for cancer biology annual report 2010 Cell Growth and Differentiation Laboratory Dr Mark Guthridge PhD cells in the body are able to accomplish an impressive range of functions within their lifetime. Underlying this diversity in cellular functions are a number of fundamental responses that include cell survival, cell proliferation (growth) and cell differentiation (commitment to a more mature cell identity).
Growth factors and cytokines phosphorylation of growth are central regulators of these factor receptors, such as the key discoveries in 2009-2010 cellular responses through granulocyte macrophage their ability to bind and colony stimulating factor activate specific cell surface (GM-CSF) receptor and 1 2 receptors. fibroblast growth factor Using innovative proteomic We have also shown that novel receptor. These site-specific approaches for the analysis of phosphoserine docking sites in The overall focus of the Cell serine phosphorylation events site-specific tyrosine the cytoplasmic tails of growth Growth and Differentiation allow the activated receptors phosphorylation sites, we have factor and cytokine receptors can Laboratory lies in to couple to specific shown that in addition to their act as ’oncogenic scaffolds‘ to understanding the intracellular signalling fundamental molecular pathways and control cell well known properties of binding deregulate cell survival programs mechanisms by which growth survival, proliferation and phosphoserine/threonine motifs, in cancer. In the case of the factors and cytokines regulate differentiation. the 14-3-3 proteins are also GM-CSF and IL-3 receptors, specific cell functions and phosphorylated on Tyr179, Ser585 acts as an oncogenic what goes wrong in the This work challenges the allowing them to directly couple scaffold to recruit PI3K signalling regulation of these well-established paradigm that with phosphotyrosine signalling complexes and promote mechanisms in pathologies growth factor and cytokine pathways. We have shown that deregulated cell survival in acute such as inflammatory receptors initiate and regulate 14-3-3ζ is tyrosine myeloid leukaemia (AML). disorders, developmental intracellular signalling and phosphorylated, and functions disorders and cancer. cellular responses primarily We have performed a global as an intermolecular bridge that via receptor tyrosine expression screen to identify simultaneously binds We have identified a new phosphorylation and shows gene targets of the Ser585 ‘switch mechanism’ by which that diverse growth factor phosphoserine residues and the survival pathway, and have growth factors are able to receptors also utilise novel SH2 domain of Shc via Tyr179. identified a unique control cell survival, phosphoserine docking sites We have shown for the first time transcriptional program enriched ζ proliferation and for the regulation of that the dual ability of 14-3-3 for PI3K targets. We showed differentiation. This pleiotropic biological to transduce signals via both that one Ser585-regulated gene, mechanism involves site- responses. phosphoserine/threonine and osteopontin (OPN), promotes the specific serine phosphotyrosine is essential for autonomous survival of AML the assembly of a PI 3-kinase stem and progenitor cells. signalling complex and cell Importantly, we have also shown survival (Barry et al, J Biol Chem that increased expression of OPN 284: 12080-12090, 2009). in patients at diagnosis is significantly associated with poor
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1 Yang Kong 5 Hui Lim 2 Nhan Truong 6 Jason Powell 3 Mark Guthridge 7 Emma Barry 4 Daniel Thomas 8 Ana Lonic prognosis and decreased overall benefit, and overcome drug patient survival. Thus, OPN resistance in CML (Hiwase et al, represents both a potential Leukemia 24: 771-778, 2010). therapeutic target and 4 prognostic factor in AML (Powell et al, Blood 114: 4859-4870, In collaboration with Dr Nikki 2009). Verrills (University of 3 Newcastle) we have shown that targeting serine-threonine In collaboration with Professor phosphatases may have clinical Tim Hughes (Melissa White benefits in the treatment of AML. Memorial Laboratory–Clinical), In particular, we have been able we have also found that the to show that the novel activator Ser585 survival pathway is of the PP2A phosphatase, constitutively activated in >70% FTY720, is able to induce Outcomes for the community of primary human CML samples. apoptosis in primary human >> In fact, we have shown that such AML cells that are refractory Cancer remains one of the most difficult diseases cytokine receptor-mediated to inhibition of tyrosine kinase to treat, with the human and economic cost of this pathways may provide a inhibitors. These findings suggest disease increasing substantially over the last mechanism by which CML cells that targeting PP2A, either in 3 decades. It is clear that continuous incremental can overcome inhibition of conjunction with conventional improvements in conventional therapies is not the Bcr-Abl by the tyrosine kinase therapeutics or in combination answer and that new approaches that target the inhibitors, imatinib or dasatinib. with tyrosine kinase inhibitors, molecular defects in cancer cells are required. Thus, our findings suggest that may provide improved clinical We have identified several new potential targeting oncogenic Bcr-Abl outcomes in AML (Roberts et al, therapeutic targets in cancer cells and our findings tyrosine kinase pathways with Cancer Research 70: 5438-5447, suggest that they may have clinical potential. imatinib or dasatinib in 2010). We hope that our discoveries will provide new combination with inhibitors of approaches and therapies for the diagnosis and cytokine-mediated survival treatment of cancer, thereby providing improved pathways may have therapeutic clinical outcomes in the future.
