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Brisbane Prostate Cancer Research NetworkChief InvestigatorsProf Judith Clements, Head 1, Scientific Director 2 Prof Colleen Nelson, Chair Prostate Cancer Research 1, Executive Director 2 Prof Adrian Herington1 Dr Lisa Chopin, Head, Ghrelin Group1 Dr John Hooper, Head, Protease Group1 Dr Jon Harris, Head, Molecular Therapeutics Group1 Dr Terry Walsh, Head, Proteomics1 Prof Martin Lavin, Radiation Biology and Oncology3,4 Prof Pam Russell 2 Dr Lidija Jovanovic 2 Dr Patrick Ling 2 Dr Chris Schmidt, Cancer Immunotherapy4 Dr Kay Ellem, Cancer Immunotherapy4 Dr Amanda Spurdle, Head, Molecular Cancer Epidemiology4 Dr Kristen Radford, Research Fellow5 Dr Rebecca Prue, Research Fellow5 Prof Derek Hart, Director5 Prof RA (“Frank”) Gardiner, Urologist 1,3,4,6,7 A/Prof David Nicol, Urologist 1,2,3,6,7,8 Dr John Yaxley, Urologist 6,8 Dr Peter Swindle, Urologist 5,6 Dr Glen Wood, Urologist 6 Dr Peter Heathcote, Urologist 6 Dr Graham Holmes, Urologist 6 Dr Greg Malone, Urologist 6 Dr John Preston, Urologist 6 Dr Hema Samaratunga, Pathologist 13 Dr Ian LeFerve, Pathologist 10 Dr Angus Collins, Pathologist 9 Dr Suzanne Chambers, Director, Psycho-oncology Research Unit11 Ms Megan Ferguson, Project Manager11 Ms Pamela Saunders, QLD Coordinator 1, 12 Ms Trish van den Bergh, Research Nurse 2, 12 Affiliations
Research ActivityThe Brisbane Prostate Cancer Research Network is investigating aspects of prostate tumour cell biology and its association with cancer progression. From these studies, we are attempting to identify more discriminating tumour bio-markers (than the current PSA test/TRUS biopsy approach) for early cancer detection in ejaculate, urine and blood and more discriminating prognostic indicators, particularly for the more aggressive spectrum of disease. These tumour-associated antigens, along with cell-based and whole vaccine approaches, are also being used for targeted immuno-therapeutic strategies. These latter basic and pre-clinical studies are focussed on understanding the specific nature of prostate cancer immuno-biology and generating new prostate cancer cell lines that more typically reflect the broad spectrum of disease that is seen clinically. Other aspects of our research include generating in vitro and in vivo models of prostate cancer bone metastasis in order to understand why prostate cancer cells preferentially spread to the bone. We are also assessing the identified candidate genes for their potential as genotypic markers for prostate cancer risk and disease progression. Clinicians in the group have initiated vaccine trials at RBWH/ QIMR and the Mater, and have been centrally involved in pharmaceutical industry-sponsored studies examining the role of new drugs in both early prostate cancer and those with hormone escape disease. In addition, the impact on men with prostate cancer of new and established treatment regimens is being examined with respect to psychosocial and decision-related adjustment and cognitive effects. The new Australian Prostate Cancer Research Centre-Queensland (APCRC-Q) is also currently establishing a comprehensive, multi-disciplinary research team dedicated to accelerating the development of practical applications and treatments for prostate cancer patients in Australia. The Centre will focus on supporting a range of translational activities for the development of prostate cancer therapeutics and biomarkers, early detection, differentiation of