Research Interests

Myeloma and Bone Cancer Research

Multiple myeloma is haematological malignancy characterised by the clonal proliferation of plasma cells, an immune cell type that normally protects us against infection. Myeloma is the second most common blood cancer and more than 140,000 people are diagnosed each year worldwide. Despite recent advances in treatment, myeloma remains universally fatal and has a 10-year survival rate of approximately 28%. The main clinical manifestations of myeloma are the development of osteolytic bone lesions, bone pain, hypercalcaemia, renal insufficiency, suppressed immunoglobulin production and increased bone marrow angiogenesis (blood vessel formation). Myeloma is preceded by a premalignant (asymptomatic) monoclonal gammopathy of uncertain significance (MGUS) stage. The factors that trigger the progression from MGUS to myeloma remain to be determined; however, our studies show that both intrinsic genetic changes and extrinsic factors play a role in disease progression. The Myeloma Research Laboratory’s research is focussed on detecting the key signalling pathways that are deregulated during disease development and determining what microenvironmental changes occur during disease pathogenesis. We believe that these approaches will enable us to identify new molecular markers of disease risk and to design drugs against novel therapeutic targets.

The MRL has made, and continues to make significant contributions to the field through ongoing projects in:

• Identifying the mechanisms of myeloma associated bone loss
• Identifying the genetic, transcriptional and epigenetic changes that trigger the progression from asymptomatic MGUS to myeloma
• Determining why the bone marrow is a “hot-spot” for myeloma plasma cell metastasis
• Identifying the mechanisms governing dissemination and relapse in multiple myeloma
• Identifying how myeloma plasma cells affect mesenchymal stem cell differentiation.
• The use of single cell sequencing to discover tumour-associated changes in the bone microenvironment of myeloma patients: identification of prognostic markers and novel therapeutic targets
• The use of high-precision proteomics to identify novel serum biomarkers to identify high-risk smouldering myeloma patients prior to progression to active multiple myeloma
• Identifying a role for the mTOR pathway in mesenchymal stem cell biology and bone formation.
• Assessing the effectiveness of targeting skeletal mTORC1 as a novel approach to treat diet-induced insulin resistance

Therapeutic Use of Mesenchymal Progenitor Cells

Mesenchymal Progenitor Cells (MPC) are rare stem cells present within post-natal tissues which possess promising therapeutic properties. In the late 90’s, collaborative studies in association with Professor Stan Gronthos (Mesenchymal Stem Cell Laboratory, UA/SAHMRI) and Professor Paul Simmons (Mesoblast Ltd.) led to the patenting of technologies covering the identification and isolation of these rare cells from bone marrow. The family of patents surrounding this technology were assigned to Angioblast Systems Inc., New York, USA in November 2004 facilitating the formation of Mesoblast Ltd, an Australian Stock Exchange listed company (http://www.mesoblast.com). In return for the assignment of these patents, the IMVS/Medvet/SA Pathology (my substantive employer at that time) received a significant parcel of shares in this company. From January 2005 until December 2016, I have served as a consultant to both Angioblast Systems Inc. and Mesoblast Ltd. and continued to receive funding to support the improvement/development of existing/new intellectual property and to fund large pre-clinical animal models of disease.

Research Collaborations

My expertise in the fields described above has led to active collaborations with scientists/clinicians throughout the world as detailed below.

In 1994-1995, I developed a powerful retroviral-based expression cloning strategy to enable isolation of genes encoding cell surface molecules that participate in intercellular interactions. This methodology has led to numerous collaborations and ongoing consultation work with scientists including:

• Dr H-J. Buhring, University of Tubingen, Germany. Retroviral Expression cloning of cell surface antigens expressed by normal and leukaemic haemopoietic stem cells;
• Prof. Leonie K. Ashman, University of Newcastle. Retroviral Expression cloning of drug resistance genes;
• Prof. James T. Triffit, Botnar Research Centre, Nuffield Department of Orthopaedic Surgery, University of Oxford, Nuffield Orthopaedic Centre, Oxford, UK. Retroviral Expression cloning of osteoblast-related cell surface antigens;
• Dr S. Watt, MRC Molecular Haematology Unit, The Institute of Molecular Medicine, University of Oxford, UK. Retroviral Expression cloning of novel cell surface molecules.