9 centre for cancer biology annual report 2010 Cell Signalling Laboratory Dr Yeesim Khew-Goodall PhD cells secrete factors that can act upon themselves or on other cells for normal maintenance or homeostasis.
Cancer cells, through Recent studies have shown MicroRNAs are relatively may be altered during cancer mutations, can have an that the cancer ‘secretome’ newly-discovered small non- progression to bring forth altered composition of can also prepare a metastatic coding RNAs. Recognition changes to the secreted factors, which can niche in secondary organs to of their roles in regulating microenvironment to facilitate act to alter their immediate facilitate their ability to cellular functions has metastasis. In ongoing microenvironment, turning embed in those organs. To increased enormously in the collaborations with the it from one that suppresses date however, little is known last few years. Using a cell Cytokine Research Laboratory cancer progression to one about the mechanism(s) by culture model of epithelial- and Peter MacCallum that supports metastasis and which the cellular secretome mesenchymal transition Research Institute in resistance to chemotherapy. is regulated or how this developed in our laboratory Melbourne, we have regulation might be altered in collaboration with the established mouse models to Of key interest to the Cell in cancer cells. Cytokine Research assess the roles of various Signalling Laboratory are the Laboratory, we previously proteins and microRNAs in interactions of the cancer cell We have shown that the discovered a family of metastasis. with its microenvironment protein tyrosine phosphatase microRNAS (the miR-200 and to understand how signals Pez, a protein that we have family) that are crucial In addition to our interest in that are normally generated studied for many years, inhibitors of epithelial cell breast cancer, the Cell to maintain homeostasis, give regulates TGFβ secretion. motility and invasiveness, Signalling Laboratory also rise to disease when In some cells, increased Pez thus making them crucial has an interest in identifying dysregulated. Our disease expression resulting in TGFβ regulators of metastasis. microRNAs that are altered model is breast cancer secretion can cause them to in scleroderma, a debilitating metastasis and our long term undergo an epithelial- Bolstered by our success with fibrotic disease with no cure. focus is to understand what mesenchymal transition, an this previous discovery, the Ongoing work will go towards turns a local and treatable early step deemed necessary Cell Signalling Laboratory establishing the role(s) these benign cancer cell into a for the dissemination of breast has embarked on a search microRNAs play in malignant cell capable of cancer cells. Recent highlights for other microRNAs whose establishment or progression spreading to multiple organs. include elucidation of new dysregulation may drive of scleroderma. In solid tumours, which make functions for the protein breast cancer metastasis. up ~80% of human cancers, tyrosine phosphatase Pez, To this end, we have also metastasis is the main cause whereby its expression in identified microRNAs that of death. breast cancer cells, in addition to its cell autonomous actions, may lead to alterations in the local microenvironment to promote or retard metastasis.