disease and prognosis. The pipeline of activities undertaken by the Centre will span the development spectrum, supporting discovery-based and translational research and Phase I, II and III clinical trials. Research Areas of Expertise:Molecular and cell biology, bioinformatics and protein chemistry, particularly in prostate cancer cell biology, with a particular focus on proteases (PSA & the related kallikreins, transmembrane serine proteases, ADAMs), growth factors (ghrelin and the IGF axis) and transmembrane signalling proteins (such as the protease-activated receptors, PARs). Structure-function analysis of these factors and nuclear receptor (AR) co-factor interactions. Genetic and proteomic approaches for predictive and early cancer bio-markers, as well as markers of disease progression. Ejaculate as a tool for diagnostic and prognostic bio-markers. Dendritic cell biology; in vitro and in vivo bone metastasis models; xenograft tumour models. Immunotherapy and pharmaceutical clinical trials; psychological and cognitive aspects of prostate cancer treatment. Major Prostate Cancer Related Grants (last 5 years):Characterisation of a novel prostate-expressed kallikrein-like protease and its target proteins. 2000-2004, $709,000, NHMRC; J Clements. The role of growth hormone releasing hormones in the autocrine/paracrine regulation of prostate cell growth. 2002-2004, $240,000, NHMRC; AC Herington & LK Chopin. Phase I trial of autologous dendritic cell vaccine for hormonal-refractory prostate cancer with novel tissue and immunologic monitoring techniques. 2003-2004, $130,000, QIMR Cell-Based Therapies Grants Committee; RA Gardiner, C Schmidt, KAO Ellem. Cell based vaccine therapies. 2003-2004, $1.17 million, Onyvax Ltd (United Kingdom); J Clements, D Nicol. PSA testing: a population-based longitudinal study of decision making, psychological effects and patterns of care. 2004. $572,601, NHMRC; D O’Connell, D Smith, M Gattellar, J Ward, SK Steginga, C Pinnock. A Phase I Clinical Trial of Novel Blood Dendritic Cell Preparation for the Immunotherapy of Prostate Cancer. 2004-2005, US$100,000, US Army Prostate Cancer Program; D Hart. Proteomic approaches to the early detection of prostate cancer. 2004-2005, $140,000, Queensland Cancer Fund; RA Gardiner, JA Clements, T Walsh, J Bartley, J Gorman, A Pettitt, J Yaxley, D Nicol. Characterisation of prostatic kallikrein gene expression during crosstalk between osteoblasts and prostate cancer cells. 2004-2005, $140,000, Queensland Cancer Fund; JA Clements, J Gao, D Nicol, & AC Herington. A novel one-step approach in the early diagnosis of prostate cancer. 2004-2005, $102,510, NHMRC; RA Gardiner, MF Lavin Regulation and functional roles of ADAM 10 in prostate cancer. 2004-2006, $456,000, NHMRC; AC Herington, JA Clements, D Odorico. Development of a novel, non-invasive diagnostic test for prostate cancer. 2004-2007, US$516,360, US Department of Defence; RA Gardiner, MF Lavin. Selection of prostate-derived kallikreins for dendritic cell immunotherapy. 2005-2006, $143,400, Queensland Cancer Fund; K Radford, R Wilkinson, P Swindle. A Phase I Clinical Trial of cmrf-56+ blood dendritic cell preparation for the immunotherapy of metastatic hormone refractory prostate cancer. 2005-2006, US$1million, US Army Prostate Cancer Program; D Hart. Ghrelin receptor isoforms in prostate cancer proliferation;roles of heterodimerisation and signalling cross-talk. 2005-2006, $140,000, Queensland Cancer Fund; LK Chopin & AC Herington. Multiple molecular markers for prostate cancer diagnosis from enriched prostatic cells from ejaculate. 