My research into myeloma-associated bone loss and molecular mechanisms of myeloma disease pathogenesis has led to further collaborations with a number of academic and industry-based scientists including:

• Prof. John Shaughnessy, Formerly of University of Arkansas, Little Rock, Arkansas, USA and founder of SignalGenetics^TM, Carlsbad, CA.  The role of DKK-1 in myeloma-associated bone loss;
• Dr Daniel Peet, Department of Bichemistry, Molecular Life Sciences, University of Adelaide: Role of CXCL12 (SDF-1)/CXCR4 in Pathological Angiogenesis and Osteolytic Bone Disease in Multiple Myeloma;
• Dr Phil Kearney, Santaris Pharma, Copenhagen, Denmark: Role of CXCL12 (SDF-1)/CXCR4 in Pathological Angiogenesis and Osteolytic Bone Disease in Multiple Myeloma;
• Prof. Nobutaka Fujii and Prof. Hirokazu Tamamura, Graduate School of Pharmaceutical Sciences Kyoto University Department of Bioorganic Medicinal Chemistry, JAPAN, Role of SDF-1 in myeloma;
• A/Prof. Kevin Lynch, Novartis, Sydney, Australia, Tyrosine Kinase Inhibition as a Potential Modality to Control Osteolytic Bone Disease: A New Role for Imatinib Mesylate and Second Generation Bcr-Abl Inhibitors;
• Dr Elisabeth Buchdunger and Dr Paul Manley, Novartis Pharma, Skeletal Effects of the Abl Kinase Inhibitors, Nilotinib and Imatinib;
• Dr Francis Lee and Dr Richard Smykla, Bristol-Myers Squibb, Skeletal Effects of the Abl Kinase Inhibitors, Dasatinib;
• Prof. Vijay Modur, Novartis Pharmaceuticals Corporation, Cambridge, MA, USA. Novel mediators of multiple myeloma metastases to the bone;
• Prof. William Dougall, Amgen, Seattle, Washington, USA, The role of RANKL in myeloma-associated bone loss;
• Dr Daniela Niepel, Global Medical Executive Director, Amgen GmbH, Rotkreuz, Switzerland. The application of bone targeting agents (BTA) in oncology.
• Prof. Peter Croucher, Bone Biology Laboratory, Bone Biology Division, Garvan Institute of Medical Research, NSW, AUS. The role of the bone marrow microenvironment in the pathogenesis of myeloma;
• Dr Daniel Worthley, University of Adelaide, Adelaide, Australia, The role of the bone marrow microenvironment in the pathogenesis of myeloma;
• Prof. Siddhartha Mukherjee, Columbia University, NY, USA. The role of the bone marrow microenvironment in the pathogenesis of myeloma;
• Prof. Orest Blaschuk, Urology Research Laboratories, Division of Urology, McGill University Health Centre, Canada and Zonula Inc. The use of Cadherin antagonists to treat multiple myeloma;
• Prof. Jonathan Licht, University of Florida Cancer Centre. The role of EMT in myeloma disease dissemination and disease progression;
• Prof. Ricky Johnstone, Gene Regulation Laboratory, Peter MacCallum Cancer Centre, The role of the bone marrow microenvironment in the pathogenesis of myeloma;
• Associate Professor Simon Leedham, Wellcome Trust Centre for Human Genetics, Oxford, The role of the bone marrow microenvironment in the pathogenesis of myeloma;
• Prof. Charles Mullighan, Hematological Malignancies Program, St. Jude Children’s Research Hospital, Understanding clonal evolution in multiple myeloma;
• Dr Gareth Davies, Senior Research Scientist / Project Leader, UCB Celltech – New Medicines, Slough, UK. Targeting stromal derived Gremlin 1 as a novel therapeutic modality to treat multiple myeloma
• Prof. Gareth Morgan, University of Arkansas, Myeloma Institute for Research and Therapy (UAMS), Understanding clonal evolution in multiple myeloma.
• Prof. Tilman Brummer, Institute of Molecular Medicine and Cell Research Albert-Ludwigs University of Freiburg, Germany. The role of the novel tumour suppressor gene, SAMSN1, in the pathogenesis and metastasis of multiple myeloma.