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1 Ana Lonic 5 Sam Dyer 2 Freya Gehling 6 Leila Belle key discoveries in 2009-2010 3 Lesley Crocker 7 Xiaochun Li 4 Yeesim Khew-Goodall 8 James Paltridge 1 3 We identified novel functions for We have also discovered a novel the protein tyrosine phosphatase signalling pathway for the Pez that would help us recruitment of neutrophils into understand the normal sites of inflammation (Williams physiological functions of this et al, J Immunol 185: 3057-3063, protein. Importantly, these 2010). findings could be a key to understanding how mutations in this protein, which have been identified in breast and colon cancers, may facilitate metastasis or oncogenesis. 2 Outcomes for the community We have identified a number of >> Solid tumours make up the majority of human cancers, microRNAs whose expression are and the progression to metastasis is the main cause altered upon transdifferentiaion of morbidity and mortality in these patients. of fibroblasts to myofibroblasts, Currently, there is little effective treatment for a process that has been shown metastatic diseases. In part, this is due to our lack to occur in the stroma of breast of understanding of the way metastatic cells spread, cancers, and thought to play survive and colonise secondary organs and become a role in enhancing metastasis resistant to standard chemotherapy. Our studies aim and chemoresistance. These to increase knowledge of these processes using microRNAs therefore have multiple strategies so that we may identify and open potential roles in altering the stroma of breast cancers to up avenues for new therapeutics to be developed. promote cancer progression.
11 centre for cancer biology annual report 2010 Cytokine Receptor Laboratory Professor Angel Lopez MBBS, PhD, FRCPA cytokine receptors present on the surface of hemopoietic cells are the conduit by which cells interact with the immediate microenvironment. Excessive stimulation of cytokine receptors, their abnormal expression or dysfunctional downstream signalling can lead to inflammatory diseases and cancer.
This laboratory seeks to functional significance of the ‘cell survival-only’ experiments in collaboration understand the mechanism of each site and develop new pathway, and on the kinases with Dr Michele cytokine receptor activation, tools and potential drugs to that associate to the receptor Grimbaldeston (Mast Cell in particular the GM-CSF, IL-3 interfere with receptor complexes in normal and Laboratory), are seeking to and IL-5 receptors, in health activation. leukaemic stem cells. We identify new signalling and disease. This will reveal believe that this may reveal molecules uniquely associated universal biological rules and An important aspect of our the molecular basis of with the mast cell IL-3 allow the development of new work is to link the structural dysregulation in leukaemia. receptor. drugs for unmet clinical needs insights gained above to In particular, the ‘survival- such as leukaemia, asthma specific receptor activation only‘ pathway may be critical As we obtain a detailed and arthritis. functional outcomes. For for the patient’s relapse seen understanding of cytokine example, we have previously in acute myeloid leukaemia receptor structure and how Our research program reported that the pleiotropic and in chronic myeloid they signal, we seek to use incorporates structural activities of the GM-CSF leukaemia, with the current this new knowledge to biology approaches (in receptor can be dissected to collaboration with Professor develop potential new collaboration with Professor the point where activation of Tim Hughes (Melissa White therapies for leukaemia and Michael Parker, St Vincent’s cell survival can be seen to be Memorial Laboratory – for chronic inflammatory Institute of Medical Research) distinct from other functions Clinical) already yielding conditions. In collaboration to elucidate the structure and such as proliferation (‘cell important insights. with Professor R Lock (Lowy function of the GM-CSF, IL-3 survival-only’ pathway). Our Institute, Sydney), J Dick and IL-5 receptors; and aim is now to molecularly Interestingly, a central (Canada Research Chair in functional and proteomics define the distinct functional component of these receptor Stem Cell Biology, Toronto) approaches to elucidate the signosomes