Adelaide Prostate Cancer BioResource Consortium

Chief Investigators

Professor Wayne Tilley, Head, Dame Roma Mitchell Cancer Research Laboratories1
Professor Villis Marshall, Director, Surgical Specialties Service1,2
Professor Howard Morris, Director, Hanson Institute3
Associate Professor David Horsfall, Project Manager, APCC BioResource1
Dr Tom Dodd, Head, Tissue Pathology4
Dr Lisa Butler, Head, Molecular Cancer Therapeutics Group, Cancer Council Senior Research Fellow1
Dr Grant Buchanan, Head, Molecular Ageing Laboratory, NHMRC CJ Martin Fellow1,5
Dr Tina Bianco-Miotto, NHMRC Peter Doherty Fellow1
Dr Michael Brown, Head, Medical Oncology6
Dr Penny Cohen, Pathologist4
Dr Carmela Ricciardelli, Hilda Farmer Research Fellow7
Dr Eleanor Need, Freemasons Foundation Postdoctoral Research Fellow1,5
Dr Margaret Centenera, Post-Doctoral Fellow1
Dr Jurgen Stahl, Pathologist8
Dr Alan Stapleton, Urologist 2,9
Dr Peter Sutherland, Urologist2
Stephen Nygaard, Scientist4
Helen Hughes, Research Nurse1, APCC BioResource Node Coordinator

Affiliations

1. Dame Roma Mitchell Cancer Research Laboratory, University of Adelaide/Hanson Institute
2. Surgery, Royal Adelaide Hospital
3. Endocrine Bone Laboratory, Hanson Institute
4. Tissue Pathology, Institute of Medical and Veterinary Sciences
5. Freemasons Foundation Centre for Men’s Health, University of Adelaide/Hanson Institute
6. Medical Oncology, Royal Adelaide Hospital
7. Obstetrics and Gynaecology, University of Adelaide
8. Adelaide Pathology Partners
9. Surgery, Repatriation General Hospital, Daw Park

Research Activity

The Adelaide prostate cancer research group is involved in studying many aspects of prostate cancer, including disease susceptibility, progression and new therapeutic strategies. A particular focus is the mechanism(s) of disease progression in patients treated by surgery for clinically localised disease, and in patients treated with androgen ablation therapy (castration or drug-induced) for advanced disease where the cancer has spread to the bones. During the course of androgen ablation therapy, most tumours become resistant to treatment. Although this involves diverse cellular pathways, many of these pathways interact with the androgen receptor, a key cellular mediator of the effects of testicular androgens in prostate cancer cells. Studies of the androgen receptor pathway, and other pathways involved in regulating cancer cell motility and tissue invasion, have identified new targets to ablate androgen control of cancer growth as well as new treatment strategies that are currently being investigated in clinical trials.

There is considerable epidemiological evidence that men with a low vitamin D status have an increased risk for developing prostate cancers. The Adelaide group are studying the transcriptional control of vitamin D metabolism, and the effect of vitamin D status on the development of the prostate gland using rodent models.

Major Prostate Cancer Grants (last 5 years)

Androgen-regulated proteins: predictors of prostate cancer development and progression. 2001-2003, $245,000, NHMRC; Choong CS, Horsfall DJ, Tilley WD and Marshall VR.

Geldanamycin derivatives: novel inhibitors of androgen signalling for the treatment of metastatic prostate cancer. 2002-2004, $315,000, NHMRC; Tilley WD and Marshall. VR

Dominant negative androgen receptors: a novel approach to the treatment of metastatic prostate cancer. 2002-2003, $126,416. The Cancer Council of South Australia, Tilley WD, Neufing P, Butler LM, Yang M.

Geldanamycin analogs: effects on wild-type and mutant androgen receptor function. 2003, USD$200,000. CaPCURE, Rosen N, Scher H, Tilley WD.