My research into physiological and aberrant bone remodelling and novel skeletally-derived factors that regulate glucose metabolism has led to collaborations with a number of academic and industry-based scientists including:

• Prof. D.M. Findlay, Dr Gerald J. Atkins and Dr. Andreas Evdokiou, Discipline of Orthopaedics and Trauma, Royal Adelaide Hospital and the University of Adelaide. Normal and pathological bone remodelling;
• Dr Colin Dunstan, University of Sydney and formerly of Amgen Inc, CA, USA; The Role of OPG in bone metabolism;
• A/Prof Barry C Powell, Dr Peter J Anderson and Prof David David, Child Health Research Institute and The Women’s and Childrens Hospital, Adelaide, South Australia: Mechanisms of premature cranial fusion and development of novel adjunct approaches to treatment;
• Prof H. Zreiqat, School of Pathology, University of New South Wales, Sydney, Australia. Behaviour of osteoclasts and bone cells on bio-material surfaces;
• Prof D. R. Haynes, Department of Pathology, University of Adelaide, Adelaide, South Australia. The role of TNF family members TWEAK and TNF-alpha in bone remodelling;
• A/Prof Sofianos Andrikopoulos, The University of Melbourne, The University of Melbourne. Skeletal endocrine signalling in the regulation of glucose metabolism;
• Dr Paul Baldock, Garvan Institute of Medical Research, Garvan Institute of Medical Research. The University of New South Wales, Skeletal endocrine signalling in the regulation of glucose metabolism;
• Christopher Proud, South Australian Health and Medical Research Institute, SA, AUS. Targeting skeletal mTORC1 as a novel approach for the treatment of diet-induced insulin resistance.
• William Cawthorn, University/BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, Edinburgh, Scotland. The role of raptor/mTORC1 and bone marrow adipose tissue (BMAT) in the control of whole-body glucose metabolism

My research into mesenchymal precursor cell biology and application has led to collaborations with a number of biotechnology companies, including Angioblast Systems Inc., Mesoblast Ltd. and Genzyme International. In addition, I also collaborate and consult for a number of academic scientists including:

• Prof. Silviu Itescu, Mesoblast Ltd.: Clinical Application of Mesenchymal Precursor Cells for bone repair, articular cartilage regeneration, disc cartilage regeneration, cellular therapy of heart attack/heart failure, peripheral arterial disease and wound ulcers;
• A/Prof. Robert Moore, formerly head of the Adelaide Centre for Spinal Research, Institute of Medical and Veterinary Science, Adelaide, South AUSTRALIA: A Preclinical trial of the potential for cultured mesenchymal precursor cells to restore extracellular matrix and normal mechanical function to degenerate intervertebral discs;
• Prof. Peter Ghosh, Institute of Nutraceutical Research, Brookevale, NSW, Australia: Cartilage Regenerative Potential of Ovine Mesenchymal Precursor Cells (MPC);
• A/Prof John Field, Flinders University of South Australia, School of Medicine, Bedford Park, South Australia: Evaluation of the safety and efficacy of Allogeneic Mesenchymal Progenitor Cells (MPC) for the repair of critical size defects in an ovine tibial model;
• Prof. Stephen Worthley, formerly Cardiovascular Investigation Unit, Royal Adelaide Hospital, Adelaide, South Australia: A study of the cardiac regenerative potential of immunoselected ovine bone marrow mesenchymal stem cells;
• Dr Cory Xian and Prof. Bruce Foster, Bone Growth Foundation, University of South Australia and Department of Orthopaedic Surgery, Women's and Children's Hospital. Molecular pathways for the bony repair of injured growth plate cartilage;
• Prof. Richard Harvey and Professor Robert Graham, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia. Identification of endogenous cardiomyogenic stem cells.