downstream of the proximal signosomes, which and CSL Ltd, we are signalling mechanisms and GM-CSF and IL-3 receptors, control the balance of cell continuing to develop the functional consequences of and link their activation to survival versus death, is the IL-3 receptor α chain-specific cytokine receptor the different forms of cytokine scaffold protein 14-3-3, and MAb 7G3 towards use in engagement. receptor assembly revealed in collaboration with clinical trials. In collaboration by the crystal structures of the Dr Jo Woodcock and Associate with Professor Michael Parker, Our initial solving of the cytokine receptor complexes. Professor Stuart Pitson we are also screening for structure of the human (Molecular Signalling small inhibitory molecules GM-CSF receptor complexed We are continuing our Laboratory), we are studying based on the 3-D structure to GM-CSF (Cell 134: 496-507, collaboration with Dr Mark its regulation by lipids and of these cytokine receptors. 2008) has already revealed Guthridge (Cell Growth and cytokines. Whilst these Ultimately, we seek a new mode of cytokine Differentiation Laboratory), experiments have important collaborations with clinical receptor activation and new Associate Professor Richard implications in cancer, the colleagues and the specific receptor sites. Based D’Andrea (Acute Leukaemia fact that receptors such as pharmaceutical industry to on this new proprietary Laboratory), and Associate IL-3 are key regulators of mast develop new drugs that can information, approaches are Professor Paul Ekert (Walter cells suggests a likely role in change clinical practice. under way to understand the and Eliza Hall Institute) on allergic inflammation, and
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1 Bill Panagopoulos 6 Nicole Christie 2 Rebecca Krake 7 Barbara McClure key discoveries in 2009-2010 3 Hayley Ramshaw 8 Natasha Pyne 4 Angel Lopez 9 Anna Sapa high resolution solving of monoclonal antibody- 5 Tim Hercus 10 Frank Stomski the human gm-csf receptor α mediated targeting of cd123, chain; gm-csf complex il-3 receptor α chain, eliminates human acute In collaboration with Professor myeloid leukaemic stem cells Michael Parker, following our (lsc) earlier determination of the human GM-CSF dodecameric In collaboration with Professors complex, we have now solved the Richard Lock, John Dick and structure of the human GM-CSF CSL Ltd, we showed that the receptor α chain in complex with anti-interleukin-3 (IL-3) receptor GM-CSF to a resolution of 2.8Å α chain (CD123)-neutralising that reveals for the first time antibody (7G3) targeted AML- intimate contact points between LSCs, impairing homing to bone GM-CSF and its receptor α chain marrow and activating innate (Site 1). Interestingly, Site 1 is immunity in a mouse model (Cell survival, proliferation and differentiatian composed of domains 1 and 2 of Stem Cell 5: 31-42, 2009). 7G3 the cytokine receptor module, treatment profoundly reduced and unexpectedly also by its AML-LSC engraftment and Outcomes for the community N-terminal domain. Mutagenesis reduced AML burden in the >> analyses and molecular bone marrow and periphery, Cancer and inflammation affect the vast majority modelling have revealed a unique and impaired secondary of our community at a significant human cost. arrangement for Site 1 likely to transplantation upon treatment, There is also a growing economic burden in managing extend to other members of this establishing that AML-LSCs were these health problems. Our effort to understand the cytokine receptor family, and a directly targeted. These results basics of how cells behave in normal and disease significant contribution of the provide clear validation for circumstances is fundamental to devising new strategies N-terminal domain. therapeutic monoclonal antibody to ameliorate disease. We are very encouraged by the 7G3 targeting of AML-LSCs, and ongoing translation of this newly-gained knowledge for translation of in vivo into drug candidates that may provide longer-lasting preclinical research findings treatments with minimal side-effects. toward a clinical application.
13 centre for cancer biology annual report 2010 Cytokine Research Laboratory Associate Professor Greg Goodall PhD the majority of solid cancers (including most lung, breast, colon, prostate and liver cancers) arise from epithelial cells.
