A lifetime dedicated to prostate and bladder cancer research

A new, targeted antibody-based treatment and diagnostic for prostate and bladder cancers is one of several important outcomes from the research career of Emeritus Professor Pamela Russell AM, which spans more than five decades, $35 million in research funding and 200 plus journal papers.

The internationally renowned Professor Russell also has been instrumental in helping establish some of Australia’s most important prostate research groups and charities. Having moved to Queensland in 2009 with a Queensland University of Technology appointment, and been working within the TRI since it opened, we spoke to Professor Russell about her achievements.

TRI:                       What is the most significant discovery you made in your career?

Prof Russell:      A series of discoveries and breakthrough studies led to the development of a potential new treatment and imaging diagnostic for prostate and bladder cancers known as Miltuximab®. After 30 years of laboratory work, it is now being trialled in patients.

TRI:                      Can you tell us more about the journey you went on with Mituximab?

Prof Russell:     The journey from discovery to therapeutic began in 1984 when I started working with the oncologist Dr Derek Raghavan and the iconic urological surgeon, Dr Bruce Pearson at The University of Sydney. To understand urological cancers, we knew we needed to develop a good laboratory model. To this end, we successfully created several new mouse models of bladder and prostate cancers by xenografting small fragments from patient tumours as well as three new human bladder cancer cell lines.

With Dr Karen Walker, we made a series of monoclonal antibodies against one of the bladder cancer lines. Excitingly, we found we could use these antibodies to detect bladder cancer cells in urine specimens. We went on to show that one of the antibodies, MIL-38, could be labelled for PET imaging of bladder cancer. Importantly, we discovered this particular antibody also interacted with other cancers, including prostate cancer.

After a decade’s worth of research – including a collaboration with CSIRO and the pharmaceutical company, CSL – we had enough preclinical data to show that MIL-38 had potential both for imaging and treatment of tumours when appropriately radiolabelled.

To help get the antibody developed as a therapeutic, we provided it to the biotech, Minomic International Ltd in 2007. The company used the antibody to create Miltuximab®, which is a chimeric version (engineered on a human IgG1 wild-type backbone) of MIL-38.  They also showed the antibody reacts with the target, glypican-1, which is expressed by various solid tumours in addition to bladder and prostate cancer, including pancreatic cancer.

Miltuximab® is now being commercialised by GlyTherix. The company has completed a first in human clinical trial with Miltuximab®, where the antibody demonstrated an excellent safety profile with no drug related adverse events reported.

Based on these results and further preclinical work by my QUT team, which was published in 2020, GlyTherix is now planning a Phase I theranostic clinical trial using 89-Zirconium labelled Miltuximab^® to identify patients suitable for treatment with 177-Lutetium labelled Miltuximab.

Our work in laboratory still isn’t finished though, as we will continue to work with GlyTherix to better understand the role of glypican-1 in prostate cancer.

TRI:                      Are there any other research breakthroughs that you are proud of?

Prof Russell:     Yes, there are! I completed my PhD studies with [the famous immunologist] Sir Gustav JV Nossal on mouse models of autoimmunity. My great interest in ‘translational’ research began at this time as I could see the possibility for research to translate to clinical treatments. During my PhD, I showed that the drug, cyclophosphamide , could be used successfully to treat mice with autoimmune disease. Publication of the work in The Lancet in 1965 and 1966 led to cyclophosphamide being used to treat patients with Systemic Lupus Erythematosus. This treatment remains in use for some patients 50 years later!

                            During my early bladder cancer research, our in vivo studies using the bladder xenografts lines showed that a new drug, isopropyl cisplatin, was effective against bladder cancer. Since this work was published in 1986, the drug has been translated to the clinic.

                        I have also been very interested in targeted imaging and therapy and a theranostic approach to the treatment of urological cancers. I’ve furthered the development of my theranostics research, including the use of nanotechnology for real time imaging for diagnosis and therapeutic delivery, targeted gene therapy of prostate cancer, and finding biomarkers to predict treatment response in patients undergoing therapy. We are hopeful that some of these preclinical studies will realise potential in the clinic.

TRI:                     Outside of the lab, you’ve played a key role in helping develop the urological research community and prostate charities. Can you tell us a little bit about the roles you’ve played?

Prof Russell:     In the 1980s, I realised funding from the NHMRC was much higher for breast cancer than prostate cancer so I approached Roger Climpson, a television star who suffered from prostate cancer, to see if he might help. Together with his Rotarian colleagues, we set up the Prostate Cancer Research Foundation, which subsequently joined with Prostate Cancer Support Groups to form the Prostate Cancer Foundation of Australia. I was an inaugural director.