2005-2006. $71,700, Queensland Cancer Fund; RA Gardiner, M Burger, J Yaxley, H Samaratunga, MF Lavin. PSA testing: a population-based longitudinal study of decision making, psychological effects and patterns of care. 2005-2007, $572,601, NHMRC; O’Connell D, Smith D, Gattellari M, Ward J, Steginga SK, Pinnock C. Kallikrein Gene Variants in Prostate Cancer: Analysis of Gene Regulation and Diagnostic/Prognostic Use. 2006-2008, $479,125, NHMRC; Kedda MA, Spurdle AB, Clements JA. A randomised vaccine trial of men at very high risk of metastasis following radical prostatectomy. 2007-2008, $100,000, Atlantic Philanthropies; Gardiner, Vieweg, Nicol, Schmidt, Burger, Lopez A randomised vaccine trial of men at very high risk of metastases following radical prostatectomy. 2007-2008, $156,000, Queensland Cancer Fund; Gardiner, Vieweg, Nicol, Schmidt, Burger, Lopez Predicting and promoting long-term adjustment for men with localised prostate cancer: Proscan. 2007-2011, $289,563, NHMRC; Steginga, Gardiner, Nicol, Aitken, Occihipinti Randomised controlled trial of early intervention to improve sexual and couple functioning after prostate cancer. 2008-2010, $577,438, NHMRC; Chambers, Shover, Halford, Occhipinti, Gardiner & Dunn A novel receptor activated pathway in prostate cancer and bone metastasis. 2009-2010 $160,000, Cancer Council Queensland; Hooper, Mackie, Wu, Clements EPHB4 as a target for anti-prostate cancer therapy. 2008-2009, $183,352, PCFA; Stephenson & Clements Application of a human bone engineering platform to an in vivo prostate cancer model. 2008-2009, $291,920, PCFA; Hutmacher, Clements, Nicol & Nelson Inhibition of sex hormone binding globulin proteolysis by kallikrein-related protease 4; a potential target for prostate cancer therapy. 2008-2010, $253,854, PCFA; Harris & Clements Potential of Human Kallikrein 4 as a novel target for prostate cancer immunotherapy. 2008-2010, $240,000, PCFA; Radford, Hart & Clements MicroRNAs in Prostate Cancer: Novel Biomarkers and Potential Therapeutic Targets. 2008–2011, $600,000, PCFA/ Cancer Australia; Nelson, Risbridger, Clements, Nicol & Tilley The role of kallikrein gene variants in prostate cancer etiology, detection and disease progression. 2009-2010, $249,847, PCFA; Spurdle, Lose, Batra, Clement Establishment of the Australian Prostate Cancer Research Centre – Queensland. 2009-2013, $7.5mil,Australian Federal Government; Nelson, Clements & Nicol Proteolytic and non–proteolytic roles for PSA and related kallikrein serine proteases in prostate cancer progression. 2007–2009, $462,000, NHMRC; Clements & Nicol In vivo and in vitro evaluation of SFTI-RCQR, a novel kallikrein 4 specific inhibitor. 2008-2009, $160,000, NHMRC Development Grant; Harris, Clements & Russell Collaborative Oncological Gene-environment Study (EU-COGS). 2009-2013, $783,750, NHMRC; CI: Giles, Assoc-I: Clements, English, Hayes, Hopper, Kedda, Nelson, Pedersen, Severi, Southey, Spurdle National & International Research Alliances Program - Australian-Canadian Prostate Cancer Research Alliance. 2009-2011, $2mil, Queensland Smart State; Nelson, Gleave, Clements & Nicol A randomised trial of robotic and open prostatectomy: integrated multidisciplinary studies to guide patient management. 2009-2014, $1.25mil, Cancer Council Queensland; Gardiner, Chambers, Dunglison, Yaxley, Occhipinto, Carter, Williams, Lavin Prostate Cancer detectio employing novel PCA3 isoforms. 