Most deaths from these Our current work focuses on cancers are due to the developing our understanding key discoveries in 2009-2010 transition of the cancer to an of how microRNAs control invasive form, a step that is EMT and examining their enforced expression of an autocrine tgf-β/zeb/mir- now widely recognised to consequences for cancer mir-200 can inhibit lung 200 signalling network involve a recapitulation of the progression. The project areas adenocarcinoma metastasis regulates establishment and developmental process known include: maintenance of epithelial- as epithelial to mesenchymal investigating the Our previous work identifying mesenchymal transition transition (EMT). mechanisms that regulate miR-200 as a controller of EMT expression of microRNAs raised the possibility that miR- Epithelial-mesenchymal This, along with the recent in EMT 200 may prevent EMT in cancer transition (EMT) is a form of discoveries that cancer stem identifying coordinated cells and thereby prevent the cellular plasticity that is critical cells have EMT-like features effects of microRNAs on initial steps in tumour for embryonic development and and that EMT typically EMT pathways, in confers resistance to metastasis. In collaboration with tumour metastasis. We previously particular, control of the chemotherapy, places studies Don Anson and Jonathan Kurie at discovered a double-negative actin cytoskeleton and cell on the mechanisms that the MD Anderson Cancer Center, feedback loop involving the miR- motility by miR-200 and determine EMT at the nexus using a mouse model in which 200 family and ZEB transcription coregulated microRNAs of investigations of the cause human lung adenocarcinoma factors, and postulated that this of cancer progression and discovering other EMT calls are engrafted into mice, controls the balance between pathways controlled by resistance. we found that the enforced epithelial and mesenchymal microRNAs expression of miR-200 does states. EMT is driven by coordinated identifying microRNAs indeed reduce metastasis. This changes in the expression of controlling the provides encouragement for the In collaboration with hundreds of structural and maintenance and long term prospect of using miR- Dr Yeesim Khew-Goodall and the regulatory proteins. These properties of cancer stem Cell Signalling Laboratory we changes are determined by 200 in a therapeutic mode to cells have now demonstrated, using integrated gene expression inhibit cancer metastasis. investigating the role of the epithelial MDCK cell line networks that themselves microRNAs in cancer cell model, that although involve numerous resistance to chemotherapy components. We have manipulation of the ZEB/miR-200 development of identified microRNAs that balance is able to repeatedly microRNA-derived play a central role in switch cells between epithelial diagnostic and therapeutic controlling and coordinating and mesenchymal states, the possibilities. the regulatory networks that induction and maintenance of a underlie EMT in cancer cells. stable mesenchymal phenotype
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1 Jo Attema 7 Anna Tsykin 2 Cameron Bracken 8 Daniel Thomson 3 Emily Paterson 9 Victoria Arnet 4 Matthew Anderson 10 Suraya Roslan requires the establishment of identification of widespread complementarity to miRNAs, 5 Jo Wright 11 Natasha Kolesnikoff 6 Greg Goodall 12 Andrew Bert autocrine TGF-β signalling to mirna-dependent and mirna- along with a deep sequencing drive sustained ZEB expression. independent endonucleolytic approach designed to directly
Furthermore, we found that cleavage of mrnas in identify sites of cleavage. > prolonged autocrine TGF-β mammals We identified numerous mRNAs > signalling induced reversible DNA The mechanisms through which that are targeted for cleavage methylation of the miR-200 loci microRNAs control gene by endogenous microRNAs, with corresponding changes in expression are of intense interest although at low level relative miR-200 levels. and incompletely resolved. It is to the mRNA abundance, and well established in plants that identified N4BP1 mRNA as an Collectively, these findings miRNAs frequently target mRNAs efficient target of cleavage by Outcomes for demonstrate the existence of for direct cleavage by the miR-151-5p. an autocrine TGF-β/ZEB/miR-200 the community Argonaute subunit of the RISC signalling network that regulates We also found numerous The majority of deaths from complex. However, it has been plasticity between epithelial and examples of non-miRNA-directed cancer are due to metastasis, an enigma that although mesenchymal states. We found cleavage, including cleavage the secondary tumours that arise mammals possess a functional a strong correlation between of a group of mRNAs within a from the progression of the Agonaute 2 and the capacity to ZEBs and TGF-β, and negative CA-repeat consensus sequence. primary tumour to an invasive directly cleave mRNA targets, correlations between miR-200 We also identified many stage. Our work has improved the as demonstrated by the versus TGF-β and between examples of adenylated small understanding of the molecular effectiveness of siRNA-mediated miR-200 versus ZEBs in invasive non-coding RNAs, including mechanisms that determine how knockdown in mammalian cells, ductal carcinomas, consistent microRNAs, tRNA processing metastasis occurs. This will there were almost no mRNAs with an autocrine intermediates and various other ultimately lead to identification identified as substrates for this TGF-β/ZEB/miR-200 signalling small RNAs, consistent with form of targeting. of molecules that are useful for network being active in breast adenylation being part of a diagnosing and treating cancer cancers. We performed a genome wide widespread proof-reading metastasis. Our work is having an assessment of miRNA cleavage and/or degradation pathway influence on cancer research for small RNAs. targets using bioinformatics to internationally, with one of our identify mRNAs that contain 2008 papers listed as being sequences with high among the 20 most cited papers on cancer published since 2008.