Modulation of prostate cancer cell attachment to stromal matrix by versican. 2003, $69,658. Cancer Council South Australia, Horsfall DJ.

A cohort study of health and aging in North West Adelaide men. 2004-2006, $450,000. University of Adelaide, Florey Foundation, Wittert G, Marshall VR, Hiller J, Warin M, Taylor A, O’Loughlin P, Tilley WD, Choong CS, Wallace J.

Androgen receptor signalling and progression of prostate cancer. 2004–2006, $455,250. NHMRC, Tilley WD, Butler LM and Marshall VR.

Versican: a cell motility-promoting proteoglycan pivotal for prostate cancer metastasis. 2004-2005, $148,034. Cancer Council South Australia, Horsfall DJ, Tilley WD.

Australian Prostate Cancer Collaboration (APCC) BioResource. 2004-2009, $2.1million. NHMRC Enabling Grant, Clements J, Sutherland R, Risbridger G and Tilley WD

Prostate cancer cell synthesis of 1,25 dihydroxyvitamin D and cell growth. 2005-2006, $168,000. Cancer Council of South Australia, Morris HA, May BK, Tilley WD.

Prognostic importance of androgen receptors in epithelium and stroma in early stage prostate cancer. 2005-2007, $343,000. NHMRC, Horsfall DJ, Marshall VR, Ricciardelli C, Tilley WD.

Androgen receptor signalling in development and progression of prostate cancer. 2007–2009, $723,750. NHMRC, Tilley WD, Butler LM, Marshall VR.

Mechanism of prostate cancer tumorigenesis, 2007-2010, USD$393,000. US Army Medical Research and Material Command Congressionally Directed Medical Research Programs, Tilley WD, Butler LM, Marshall VR.

A novel regulator of androgen receptor function in prostate cancer. 2008-2012, $513,478. Prostate Cancer Foundation of Australia, Buchanan G, Koff A, Hakim D, Coetzee G.

Histone Deacetylase Inhibitors (HDIs) in bone cancer therapy. 2008-2010, $513,750. NHMRC, Evdokiou A, Findlay D, Butler LM.

Identification and characterization of MicroRNA expression in prostate cancer for development of novel biomarkers and therapeutic targets. 2008-2010, $600,000. Prostate Cancer Foundation Australia/NHMRC, Nelson C, Risbridger G, Clements J, Nicol D, Tilley WD.

Selected Prostate Cancer Related Publications (last 5 years)

      Book Chapters:

Tilley WD, Buchanan G and Coetzee GA. Hormones and Cancer. Androgen receptor signaling in prostate cancer. In: Hormones and Cancer. (Eds. Henderson, Ponder and Ross). Oxford University Press pp 288-315, 2003.

Beekman KW, Buchanan G, Tilley WD, Scher HI. Beyond first line hormones: options for castration-resistant disease. In: Comprehensive Textbook of Genitourinary Oncology. (Eds. Vogelzang NJ, Scardina PT, Shipley WU, Coffey D). Wiley and Williams, Lippincott, Philadelphia  pp 330-340, 2005.

Beekman KW, Buchanan G, Tilley WD, Scher HI. Anti-Androgen Withdrawal Syndromes: Pathophysiology and Clinical Implications. In: Prostate Cancer: Principles and Practice. (Ed. Partin AW). London, Taylor and Francis, 2005.

Buchanan G, Need EF, Bianco-Miotto T, Greenberg NM, Scher HI, Centenera, MM, Butler LM, Robins DM, Tilley WD. Insights from AR gene mutations. IN: Tindall DJ & Mohler JL (Eds) Androgen action in prostate cancer. Springer, New York (In press).

Journal articles:

Severi G, Giles GG, Southey MC, Tesoriero A, Tilley WD, Neufing P, Morris H, English DR, McCredie MRE, Boyle P and Hopper JL. ELAC2/HPC2 polymorphisms are not associated with prostate cancer or serum prostate-specific antigen level. J. Natl. Cancer Inst. 95: 818-824, 2003.

