South Eastern Sydney Area Tissue Bank

Chief Investigators

Professor Pamela J Russell, Director, Oncology Research Centre¹

Professor Barry Allen, Director, Centre for Experimental Radiation Oncology (CERO)²

Dr Paul Cozzi, Urologist^2,3

Dr Paul Jackson, Principal Hospital Scientist¹

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

Mr Kim Ow, Senior Hospital Scientist¹

Dr Syed Rizvi, Senior Research Officer, CERO, Research Fellow US DOD Prostate Cancer Research Program²

Affiliations

1. Oncology Research Centre, Prince of Wales Hospital, Department of Clinical Medicine, UNSW

2. Centre for Experimental Radiation Oncology (CERO), St George Cancer Care Centre, St George Hospital

3. 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. Studies on the role of the tumour suppressor gene, p53, using unique human prostate cancer cell lines expressing wild type or mutated p53, as found in patients, are being performed. The p53 gene is often mutated in prostate cancer metastases. The 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. Combination gene therapy involving gene directed enzyme-prodrug therapy (GDEPT) together with genes that augment an immune response against prostate cancer 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 hope to develop targeted oncolytic viruses that can deliver a greater payload together with cytokine genes to upregulate the immune response. 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.

Centre for Experimental Radiation Oncology (CERO): The Targeted Alpha Therapy  (TAT) project involves the labelling of targeting vectors with an alpha-emitting radioisotope, and in vitro and in vivo studies with these alpha-conjugates to determine efficacy and toxicity.

The alpha-emitting radioisotope Bi-213 is eluted from an Ac-225 generator, and chelated to monoclonal antibodies against melanoma, leukaemia, colorectal, prostate, pancreatic and ovarian cancers and to plasminogen activator inhibitor (PAI2) protein for breast and prostate cancer. Our group is currently engaged in a phase 1&2 clinical trial of TAT for subcutaneous (sc) recurrent melanoma, having obtained approval from the SESAHS Ethics Committee and the NSW Radiation Advisory Council.

We have already demonstrated that TAT, using a single vector of ²¹³Bi-labeled MAb (J591) or PAI2 protein, is effective against prostate cancer (CaP) cells, being selectively cytotoxic to CaP cells in vitro and inhibiting the development of tumours in vivo. Alpha-PAI2 has been extensively studied, and toxicity studies in mice (MTD = 10 mCi/kg) have been competed and are underway in rabbits (MTD~2 mCi/kg) (unpublished data). ). PAI2 is a recombinant humanized protein, and as such, should not elicit an immune response.

The objective of the TAT project is to move to clinical trials. Currently, TAT for intralesional secondary melanoma is ongoing, and a systemic study has been approved. TAT for prostate cancer, after hormonal therapy, is on track to commence in the near future.

Major Prostate Cancer Related Grants (last 5 years)

• Gene therapy for prostate cancer. 1998-2003. Oncology Research Centre, Prince of Wales Hospital received 1999:$312,756, 2000:$186,229, 2001:$259,394.80, 2002: $389,000, 2003: $67,000 FH Faulding Limited, then Mayne Pharma Pty Ltd: support for CSIRO, SESAHS:

• Studies of proteases produced by prostate cancer cells. 2001-2002, 2000: $166,585, 2001: $81,838, Sydney Foundation for Medical Research; Russell PJ and Daja MM.

• Targeted alpha therapy: development of a new treatment for metastatic cancer, 2002-3, $390,000, NHMRC Development; Allen BJ.

• Studies of proteases in prostate cancer cells. 2002-2004, $176,000 (total), Sydney Foundation for Medical Research; Russell PJ and Zhao Z.

• Studies of the role of p53 mutations in metastases of prostate cancer to bone. 2002-04, US$456,000. Department of Defense, US Army. New Idea Award: Russell PJ, Brown JM (ORC):

• 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. 2002-2004, US$522,000, Department of Defense, US Army, Alternative funding: Russell PJ, Both GW, Molloy PL and others from CSIRO (ORC and CSIRO.  We obtained a no-cost extension: 2003-2005 Authors now: Russell PJ, Khatri A.

• Studies on the metastasis to bone of human prostate cancer. 2003, $60,000, Cure Cancer Australia Foundation grant; Brown JM and Russell PJ.

• Role of Bone Resorption in the Metastasis of Prostate Cancer to Bone. 2003, US$25,000 to ORC and US$25,000 to Anzac Research Institute, Amgen Corporation funding; Brown JM, Seibel M and Dunstan CR.

• Augmentation of novel enzyme/pro-drug gene therapy “distant bystander effect” to target prostate cancer metastasis. 2001-2002, postponed to 2003-2004, US $97850, Division of Defense, US Army, Trainee Fellowship award, Martiniello-Wilks R.

• The role of IL-18 in preventing metastasis of prostate cancer to bone. 2003–2005, US $200,000. NIH CA 03-013 application; Russell PJ, Power C.

• Targeted alpha therapy for metastatic breast cancer using alpha-herceptin, 2003-5, $330,000, NHMRC Development ; B J Allen.

• Preclinical studies of multi-targeted alpha therapy for prostate cancer, 2004-6, $471,000; US Department of Defense; Y Li (PJ Russell, mentor)

• 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.

Selected Prostate Cancer Related Publications (last 5 years)

• Martiniello-Wilks R, Tsatralis T, Russell P, Brookes DE, Zandvliet D, Lockett LJ, Both GW, Molloy PL and Russell PJ.  Transcription-targeted gene therapy for androgen-independent prostate cancer.  Cancer Gene Therapy, 9: 443-52, 2002.

• Voeks D, Martiniello-Wilks R, Madden V, Smith K, Bennetts E, Both GW, and Russell PJ.  Gene therapy for prostate cancer delivered by ovine adenovirus and mediated by purine nucleoside phosphorylase and fludarabine in mouse models. Gene Therapy, 9: 759-768, 2002.

• Li Y, Rizvi S, Ranson M,  Allen BJ.   ²¹³Bi-PAI2 conjugate selectively induces apoptosis in PC3 metastatic prostate cancer cell line and shows anti-cancer activity in a xenograft animal model. Brit J Cancer, 86: 1197-1203, 2002.

• 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.

• Downing SR, Bumac C, Nixdorf S, Ow KT, Russell PJ, Jackson P.  Elevated levels of prostate-specific antigen (PSA) in prostate cancer cells expressing mutant p53 is associated with tumor metastasis, Molecular Carcinogenesis, 38: 130-140, 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, In press, Jan 11, 2005.

• Zhang A-L, Russell, PJ.  Paclitaxel suppresses the growth of primary prostate tumours (RM-1) and metastases in the lung in C57BL/6 mice.  Cancer Lett. 233:185-191, 2006.

• 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.

• Perryman LA, Blair JM, Kingsley EA, Szymanska B, Ow KT, Wen VW, MacKenzie KL, Vermeulen PB, Jackson P, Russell PJ. Over-expression of p53 mutants in LNCaP cells alters tumor growth and angiogenesis in vivo Biochem Biophys Res Commun. 345(3):1207-14, 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 a radioimmunoconjugates.  Prostate, accepted July 19, 2006.

Books/Book Chapters

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

• PCT/AU90/00218, 24/5/1991; 100743.3207@CompuServe.COM (1996) Pamela J Russell, Karen Z Walker. Monoclonal antibodies which recognise malignant cells from bladder carcinoma.

• 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.