15 centre for cancer biology annual report 2010 Haematology Clinical Research Unit Professor L Bik To MBBS (HK), MD (Adel), MRCP (UK),PhD, FRACP, FRCPA Dr Ian Lewis MBBS, PhD, FRACP, FRCPA the Haematology Clinical Research Unit manages an active clinical trial program, which is based in the Royal Adelaide Hospital and is also linked to clinical trial units in the South Australian public hospital system.
This brings new treatment The Therapeutic Products This bank has been building During 2009 and 2010, the modalities to South Australia, Facility and the Central over many years and Haematology Clinical provides opportunities for Liquid Nitrogen Facility continues to grow. It is an Research Unit conducted collaborative research, and is (CLNF), maintained by the invaluable resource to basic 32 clinical trials. Key trials are a crucial factor for attraction Haematology Directorate of and clinical researchers alike, presented in the table, with and retention of staff. SA Pathology, are important permitting retrospective a full list available on the components of the Clinical studies of many disease states, Centre for Cancer Biology Another important function Research Unit. The and will ultimately lead to website. of the Unit is to maintain the Therapeutic Products Facility new discoveries and disease Leukaemia Myeloma Tumour is the only TGA certified cell treatments. Bank. Specimens are stored processing facility and is and the correlated clinical involved in mesenchymal cells The material stored in this information allows major and haemopoietic stem cell facility is largely irreplaceable, translational research studies processing for therapeutic and of immense value to to be carried out, with many use. current clinical practice and significant publications having furthering scientific and come out of this valuable The CLNF commenced clinical research endeavours resource. These include novel operations in November for future generations. gene targets and leukaemic 2006 to provide a centralised Currently, there are immuophenotypes in acute cryogenic facility service for approximately 180,000 myeloid leukaemia, genetic the SA Pathology campus. specimens in the collection, studies and therapeutic trials This cryogenic facility with a net increase of 13,300 in chronic myeloid leukaemia provides medium to long-term samples in 2009, and an and bone changes in chronic storage solutions to a large estimated 15,000 additional myeloid leukaemia and variety of users. samples added in 2010. multiple myeloma. Collections previously held in A significant use of the facility the Women’s and Children’s is the storage of specimens for Hospital Haematology the Haematology Biospecimen Department have also been Bank, involving several migrated into the collection. research groups within the Centre for Cancer Biology.
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1 Ian Lewis 6 Kylie Chaplin 11 Thanh Nguyen 2 Bik To 7 Meng Jun Zhu 12 Julia Hamilton 3 Lisa Carne 8 Peter Harrison 13 Andrew Vanlint key clinical trials 4 Bronwen Cox 9 Kerry Munro 14 Noemi Horvath 5 Venus Au 10 Monika Kutyna 15 Devendra Hiwase
principal drug 2009 investigator company
A Phase 1/2 Study of Oral SB1518 in Subjects with Chronic Idiopathic Myelofibrosis To, B S*BIO Pty Ltd
A Safety and Efficacy Trial Evaluating the Use of Apixaban for the Extended McRae, S BMS/Pfizer Treatment of Deep Vein Thrombosis and Pulmonary Embolism
A Phase II Study of Dasatinib Combined with Induction Chemotherapy in Previously Hughes, T Untreated de novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukaemia
principal drug 2010 investigator company
A Randomised Controlled Trial of Prophylactic Vs No-Prophylactic Platelet Bardy, P Transfusions in Patients with Haematological Malignancies
A Randomised Multicentre Study Comparing G-CSF Mobilized Peripheral Blood Lewis, I and G-CSF Stimulated Bone Marrow in Patients Undergoing Matched Sibling Transplantation for Haematologic Malignancies
Response Post Tyrosine Kinase Inhibitor: Assessment of Sensitivity and Therapeutic Hughes, T ALLG Response to Next-Line Therapy in CML: The Australasian RESIST Study
>> Outcomes for the community The active clinical trial program gives patients with haematological malignancies the opportunity to receive novel therapeutic agents which may not otherwise be available to them. The prospective storage of leukaemia and myeloma specimens is a valuable resource, which underpins a number of research projects that will have many benefits for the community.
17 centre for cancer biology annual report 2010 Hepatitis C Virus Research Laboratory Associate Professor Michael R Beard PhD there are over 170 million persons worldwide infected with the hepatitis C virus (HCV), which results in significant liver disease (fibrosis/cirrhosis) and cancer (hepatocellular carcinoma) in many of those infected.