2009, $100,000, Bruce Pearson Fellowship; Gardiner & Lavin Molecular strategies for staging prostate cancer. 2009-2010, $164,000, Cancer Council Queensland; Gardiner & Clarke The relationship between PCA3 and BMCC1 in prostate cancer development and detection. 2009-2011, $394,390, PCFA; Gardiner, Clarke & Lavin Selected Prostate Cancer Related Publications (last 5 years):Kaushal A, Myers SA, Dong Y, Lai J, Tan OL, Bui LT, Hunt ML, Digby MR, Samaratunga H, Gardiner RA, Clements JA and Hooper JD (2008) A novel transcript from the KLKP1 gene is androgen regulated, down-regulated during prostate cancer progression and encodes the first non-serine protease identified from the human kallikrein gene locus. Prostate 68, 381-399. Ramsay AJ, Dong Y, Hunt ML, Linn M, Samaratunga H, Clements JA and Hooper JD (2008) Kallikrein-related peptidase (KLK) 4 initiates intracellular signalling via protease-activated receptors (PARs). KLK4 and PAR-2 are co-expressed during prostate cancer progression. J Biol Chem 283, 12293-12304. Chambers SK, Schover, L. Halford, K. Clutton, S. Ferguson M, Gordon, L. Gardiner RA, Occhipinti, S. Dunn, J. ProsCan for Couples: Randomised controlled trial of a couples-based sexuality intervention for men with localised prostate cancer who receive radical prostatectomy. BMC Cancer, 2008; 8:226 Landers KA, Samaratunga H, Teng L, Burger MJ, Scells B, Lavin MF, Gardiner RA. Identification of Metastatic Markers for Prostate Cancer. BJ Cancer, 2008; 99:491-501 Gao J*, Collard RL*, Bui L, Herington AC, Nicol D, and Clements JA. Kallikrein 4 is a potential mediator of cellular interactions between osteoblast and cancer cells in metastatic prostate cancer. Prostate 67:348-60, 2007. (*equal first authors) Vela I, Gregory L, Gardiner EM, Clements JA and Nicol DL. Bone and prostate cancer cell interactions in metastatic prostate cancer. BJU Int, 99:735-42, 2007. Lai J, Kedda M-A, Hinze K, Smith RLG, Yaxley J, Spurdle AB, Morris P, Harris J, Clements JAC (2006). PSA/KLK3 ARE promoter polymorphism alters androgen receptor binding and is associated with prostate cancer susceptibility. Carcinogenesis 28:1032-9 Kote-Jarai Z*, Easton D*, Stanford JL*, Ostrander EA* Schleutker J*, Ingles SA*, Schaid D*, Thibodeau S*, Dörk T*, Neal D*, Cox A*, Maier C*, Vogel W*, Guy M*, Muir K*, Lophatananon A*, Kedda M-A*, Spurdle A*, Steginga S*, John EM*, Giles GG*, Hopper J*, Chappuis PO*, Hutter P*, Foulkes WD*, Hamel N*, Salinas CA, Koopmeiners JS, Karyadi DM, Johanneson B, Wahlfors T, Tammela TL, Stern MC, Corral R, McDonnell SK, Schürmann P, Meyer A, Kuefer R, Leongamornlert D, Tymrakiewitz M, Liu J, O’Mara T, Gardiner RA, Aitken J, Joshi AD, Severi G, English DR, Southey M, Al Olama AA, The PRACTICAL group**, Rosalind A. Eeles. (*These people contributed equally to this work). (2008). Confirmation of prostate cancer susceptibility loci on chromosomes 3, 6, 7, 10, 11, 19 and X by an International Consortium, The PRACTICAL Study. Cancer Epidemiol Biomark Prev, 17: 2052-61 Wilson S, Greer B, Hooper J, Zijlstra A, Quigley JP and Hawthorne S. (2005) The membrane anchored serine protease, TMPRSS2, activates PAR2 on prostate cancer cells. Biochem J.388, 967-972 Gardiner RA, Burger MJ, Steginga S, Walsh T, Schmidt C, Nicol DL, Lavin MF, Clements JA. Integrating molecular, proteomic and vaccine development, quality of life and psychometric evaluations in a comprehensive research