                          More recently, Movember International Committee invited me to become a member. Their mandate is to bring together and competitively fund research groups to form international consortia who would share their experience to address difficult areas of prostate cancer research. As amember of this international committee, I was also a member of the Research Advisory Committee of Movember’s Global Action Plan One. Movember are now contributing to the funding some important clinical trials.

                          In terms of furthering prostate research, prior to the days of multidisciplinary team clinics to discuss patient treatments, I realised there was a gap in knowledge of what differently skilled groups, such as oncologists, radiation oncologists, surgeons, scientists, pathologists and others were attempting to achieve. Together with my colleagues from different disciplines, we set up the Genitourinary Oncology Group (GUOG) in an attempt to overcome this problem.

                         The group was initially set up in NSW and eventually throughout Australia and New Zealand. It enabled people to interact in their research and clinical studies and develop friendships with people in different disciplines. We also ran a series of expert-led education programmes and three international conferences, but did not fully attain our goal of increased involvement in clinical trials.

                         Around this time, I joined in discussions around developing the Australian Prostate & Urogenital Cancer Group (APUG) and then later the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) when APUG joined with its New Zealand counterpart in 2008. I was on the initial board for both groups. ANZUP was able to fulfil the need for collaboration on clinical trials along with a multidisciplinary focus and ANZUP members are at the forefront of many clinical trials for bladder, germ cell, renal prostate and kidney cancers.  I’ve only recently retired from membership of their Scientific Advisory Committee.

TRI:                     What do you think is the future of prostate and bladder cancer research?

Prof Russell:      My belief is that combination therapies will become a more prominent feature of new clinical trials. Immunotherapy, together with current therapies, is already being proposed for bladder, renal and other cancers.

                        Understanding the role of the microbiome in the response to therapy will become an increasing area of research given the role of the gut in stimulating immune responses and how this can be affected by “bad” bacteria. Combined preclinical and clinical studies of patients with melanoma have shown that the microbiome can affect responses to immunotherapy or combined therapy for treating this cancer.

                              In addition, given the enormous costs involved in the development of new drugs, I believe there will be an increased energy in studies for repurposing existing drugs.

TRI:                      Why is medical research so important?

Prof Russell:      Research is a critical and necessary step in the development of new treatments, in ironing out difficulties experienced with current procedures and in moving forwards into new areas of endeavour to help treatment of patients with cancer.

TRI:                      What attracted you to move to the TRI?

Prof Russell:      Well, the Australian Prostate Cancer Research Centre – Qld , QUT, which I joined in 2009, had laboratories within the TRI. We moved in as soon as TRI opened. This Institute is situated adjacent to the Princess Alexandra Hospital in Brisbane, and houses some 1000 researchers, including scientists and medical specialists along with some companies developing new medical products and devices. This combination offers enormous benefit to all involved for potential fast-tracking of translation of new scientific and medical endeavours to the clinic.

TRI:                      You recently retired, but are still planning on doing more research?

Prof Russell:      No, I am essentially retired, although we have some work yet to be published on examining the role of glypican-1 in tumour growth. This is being achieved by examining effects of glypican-1 knock down in human prostate cancer cell lines both in vitro and in vivo.

Thank you for your time Prof Russell and sharing your thoughts and accomplishments.

About Emeritus Professor Russell BSc, MSc, PhD, Dip Ed, AM, FAHMS

Emeritus Professor Russell began her career in research by training in immunology at Walter & Eliza Hall Institute, where she obtained her Masters in Science with the Nobel Prize winner, Sir Macfarlane Burnet, and a PhD with Sir Gustav JV Nossal. Her postdoctoral studies were undertaken with Professor Gordon Ada in Canberra at the John Curtin School of Medical Research and in Sydney with Prof David Nelson at the Kolling Institute of Medical Research.

In 1984, Prof Russell changed her research focus to cancer and, with Dr Derek Raghavan, established the Urological Cancer Research Centre at the Royal Prince Alfred Hospital/University of Sydney. Prof Russell subsequently became Director, Oncology Research Centre (ORC), Prince of Wales Hospital from 1992 to 2010, as conjoint Professor of Medicine, University of New South Wales. In 2009, Prof Russell joined the Australian Prostate Cancer Research Centre - Queensland (APCRC–Q) as Professor, Head of Biomedical Imaging and Prostate Cancer Models and a member of the Institute of Health and Biomedical Innovation, Queensland University of Technology. Based at TRI from 2014, Prof Russell also took up a role as the Institute’s Project Development Co-ordinator in the Clinical team. In 2017, the Queensland University of Technology made Prof Russell an Emeritus Professor.

Prof Russell helped to initiate and was a Director of the Australian Genitourinary Oncology Group and an inaugural founder and Director of the Prostate Cancer Foundation of Australia (PCFA) (of which she is a life member). From 2007 to 2010, Prof Russell served as an inaugural Director/Secretary of the Australasian Urological and Prostate Cancer Clinical Trials Group (ANZUP) and until 2020 was a member of their Scientific Advisory Committee (SAC).  She was also an Australian editor for Urological Research and a represented Australia as a member of Movember’s Global Scientific Committee.