From 2005 to 2016, I served as a scientific consultant for Mesoblast Ltd. where I helped to consolidate and expand our stem cell-based technology patent family and successfully completed key milestones such as the development of GMP-grade MPC isolation and culture expansion standard operational protocols. This resulted in an increase in capital investment to support the commencement of several phase II/III cardiac and orthopaedic clinical studies. Funds from Mesoblast Ltd were used to continue basic R&D in our laboratory and for initiating new pre-clinical animal studies within the IMVS/ Hanson Institute/ RAH/ University of Adelaide campuses. Collectively, these studies formed the foundation of new IND (investigative new drug) applications submissions to the USA FDA for future phase I/II/III human clinical trials involving different health centres and laboratories in Adelaide, Australia and the USA.

Research Output

I have co-authored more than 300 refereed publications, book chapters and review articles (not including published abstracts). Many of these articles are published in premier Haematology and Orthopaedic journals (BLOOD, Leukemia, BJH, JBMR, Bone), Cancer journals (Cancer Research, Clinical Cancer Research) and Stem Cell journals (Cell Stem Cell, Stem Cells). My publications have received in excess of 17,000 citations and my H Factor = 73. Refer to Publications section for full details.

Presentations

I have been invited to present my laboratory’s findings at more than 45 national and international forums since 2010. In addition, I have co-authored more than 100 abstracts with more than 60 of these being published as Meeting Proceedings.

Additional Evidence of Research Leadership

When I joined the UA School of Medical Sciences (SoMS), I served as a member of the Research Committee. In January 2014, I was appointed as Chair of this committee, and immediately instituted 4 new funding programs designed to drive research activity, including an ECR “kick start” award, a strategic equipment fund, an ECR/MCR travel award and a publication award program.

I was also appointed to the SoMS board, the FHMS Research Committee and was the Deputy Chair of the Adelaide Medical and Nursing School (AMNS) Project Committee overseeing the construction of a new $246 million Medical/Nursing/Research facility in the new West End Biomedical Research Precinct which will house approximately 650 Researchers. In January 2015, I was appointed to Deputy Head od School, SoMS.  In March 2015, the Executive Dean, Professor Alastair Burt appointed me to establish and chair the Research Strategy Taskforce (RSTF). The RSTF was charged with the responsibility of devising a new research strategy to promote research excellence within the FHMS. This work led to the development of an adaptable strategic framework to enhance research education (HDR/honours), develop research strengths, build enabling technologies/research infrastructure and develop pathways to improved health care and the generation of valuable intellectual property.

My national standing in the fields of cell and cancer biology has been recognised by my appointment to the NHMRC Grant Review Panel (GRP) for Cell biology (2005, 2006) and Oncology (2010) and Assigners Academy (2014-2018). In recognition of my international standing in the field of myeloma-associated bone loss, I was invited by the Leukaemia Research Fund (LRF) of UK, to participate in a “site visit” of Myeloma Program of Prof. Peter Croucher, University of Sheffield, UK, to assess his application for program funding through the LRF in both 2006 and 2009. In addition, I was invited to participate as a moderator for the 2006 American Society of Haematology (ASH) Annual Meeting, for the session titled “Multiple Myeloma: Microenvironment”. I was invited to be an Abstract Reviewer of the “Myeloma-Pathophysiology and Preclinical studies excluding Therapy” Category for the 52^nd Annual Meeting of the ASH, a prestigious appointment bestowed upon recognized experts in the field.

