South Eastern Sydney Area Tissue Bank

Chief Investigators

Professor Pamela J Russell, Director, Oncology Research Centre1, Conjoint Professor of Medicine, University of New South Wales
Dr Paul Cozzi, Urologist2,3,4
Dr Aparajita Khatri, Senior Research Associate 1
Dr Carl Power, Senior Research Associate1
Dr Yong Li, Senior Cancer Institute NSW Research Fellow, Head of Cancer Research Program2,3

Affiliations

1. Oncology Research Centre, Prince of Wales Hospital, Department of Clinical Medicine, UNSW
2. St George Cancer Care Centre, St George Hospital
3. St George Clinical School, Faculty of Medicine, UNSW
4. Department of Surgery, UNSW

Research Activity

The Oncology Research Centre conducts research into many aspects of prostate cancer, with a major focus on the molecular basis of prostate cancer progression, and studies of novel therapeutic strategies. When prostate cancer progresses, it usually becomes androgen refractory, and often spreads to the bone, causing extreme pain. Interactions between bone cells and prostate cells and of both cell types with immune cells are being studied at the molecular biology and cellular levels; this may lead to the identification of molecules that can be targeted in future therapies.

Combinations of targeted gene therapy involving gene directed enzyme-prodrug therapy (GDEPT) together with chemotherapeutic agents shown to work in some men with castrate resistant prostate cancer, eg, docetaxel are being studied, with advanced prostate cancer a particular target. GDEPT involves the delivery of a gene that expresses an enzyme that catalyses the conversion of a pro-drug (administered systemically) to a toxic metabolite, which in turn interferes with DNA, RNA and protein metabolism, killing cancer cells and nearby cells. In clinical trials conducted in the USA, gene delivery remains a problem. We are developing targeted oncolytic viruses that can deliver a greater payload together with drugs which work well when combined with the viruses in tissue culture. These viruses can enter dividing and non-dividing cells and are not eliminated by an immune response in the patient. Much of the work involves the use of unique models, including modified cell lines, transgenic mice that develop prostate cancer in a similar fashion to man, as well as the growth of prostate cancer cells in mouse bone.

We are also concentrating on using nanoparticles comprising iron oxides and gadolinium oxides to help deliver the viruses to the tumours. The advantage of this is that the nanoparticles can enhance imaging in the presence of magnets, such as when magnetic resonance imaging is used. Current imaging techniques are not sufficiently sensitive to determine whether or not prostate cancer has spread to lymph nodes; knowing this could change management practices. For example, intensity modulated radiation to the pelvis might be more suitable for men with positive lymph nodes than current external beam radiation or seed-based brachytherapy. The use of nanoparticles as image enhancers will enable real time imaging to be performed in men with prostate cancer, providing information about whether the tumour has spread, or responded to current therapies.

St George Cancer Care Centre
Yong Li completed his Ph.D. degree in Faculty of Medicine in 2000 from the UNSW, Sydney, Australia, and postdoctoral training at Cancer Care Center, St George Hospital, Sydney, UNSW, Australia, and then became an independent investigator. Currently, Dr Li is a Senior Cancer Institute NSW Research Fellow and the Head of Cancer Research Program, St George Hospital and Conjoint Senior Lecturer, Faculty of Medicine at UNSW. Dr Li’ research program is aimed at a): To investigate novel biomarkers or tumour-associated antigens for cancer diagnosis, monitoring and therapy; b): To use targeted cancer therapy and combination therapy to control micrometastatic prostate cancer and ovarian cancer; c): To investigate the mechanism of cancer metastasis. These studies will provide new insights into the mechanisms of cancer metastasis, control of micrometastatic development, which may lead to the development of novel therapies for the treatment of cancer progression. The success in identifying proteins of interest in cancer patients may be used to stage the disease, monitor cancer progression and recurrence, and to guide clinicians in choosing the best treatment methods for an individual patient.