In fact, infection with HCV is now the leading indication for key discoveries in 2009-2010 liver transplantation in many countries, including Australia. dynamic imaging of the hcv structures with lipid droplets and We are investigating the Current therapies do not work life-cycle Apo-E, suggesting that they may importance of this interaction to in all individuals and there is no vaccine. Using small (6-12 amino acid) be important in virion assembly the involvement of SR-BI in HCV genetically encoded tetracysteine and viral secretion. Through the entry. Beyond mapping domains HCV specifically infects liver peptide sequences that can be use of pharmacological inhibitors of each protein involved in this cells (hepatocytes) and the introduced into viral proteins and of cellular pathways and viral interaction, we have shown that main focus of our laboratory labeled by fluorescent dyes in protein function, we are now in knockdown of PDZK1 expression is to define the host response living cells, we are investigating a position to dissect the HCV and dominant-negative to infection with HCV using the traffic of HCV core protein life-cycle in real-time. inhibition of SR-B1/PDZK1 both laboratory-based models interaction results in inhibition (which forms the viral cellular factors involved and clinical samples. We also of HCV entry (Plos Pathogens 7: have a focus on developing nucleocapsid) and HCV NS5A in hcv entry 6-10, 2010). This work may models to study the HCV-host protein (which is a critical HCV enters the host hepatocytes therefore reveal SR-BI/PDZK1 interaction in live cells. regulator of both viral genome Through this approach we replication and viral particle by clathrin-dependent interaction as an attractive target hope to add to our assembly) during HCV particle endocytosis in a process that of therapeutic interference with understanding of how HCV assembly, maturation and involves a number of plasma HCV entry. causes disease, and identify membrane proteins. Of these, secretion. hcv replication activates novel therapeutics. CD81 (a tetraspanin), SR-B1 stat3 We have shown that NS5A exists (a high-density lipoprotein as two distinct populations; (1) receptor), claudin-1 (a tight- STAT3 is a transcription factor stationary structures and (2) fast junction protein) and occludin that is activated by a wide variety moving motile structures that are (a tight-junction protein) are of cytokines and exerts a diverse dependent on the microtubule critical entry factors. Studies range of biological responses. network for traffic. The challenge of SR-B1 function in mice have It is significantly activated in will now be to determine the indicated that its interaction many cancers including relative roles of these NS5A with a cytoplasmic adaptor hepatocellular carcinoma (HCC). structures in the HCV life-cycle. molecule, PDZK1, is necessary We have established in Interestingly, we have noted for its stability and activity at microarray studies that STAT3 is that there is dynamic interaction the plasma membrane of upregulated in HCV infected between the motile NS5A hepatocytes. hepatocytes, and demonstrated
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1 Edmund Tse 7 Michael Beard 2 Kate Muller 8 Julie Calvert 3 Sumudu Narayana 9 Kylie Van der Hoek 4 Karla Helbig 10 Gemma Sharp that STAT3 is activated (tyrosine biopsy material and cultured infection results in accelerated 5 Erin McCartney 11 Jill Carr 6 Guillaume Fiches 12 Nicholas Eyer 705) in the presence of cells stimulated with IFN, we liver disease, increased replicating HCV. Blocking STAT3 have identified hundreds of ISGs, propensity for HCC, and activation with the specific STAT3 many of which may have dominance of either one of the inhibitors AG490 and STA-21 unidentified antiviral and viruses. To investigate co- decreased HCV replication, while immunomodulatory activity infection in vitro, we infected > siRNA knockdown of STAT3 also (J Virol 83: 836-846, 2009). hepatocytes with both HBV and reduced HCV replication by HCV and showed that there was > approximately 50%. This suggests We have identified the ISG very little effect of each virus that HCV induces activation of Viperin and the IFITM family of on the other in regard to viral STAT3 to benefit viral replication ISGs to have anti-HCV activity. replication, with co-infected cells through an as yet unknown Viperin interacts with the HCV remaining viable. mechanism. This may have replication complex, specifically Outcomes for implications for the development interacting with the core and This work indicated that HBV and the community of HCC, as STAT3 is often NS5A proteins at the lipid droplet HCV can replicate in the same constitutively activated in HCC. interface, while the IFITM family hepatocyte without effect on Our work investigating the host of proteins interact with the HCV viral replication and cell viability, response to infection with HCV interferon stimulated genes cellular receptor CD81 to block and suggests that the effects has significant implications, as that control hcv HCV entry. The benefits of this noted in the co-infected liver a greater understanding of how Viral infection initiates a series research include the potential for are most likely a heightened the liver combats HCV infection of intracellular events that novel therapeutic strategies to immunological response in the is essential for the development culminate in the generation of help combat chronic HCV co-infected liver (J Hepatol 51: and implementation of new an antiviral state, directly within infection. 446-457, 2009). therapeutic strategies. the infected cell and indirectly interactions between hbv As an example, pinpointing the within the surrounding tissue, and hcv in vitro anti-HCV mechanisms of novel through the induction of host interferon stimulated Infection with hepatitis B virus interferon expression and genes will uncover novel (HBV) and HCV is not uncommon associated interferon stimulated therapeutic targets for the as transmission routes are genes (ISGs). Using microarray development of new therapies similar. In this scenario dual studies of HCV infected liver for chronic hepatitis C.