As a testament to my expertise in my chosen fields, I have been asked to present my laboratory's findings at numerous scientific meetings and institutions (see “Conference Presentations”) and I have been asked to contribute to numerous review articles and book chapters (see “Publications”). As a recognised expert in the areas of skeletal, stem and cancer biology, I am asked to review >3 manuscripts per month for more than 20 journals including BLOOD, Leukemia, Leukemia and Lymphoma, Experimental Hematology, Haematologica, Journal of Bone and Mineral Research, Leukemia, Cell Stem Cell, Clinical Cancer Research, Cancer Research, International Journal of Cancer, Bone, FASEB Journal. I am also regularly asked to review applications for a number of funding bodies including the NHMRC, Cancer Council of South Australia, Cure Cancer Australia, Leukaemia Research Fund (UK), The Health Research Board (HRB) of Ireland, Singapore Ministry of Education and the Research Grants Council (RGC) of Hong Kong. I was approached by the Wiley-Blackwell publishing house to assess the merits of publication of a book entitled: “Stem Cells: Science and Business Strategies” by A. Vertes et al.

As further evidence of my scientific standing, I have served on organising committees involved in staging both national and international scientific meetings including; the 2004 Hanson Symposium Stem Cell Meeting (Adelaide, SA, 2004); the 10th International Myeloma Congress (Sydney, NSW, 2005); the Clare Bone Meeting (Clare Valley, SA, 2006) and the Australian Myeloma Workshop (2016). I was a member of a committee comprised of stakeholders for the Commonwealth's $35 million Super Science Initiative (SSI) - Translating Health Discovery (THD) and represent the Centre for Cancer Biology (CCB) as a Subject Matter Expert (SME) charged with the role of identifying the facilities requirements for the South Australian Health and Medical Research Institute (SAHMRI). Finally, I have served on the Fellowships and Scholarships Committee for the Leukaemia Foundation of Australia.

Clinical Outcomes of Research

As a member of MSAG, I have provided guidance on both myeloma and supportive treatment strategies and have co-authored guidelines for the safe use of bisphosphonates and Clinical Practice Guidelines. Furthermore, my work has raised the awareness amongst clinicians of the importance of routine examination of CTX levels in patients. CTX (the C-telopeptide of the α1 chain of collagen type 1), a reliable marker of bone turnover, is now being used locally as a routine test for all myeloma patients at diagnosis and restaging. CTX, when used in conjunction with paraprotein levels and bone marrow assessment can detect early progression of myeloma. This is a palpable achievement and one that has led to better outcomes for patients.

As a co-inventor of the Mesenchymal Progenitor Cell (MPC) cellular therapy, I have been instrumental in developing a therapy that is likely to have a significant impact in the areas of spinal fusion, osteoarthritis, congestive heart failure, heart attacks, eye diseases, diabetes, and bone marrow repair.

Patents

I am a co-inventor of patents that describe the isolation and composition of matter of mesenchymal precursor cells (MPC), a unique population of adult stem cells with tissue reparative properties. This family of patents were assigned to Angioblast Systems Inc., New York, USA in November 2004 facilitating the formation of Mesoblast Ltd, an Australian Stock Exchange listed company. In 2010, Mesoblast acquired Angioblast Systems Inc forming the Mesoblast Group.

Initial Patents Assigned to Angioblast Systems Inc. Leading to formation of Mesoblast Ltd.

Patent: WO 01/04268 A1: AUSTRALIA, 1999

Status: Granted

Inventors: Paul Simmons, Andrew Zannettino, Stan Gronthos, Description of patent: Mesenchymal Precursor Cells. Founding patent for the formation of Mesoblast Ltd.

Applicability/Impact: Novel discovery of multi potential stem cells from connective tissue for tissue regeneration. Patent granted in AU, US, CA, ES, EP.

Patent: WO 2004/084921 A1: AUSTRALIA, 2003

Status: Granted

Inventors: Stan Gronthos and Andrew Zannettino.

Description of patent: Perivascular Mesenchymal Precursor Cell Induced Blood Vessel Formation. Founding patent for the formation of Mesoblast.