Major Prostate Cancer Related Grants (last 5 years)

Identification and validation of molecular markers of prognosis and therapeutic responsiveness in prostate cancer. 2005 (June)-2010 (June), $3,500,000, NSW Cancer Institute, Translational grant. Clark S, Henshall S, Russell PJ, Horvath L, Sutherland R, Kench J, Lee C-Soon, Molloy PL, Grygiel J, Stricker P, Boyer M.

Studies of the role of p53 mutations in metastases of prostate cancer to bone. 2002 (January)-2004 (December), US$456,000, Department of Defense, US Army New Idea Award: DAMD17-02-1-0108, Russell PJ, Brown JM.

Formulated delivery of enzyme/pro-drug and cytokine gene therapy to promote immune reduction of treated and remote tumors in mouse models of prostate cancer, 2003-(January )– 2005 (December) Department of Defense, US Army Alternative funding: DAMD17-02-1-0107, US$522,000 Russell PJ, Khatri A.

The role of IL18 in preventing bony metastasis of prostate cancer to bone 2003 (September) – 2005 (August) US$216,000. NIH grant DK067681-01 Russell PJ, Martiniello-Wilks R, Zhang A.

Oncogenic action and therapeutic potential of PLA2 in prostate cancer. 2004 – 2006. $490,500. Department of Veterans’ Affairs, Australia, Dong Q, Scott K, Graham G, Russell PJ.

Control of micrometastatic prostate cancer using multiple alpha targeted therapy 2004 - 2006, US$471,000. US Army, Department of Defense, New Investigator Award, Li Y, Cozzi PJ, Russell PJ, Diwan A, Rizvi SMA, Allen BJ.

The role of the TGF-b superfamily cytokine MIC-1 in the biology of cancer 2006 (January)-2008 (December), $375,000, NSWCC, Breit S, Russell PJ

Inhibition of bony metastases by therapeutic agents from Novartis (alone or in combination) using prostate cancer RM-1(BM)GFP metastasis model in immunocompetent mice, 2006 – 2007, $130,000, Novartis, Power C, Russell PJ.

Secreted phospholipase A2 in prostate cancer, 2007 – 2009, $300,000, NSW Cancer Council. Scott K, Graham G, Dong Q, Russell PJ.

Studies of bony metastases. 2007-2009 $225,000. Sydney Foundation of Medical Research, Power C, Russell PJ.

Identification of novel biomarkers in tears for prostate cancer diagnosis and prognosis, 2007-2009, $135,000. ARC LIEF, LP0774951, Li Y, Willcox MD, Cozzi PJ, Russell PJ, Walsh BJ, Zhao Z.

Using proteomic approaches to identify novel biomarkers in tear and serum to improve diagnosis and monitor progression in prostate cancer, 2008-2010, $580,000. Career Development Fellowship, Cancer Institute NSW, Australia, Li Y.

Studies of bone metastasis from prostate cancer.2008 – 2010, $300,000. UNSW Foundation & Prostate Cancer Foundation of Australia, Post-Doctoral Fellowship. Russell PJ, Power C.

Combined novel tumour-targeted molecular and traditional chemotherapy for treating androgen refractory prostate cancer, 2008 – 2010, $520,500. Russell PJ

Preclinical evaluation of novel prostate-targeted nanoparticles for imaging primary and metastatic prostate cancer, 2008 (July) – 2010 (June), $584,000 Cancer Australia and

Prostate Cancer Foundation of Australia (NHMRC 510239), Russell PJ, Thierry B, Walsh BJ, Bucci J, de Souza P, Khatri A.

Potential therapeutic roles for a protease inhibitor, 2008 – 2009, $160,500. NH&MRC Development Grant, 497290. Harris J, Clements J, Russell PJ.

Selected Prostate Cancer Related Publications (last 5 years)

Welsh JB, Sapinoso LM, Kern SG, Brown DA, Liu T, Bauskin AR, Ward RL, Hawkins NJ, Quinn DI, Russell PJ, Sutherland RL, Breit SN, Moskaluk CA, Frierson HG Jr, Hampton GM. Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proc Natl Acad Sci, USA, 100: 3410-5, 2003.