19 centre for cancer biology annual report 2010 Leukaemia Biology Group Professor Junia V. Melo MD, PhD, FRCPath cml is a paradigm of cancer of the haemopoietic system, in which cells that would normally develop into neutrophils, basophils, eosinophils, and monocytes become cancerous.
It was the first human disease Although a relatively rare It is timely to consider a The main focus of our to be associated with a malignancy, effective therapy change of mindset in patients, research is to understand consistent molecular has dramatically changed its carers and healthcare workers how the mutant gene Bcr-Abl abnormality, the Bcr-Abl prevalence. In fact, for an to allow patients to return to a is regulated, so that we can fusion protein, a constitutively increasingly large population normal place in society. This build a way to switch it off. activated tyrosine kinase that of patients, CML has become brings a new focus on ‘living In this early stage of the is produced as a consequence a chronic illness, like with CML’ and on finding the investigation, we are looking of a reciprocal t(9;22) hypertension, diabetes or best therapeutic and support broadly at large regions of chromosomal translocation. AIDS. approach for patients with the gene, before focusing on this chronic condition. specific components where The main area of interest of CML affects all age groups we hope to fine tune a cure. the Leukaemia Biology Group with a median age of onset Unfortunately, despite the (LBG) is the molecular in the mid-50s. It is not impressive success of TKIs for biology and cell kinetics of unreasonable to assume that CML, a significant proportion chronic myeloid leukaemia the average life span of these of patients do not achieve (CML), related patients after diagnosis is now optimal response, and many myeloproliferative disorders 30 years. With estimated TKI relapse under this form of (MPDs) and myelodysplastic costs of $30,000-50,000 per treatment. The reasons for syndrome (MDS), with the annum per patient, each this are still largely unknown. aim of identifying new successive year adds at least It is therefore vital to devise molecular targets for the $900 million in projected a treatment strategy that treatment of these diseases. drug spend, a figure that allows complete eradication does not include hospital of the leukaemic clone, With the introduction of care, regular monitoring leading ultimately to total targeted tyrosine kinase and management of non- cessation of treatment. This inhibitors (TKIs), CML has responders by stem cell can only be achieved through been transformed from a transplant, let alone the thorough investigations on disease with median survival indirect costs of failure to the molecular mechanisms of of five years, to one return to work. leukaemogenesis, as we are compatible with normal life undertaking in our laboratory. expectancy if patients comply Because TKIs are so effective, If successful in CML, the with daily oral medication for we have seen a huge change discoveries could have a far life. This is a first in cancer in the impact of diagnosis ranging applicability in other therapy and has brought from a fatal disease to a chronic illnesses. entirely new problems of chronic condition that simply management. requires a daily tablet.
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1 Duncan Hewett 6 Fong Chan Choy 2 Vicki Wilczek 7 Brett Johnson specific areas that are currently 3 Bradley Cheneda 8 Ka Chung (Stanley) Cheung being addressed 4 Junia V. Melo 9 Gink Nanxing Yang 5 Deborah Cassolari