Sakko AJ, Ricciardelli C, Mayne K, Suwiwat S, LeBaron RG, Marshall VR, Tilley WD and Horsfall DJ. Modulation of prostate cancer cell attachment to matrix by versican. Cancer Res. 63: 4786-4791, 2003.

Zhang L, Brereton HM, Hahn M, Froscio M, Tilley WD, Brown MP and Barritt GJ. Expression of the Drosophila transient receptor potential-like (TRPL) Ca2+ channel protein in a prostate cancer cell line decreases cell survival. Cancer Gene Ther. 10: 611-625, 2003.

Buchanan G, Yang M, Cheong A, Harris J, Irvine R, Lambert P, Moore N, Raynor M, Neufing P, Coetzee G and Tilley WD. Structural and functional consequences of glutamine tract variation in the androgen receptor. Hum Mol Genet 13: 1677-1692, 2004.

Jia L, Choong C, Ricciardelli C, Tilley WD and Coetzee GA. Androgen receptor signalling: mechanism of IL-6 inhibition. Cancer Res 64:2619-2626, 2004.

Scher H, Buchanan G, Gerald W, Butler LM, and Tilley WD. Targeting the androgen receptor: improving outcomes for castration resistant prostate cancer. Endocr Relat Cancer 11: 459-476, 2004.

Shen HC, Buchanan G, Butler LM, Prescott J, Henderson M, Tilley WD, Coetzee GA. GRIP1 mediates the interaction between amino- and carboxyl-termini of the androgen receptor. Biol Chem. 386: 69-74, 2005.

Han G, Buchanan G, Harris JM, Ittmann M, Yu X, DeMayo FJ, Tilley WD. Greenberg NM. Mutation of the androgen receptor causes oncogenic transformation of the prostate. Proc Natl Acad Sci USA. 102:1151-1156, 2005.

Ricciardelli C, Choong CS, Buchanan G, Vivekanandan S, Neufing P, Stahl J, Marshall VR, Horsfall DJ, Tilley WD. Androgen receptor levels in prostate cancer epithelial and peritumoral stromal cells identify non-organ confined disease. Prostate. 63:19-28, 2005.

Severi G, Hayes VM, Neufing P, Padilla EJ, Tilley WD, Eggleton SA, Morris HA, English DR, Southey MC, Hopper JL, Sutherland RL, Boyle P, Giles GG. Variants in the prostate-specific antigen (PSA) gene and prostate cancer risk, survival, and circulating PSA. Cancer Epidemiol Biomarkers Prev. 15:1142-1147, 2006.

Severi G, Morris HA, MacInnis RJ, English DR, Tilley WD, Hopper JL, Boyle P, Giles GG. Circulating insulin-like growth factor-I and binding protein-3 and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 15:1137-1141, 2006.

Butler LM, Centenera MM, Neufing PJ, Buchanan G, Choong CS, Ricciardelli C, Saint K, Lee M, Ochnik A, Yang M, Brown MP, Tilley WD. Suppression of androgen receptor signaling in prostate cancer cells by an inhibitory receptor variant. Mol Endocrinol. 20:1009-1024, 2006.

Severi G, Hayes VM, Neufing P, Padilla EJD, Tilley W, Eggleton SA, Morris H, English DR, Southey M, Hopper JL, Sutherland RL, Boyle P and Giles GG. Variants in the Prostate-Specific Antigen (PSA) gene and prostate cancer risk, survival and circulating PSA. Cancer Epidemiol Biomarkers Prev.15: 1142-7, 2006.

Severi G, Morris HA, MacInnis RJ, English DR, Tilley W, Hopper JL, Boyle P and Giles GG. Circulating steroid hormones and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 15: 86-91, 2006.

Chmelar R, Buchanan G, Need EF, Tilley WD and Greenberg, NM. Androgen receptor coregulators and their involvement in the development and progression of prostate cancer. Int J Cancer. 120:719-733, 2006.