Liu T, Bauskin AR, Zaunders J, Brown DA, Pankurst S, Russell PJ, Breit SN. Macrophage inhibitory cytokine 1 reduces cell adhesion and induces apoptosis in prostate cancer cells. Cancer Res. 63: 5034-40, 2003.

Martiniello-Wilks R, Dane A, Jeyakumar G, Mortensen E, Shaw JM, Wang X-Y, Both GW, Russell PJ. Gene-directed enzyme prodrug therapy for prostate cancer in a mouse model that imitates the development of human disease. J Gene Medicine, 6: 43-54, 2004.

Zhao Z, Raftery MJ, Niu XM, Daja MM and Russell PJ. Characterization and identification of urokinase-type plasminogen activator (uPA) in secreted proteins from a prostate cancer cell line, PC-3. Electrophoresis, 25: 1142-1148, 2004.

Russell PJ, Ow KT, Tam PN, Juarez J, Kingsley EA, Qu CF, Li Y, Cozzi PJ, Martiniello-Wilks R. Immunohistochemical characterization of the monoclonal antibody, BLCA38, for the detection of prostate cancer. Cancer Immunol Immunother, 53: 995-1004, 2004.

Martiniello-Wilks R, Wang XY, Voeks DJ, Dane A, Shaw JM, Mortensen E, Both GW and Russell PJ. Purine nucleoside phosphorylase and fludarabine phosphate gene directed enzyme prodrug therapy suppresses primary tumour growth and pseudo-metastases in a mouse model of prostate cancer. J Gene Med, 6: 1343-1357, 2004.

Wang X-Y, Martiniello-Wilks R, Shaw JM, Ho T, Coulston N, Cooke-Yarborough C, Molloy PL, Cameron FH, Moghaddam M, Lockett TJ, Webster LK, Smith IK, Both GW and Russell PJ. Preclinical evaluation of a prostate targeted gene therapy enzyme prodrug therapy delivered by an ovine atadenovirus. Gene Therapy, 11: 1559-1567, 2004.

Li Y, Rizvi SMA, Brown JM, Cozzi PJ, Qu CF, Ow, KT, Tam PN, Perkins AC, Russell PJ, Allen BJ. Antigenic expression of human metastatic prostate cancer lines and primary prostate cancer for in vitro multiple alpha-targeted therapy with 213Bi- conjugates. Int J Radiation Oncology Biology Physics (IJROBP), 60: 896-908, 2004.

Sved P, Scott KF, McLeod D, King NJC, Singh J, Tsatralis T, Nikolov B, Boulas J, Nallan L, Gelb MH, Sajinovic M, Graham GG, Russell PJ, Dong Q. Oncogenic action of secreted phospholipase A2 in prostate cancer. Cancer Res, 64: 6934-6940, 2004.

Bauskin AR, , Brown DA, Junankar S, Krishan Y, Rasiah KK, Eggleton S, Hunter M, Liu T, Smith D, Kuffner T, Pankhurst GJ, Johnen H, Russell PJ, Barret W, Stricker PD, Grygiel JJ, Kench JG, Henshall SM, Sutherland RL, Breit SN. The propeptide mediates formation of stromal stores of promic-1; role in determining prostate cancer outcome. Cancer Res, 65(6):2330-6, 2005

Brown DA, Stephan C, Ward RL, Law M, Hunter M, Bauskin AR, Amin J, Jung K, Diamandis EP, Hampton GM, Russell PJ, Giles G and Breit SN. Measurement of serum levels of macrophage inhibitory cytokine 1 combined with prostate-specific antigen improves prostate cancer diagnosis. Clin Cancer Res, 12:89-96, 2006

Khatri A, Zhang B, Doherty E, Chapman J, Ow K, Pwint H, Martiniello-Wilks R, Russell PJ. Combination of cytosine deaminase with uracil phosphoribosyl transferase leads to local and distant bystander effects against prostate-cancer in C57BL/6 mice. J Gene Medicine, J Gene Med. 8(9):1086-96, 2006

Russell PJ, Khatri A. Novel gene-directed enzyme prodrug therapies against prostate cancer. Expert Opin on Investigational Drugs. Invited review, 15(8):947-61, 2006.