program. In: Horizons in Cancer Research. Ed: Colombo F; Prostate Cancer Ed: Lucas JN. Nova Medical Books, New York. pp189-216, 2004. Landers KA, Burger MJ, Tebay MA, Purdie DM, Scells B, Samaratunga H, Lavin MF, Gardiner RA. Use of multiple biomarkers for a molecular diagnosis of prostate cancer. Int J Cancer, 114: 950-956, 2004. McCulloch D, Akl P, Samaratunga H, Herington AC & Odorico DM. Expression of ADAM-10 in prostate cancer and its regulation by dihydrotestosterone, insulin-like growth factor-I and epidermal growth factor in the prostate cancer cell model LNCaP. Clin Cancer Res 10:314-23, 2004. Steginga, S.K., Occhipinti, S., Gardiner, R. A., Heathcote, P. & Yaxley, J. A Prospective Study of Men’s Use of Alternative Therapies after Localised Prostate Cancer. Patient Education and Counseling, 55: 70-77, 2004. Swindle PW, Tepes S, Clements J. DC therapy for prostate cancer. Cytotherapy. 6:164-71, 2004. Han G, Buchanan G, Ittmann M, Harris JM, Yu X, Demayo FJ, Tilley W, Greenberg NM. “Mutation of the androgen receptor causes oncogenic transformation of the prostate” Proc Natl Acad Sci U S A. 102:1151-6, 2005. Wilson S, Greer B, Hooper JD, Zijlstra A, Quigley JP and Hawthorne S (2005) The membrane anchored serine protease, TMPRSS2, activates PAR2 on prostate cancer cells. Biochem J 388: 967-72, 2005. Steginga SK, Pinnock C, Baade P, Jackson C, Green A, Preston J, Heathcote P, McAvoy B. An educational workshop on the early detection of prostate cancer: a before-after evaluation. Aust Fam Physician. 34: 889-891, 2005. Steginga SK, Pinnock C, Gardner M, Dunn J, Gardiner RA. Evaluating peer support for prostate cancer: the prostate cancer peer support inventory. Br J Urol. 95: 46-50, 2005. Baade P, Steginga SK, Pinnock C, Aitken J. Communicating prostate cancer risk: what should we be telling our patients? Med J Aust. 182: 472-475, 2005. Yeh A, Jeffery PL, Herington AC & Chopin LK. The role of ghrelin in prostate cancer cell proliferation: ghrelin activates mitogen-activated protein kinase (MAPK) pathways in LNCaP and PC3 prostate cancer cells and a novel preproghrelin isoform is highly Expressed In Prostate Cancer. Clin Cancer Research 11: 8295-303, 2005. Veveris-Lowe, T.L.*, Lawrence, M.G.*, Collard, R.L*, Bui, L., Herington, A.C., Nicol, D.L. And Clements, J.A. Kallikrein 4 (hK4) and prostate-specific antigen (PSA) are associated with the loss of E-cadherin and an epithelial-mesenchymal transition (EMT)-like Effect in Prostate Cancer Cells. Endocrine Related Cancer 12(3):631-43, 2005 (* equal first authors). Dong, Y., Bui, L.T., Odorico, D.M., Tan, O.L., Myers, S.A., Samaratunga, H., Gardiner, R.A. And Clements, J.A. Compartmentalized expression of kallikrein 4 (KLK4/hK4) isoforms in prostate cancer: nuclear, cytoplasmic and secreted forms. Endocrine Related Cancer 12(4):875-89, 2005. Wilkinson R, Kassianos AJ, Swindle P, Hart DNJ, Radford KJ.
Numerical and functional assessment of blood dendritic cells in
prostate cancer patients. Prostate, 66; 180-192, 2006. International Patents:PCT/AU02/00582 Multiple Countries, 2002. Chopin LK, Jeffery PL & Herington AC. “Reproductive cancer diagnosis and therapy” PCT/AU02/00378 Australia, 2002. Clements JA. “Polynucleotides and poly-peptides linked to cancer and/or benign tumours” PCT/AU03/00454 Australia, 2003. Clements JA. Australian Provisional Patent application (PS1870/02)- “Condition-specific molecules and uses therefore”
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