Applicability/Impact: The use of stem cells to regenerate blood vessels during tissue regeneration. Patent granted in US, AU, EP, CA, CN, ES.

Patent: WO 2004/085630 A1: AUSTRALIA, 2003

Status: Granted

Registered in names of (Inventors): Stan Gronthos, Andrew Zannettino and Songtao Shi.

Description of patent: Perivascular Mesenchymal Precursor Cells. Founding patent for the formation of Mesoblast Ltd.

Applicability/Impact: Discovery of unique perivascular multi potential stem cell for regeneration of tissue. Patent granted in US, AU, CA, CN.

Patent: WO 2006/032092 A1: UNITED STATES OF AMERICA, 2004

Status: Granted

Inventors: Andrew Zannettino and Stan Gronthos.

Description of patent: Multipotential expanded Mesenchymal Precursor Cell progeny and uses there off. Founding patent for the formation of Mesoblast Ltd.

Applicability/Impact: Discovery of unique multi-potential adult stem cell for tissue regeneration. Patent granted in US, AU, EP, CN.

Patent: WO 2006/032075 A1: AUSTRALIA, 2004

Status: Granted

Inventors: Stan Gronthos and Andrew Zannettino.

Description of patent: Method of enhancing proliferation and/or survival of mesenchymal precursor cells. Founding patent for formation of Mesoblast Ltd.

Applicability/Impact: Novel protocols for developing GMP ex vivo expansion protocols for the manufacture of MPC for clinical use. Patent granted in US, AU, CN.

Supportive Patents Assigned to Mesoblast Ltd.

Patent: PCT/AU2016/050438: AUSTRALIA, 2015

Status: Awarded (PCT)

Inventors: Stan Gronthos, Andrew CW Zannettino, Stephen Fitter.

Description of patent: Methods and Products for Enriching and Isolating Stem Cells. Patent assigned to Mesoblast Ltd.

Applicability/Impact: Identification and characterisation of the STRO-1 antigen a marker of mesenchymal precursor cells. Purification of MPC for clinical applications.

Patent: WO 2010/019997 A1: UNITED STATES OF AMERICA, 2008

Status: Granted

Inventors: Andrew Zannettino and Stan Gronthos

Description of patent: Monoclonal antibody STRO-4 selection of mesenchymal precursor cells. Patent assigned to Mesoblast Ltd.

Applicability/Impact: First reagent for isolation of MPC for pre-clinical ovine and human clinical studies. Patent granted in USA and AU.

Patent: W02006/108229 A1: UNITED STATES OF AMERICA, 2006

Status: Granted

Registered in names of Inventors: Andrew Zannettino, Stan Gronthos and Paul Simmons.

Description of patent: Isolation of adult multipotential Cells by tissue non-specific alkaline phosphatase. Patent assigned to Mesoblast Ltd.

Applicability/Impact: Novel stem cell marker developed into a GMP reagent for clinical human trials. Patent granted in USA, AU, EP, CA, HK.

In addition to the Mesoblast Ltd-related patents, I am also a substantive inventor of the following patents:

Patent: PCT 1809946.5

Status: PCT filed June 2018, UK IPO

Registered in names of Inventors: Gareth Davies (UCB Biopharma SPRL), Andrew Zannettino, Duncan Hewett, Kimberley Clark, Kate Vandyke and Bill Panagopoulos (The University of Adelaide), (Simon Leedham) Oxford University Innovation Limited.

Description of Patent: Prevention and treatment of cancer

Applicability/Impact: Use of Gremlin 1 antagonists to prevent and treat cancer

Patent: PCT/AU2016/050438

Status: Granted

Registered in names of Inventors: Andrew Zannettino, Stephen Fitter, Stan Gronthos

Description of patent: Methods and products for enriching and isolating stem cells. Patent owned by the University of Adelaide.

Applicability/Impact: Describes HSC70 as a stem cell antigen and the use of anti-HSC7 reagents to isolate and enrich for stem cells

Patent granted in USA, AU, EP, CA, HK.