Wang J, Rizvi SMA, Madigan MC, Cozzi PJ, Power CA, Morgenstern A, Apostolidis C, Russell PJ, Allen BJ, Li Y. Control of prostate cancer spheroid growth using 213Bi-labeled multiple targeted α radioimmunoconjugates. Prostate 66(16):1753-67, 2006

Vandyke K, White MY, Nguyen-Khuong T, Ow K, Kingsley E, Rowe A, Luk SC-W, Pang S-F, Walsh BJ, Russell PJ. The herbal extract MINA-05 inhibits the proliferation of human prostate cancer cells in vitro and suppresses lymph node metastases in vivo. Neoplasia 9(4):322-31, 2007.

Zhang A-L, Russell PJ, Knittel A, Milross C. Paclitaxel enhanced radiation sensitisation for the suppression of human prostate cancer tumor growth via a p53 independent pathway Prostate 67:1630-1640, 2007.

Li Y, Cozzi PJ. MUC1 is a promising therapeutic target for prostate cancer therapy. Curr Cancer Drug Targ 7:259-271, 2007

Li Y, Cozzi PJ. Targeting uPA/uPAR in prostate cancer. Cancer Treat Rev 33:521-527, 2007

Jeet V, Ow K, Doherty E, Curley B, Russell PJ, Khatri A. Broadening of transgenic adenocarcinoma of the mouse prostate (TRAMP) model to represent late stage androgen independent cancer. Prostate 68(5):548-62, 2008.

Madigan MC, Kingsley EA, Cozzi PJ, Delprado WJ, Russell PJ, Li Y. The role of extracellular matrix metalloproteinase inducer protein in prostate cancer progression. Cancer Immunol Immun 57:1367-1379, 2008.

Cozzi PJ, Kearsley J, Li Y. Overview of tumor-associated antigens (TAAs) as potential therapeutic targets for prostate cancer therapy. Curr Cancer Treat Rev, accepted 11 June 2008.

Li Y, Song E, Rizvi SMA, Power CA, Beretov J, Raja C, Cozzi PJ, Morgenstern A, Apostolidis C, Allen BJ Russell PJ. Inhibition of micrometastatic prostate cancer cell spread in animal models by 213Bi-labeled multiple targeted α radioimmunoconjugates. Clin Cancer Res, accepted 28 July, 2008.

Books/Book Chapters

Editors: Russell PJ, Jackson P, Kingsley EA. Prostate Cancer Methods and Protocols, Humana Press, Totowa, New Jersey, 2003.

Allen BJ, Li Y, Rizvi SMA, Russell PJ. Targeted alpha therapy of prostate cancer. In: Prostate Cancer Methods and Protocols. Ed PJ Russell, P Jackson, EA Kingsley, Humana Press, P333-357 2003.

International Patents

A composition and method for killing tumours. Both GW, Lockett TJ, Molloy PL, Cameron FH, Russell PJ, Martiniello-Wilks R, Moghaddam MJ and Smith IK. WO2003AU00381, priority 28/03/03. Licensed to MaynePharma.

Provisional Patent: filed Dec, 2004. Goldstein D, Yang J-L, Qu X-J, Russell PJ, OSI Pharmaceuticals. Treatment for colon cancer by combination of erlotinib and interferon-alpha.

Provisional Patent: No 082196AU, filed March, 2008. Li Y, You J, Willcox M, Cozzi PJ, Russell PJ, Walsh B, Zhao Z. Prostate Cancer Biomarkers