Marrocco DL, Tilley WD, Bianco-Miotto T, Evdokiou A, Scher HI, Rifkind RA, Marks PA, Richon VM and Butler LM. Suberoylanilide hydroxamic acid (SAHA; vorinostat) represses androgen receptor expression and acts synergistically with an androgen receptor antagonist to inhibit prostate cancer cell proliferation. Mol Cancer Ther. 51-60, 2007.

Sakko AJ, Ricciardelli, Mayne K, Dours-Zimmermann MT, Zimmermann DR, Neufing P, Tilley W, Marshall VR and Horsfall DJ. Changes in steroid receptors and proteoglycan expression in the guinea pig prostate stroma during puberty and hormonal manipulation. Prostate. 67:288-300, 2007.

Hayes VM, Severi G, Padilla EJD, Morris HA, Tilley WD, Southey MC, English DR, Sutherland RL, Hopper JL, Boyle P and Giles GG. Complexity of 5-alpha reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia. Int J Cancer. 120: 776-80; 2007.

Dwivedi PP, Anderson PH, Tilley WD, May BK, Morris HA. Role of oncoprotein Growth Factor Independent-1 (GFI1) in repression of 25-hydroxyvitamin D 1alpha-hydroxylase (CYP27B1): A comparative analysis in human prostate cancer and kidney cells. J Steroid Biochem Mol Biol. 103:742-6, 2007.

Robzyk K, Oen H, Mandal A, Buchanan G, Butler LM, Tilley WD, Mandal AK, Rosen N and Caplan AJ. Uncoupling of Hormone-dependence from chaperone-dependence in the L701H mutation of the androgen receptor. Mol Cell Endocrinol. 268:67-74, 2007.

Jariwala U, Prescott J, Jia L, Barski A, Pregizer S, Cogan JP, Arasheben A, Tilley WD, Scher HI, Gerald WL, Buchanan G, Coetzee GA, Frenkel B. Identification of novel androgen receptor target genes in prostate cancer. Mol Cancer. 6:39, 2007.

Buchanan G, Ricciardelli C, Harris JM, Prescott J, Yu Z C-L, Jia Li, Butler LM, Marshall VR, Scher HI, Gerald WL, Coetzee GA, Tilley WD. Control of androgen receptor signalling in prostate cancer by the cochaperone small glutamine-rich tetratricopeptide repeat containing protein alpha. Cancer Res. 67:10087-96, 2007.

Ricciardelli C, Jackson MW, Choong CS, Stahl J, Marshall VR, Horsfall DJ, Tilley WD. Elevated levels of HER-2/neu and androgen Receptor in clinically localized prostate cancer identifies metastatic potential. Prostate 68:830-8, 2008.

Centenera MM, Harris JM, Tilley WD, Butler LM. The contribution of different androgen receptor domains to receptor dimerization and signaling. Mol Endocrinol. (Epub ahead of print), 2008.

Sakko AJ, Butler MS, Byers S, Reinboth BJ, Stahl J, Kench JG, Horvath LG, Sutherland RL, Stricker PD, Henshall SM, Marshall VR, Tilley WD, Horsfall DJ, Ricciardelli C. Immunohistochemical level of unsulfated chondroitin disaccharides in the cancer stroma is an independent predictor of prostate cancer relapse. Cancer Epidemiol Biomarkers Prev. 17:2488-97, 2008.

International Patents

5,804,386 USA, 1998. Tilley WD. Prostate cancer screening method which utilizes measurement of apolipoprotein-D levels in body fluids.

WO03/070 Multiple Countries, 2003. Butler LM, Richon VM, Rifkind RA, Marks PA. Method of treating TRX mediated diseases.

US2003235588 USA, 2003. Butler LM, Richon VM, Rifkind RA, Marks PA. Method of treating TRX mediated diseases.