Prof Russell has secured more than $35 million in research funding and has been on peer review committees for the National Health and Medical Research Committee (NHMRC) and Cancer Council Australia. She has also been a member of Research Advisory Committees for Cure Cancer Australia and the Movember, Global Action Plan 1 Committee. Professor Russell continues to regularly review for international grant committees and international journals.

Awards and Fellowships

• 1984: Member, International Bladder Cancer Network
• 2003: Member of the Order of Australia
• 2006: Outstanding alumni, Kolling Institute of Medical Research
• 2009: Honorary Life Member, Australasian Gene therapy Society
• 2010: Prostate Cancer Foundation of Australia award for Outstanding Excellence
• 2011: Festschrift in her honour at Prince of Wales Clinical School UNSW
• 2015: Women in Technology Life Sciences Outstanding Achievement Award

            University of Canberra Alumni excellence Award in Health
            Fellow of the Australian Academy of Health and Medical Sciences

Selected journal publications

Prof Russell is a co-author of seven patents as well as publishing two books, 19 book chapters and more than 200 papers.  Here are several papers of interest, which Prof Russell has selected.

• Yeh MC, Tse BWC, Fletcher NL, Houston ZH, Lund M, Volpert M, Stewart C, Sokolowski KA, Jeet V, Thurecht KJ, Campbell DH, walsh BJ, Nelson CC, Russell PJ., “Targeted beta therapy of prostate cancer with 177 Lu-labelled Miltuximab® antibody against glypican-1 (GPC-1).”,  Ejnmmi Research (2020) 10:46. https://doi.org/10.1186/s13550-020-00637-x

• McGovern JA, Shaf Lee A, Wagner F, Lahr CA, Landgraf M, Meinert C, Williams ED, Russell PJ, Clements JA, Loessner D, Holzapfel BM, Risbridger GP, Hutmacher DW., “Humanization of the Prostate Microenvironment Reduces Homing of PC3 Prostate Cancer Cells to Human Tissue-Engineered Bone.”, Cancers, 2018, . 13;10(11). pii: E438. doi: 10.3390/cancers1011043810 (11) 438-

• Pearce AK, Simpson JD, Fletcher NL, Houston ZH, Fuchs AV, Russell PJ, Whittaker AK, Thurecht KJ., “Localised delivery of doxorubicin to prostate cancer cells through a PSMA-targeted hyperbranched polymer theranostic”, Biomaterials, 2017;141:330-339. doi: 10.1016/j.biomaterials.2017.07.004. Epub 2017 Jul 5. PMID:28711780

• Volpert M, Tse BWC, , Ratther E, Stylianoou n, nouri M, McGowan M, Lehman ML, McPherson SJ, Roshan-Moniri M, Butler MS, Caradec J, Gregory-Evans CY, McGovern J, as R, Takhar M, Erho N, Alshalafa M, Davicioni E, Schaeffer EM, Jenkins RB, Karnes RJ, Den RB, Fazli L, , Gregory PA, Gleave ME, Williams ED, Rennie PS, Buttyan R, Gunter JH, Selth LA , Russell PJ, Nelson CC, Hollier BG., “Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality”, Oncogene, 2017;36: 3417–3427. doi: 10.1038/onc.2016.482

• Singh P, Joshi S, Russell PJ, Verma N, Wang XC, Khatri A., “Molecular chemotherapy and Chemotherapy: A new front against late stage hormone refractory prostate cancer”, Clinical Cancer Research, 2011; 17(12): 1–13.

• Tang C, Russell PJ, Martiniello-Wilks R, Rasko J, Khatri A., “Concise Review: Nanoparticles and cellular carriers - allies in imaging and therapy?”, Stem cells, 2010; 28(9):1686-702-702.

• Khatri A, Husaini Y,  Ow K, Chapman J, Russell PJ., “Cytosine Deaminase-Uracil Phosphoribosyl Transferase and Interleukin-12 and -18: a multimodal anticancer interface marked by specific modulation in serum cytokines”, Clin Cancer Res, 2009; 15(7):2323-2234.

• Martiniello-Wilks R, Garcia-Aragon J, Daja M, Russell P, Both GW, Molloy PL, Lockett LJ, Russell PJ.  In vivo gene therapy for prostate cancer: preclinical evaluation of two different enzyme-directed prodrug therapy systems delivered by identical adenovirus vectors.  Human Gene Therapy, 1998; 9:1617-1626.

• 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 213-Bi-labeled multiple targeted a radioimmunoconjugates”, Clin Cancer Res., 2009; 15:865-875.

• Millar, D, Ow KT, Paul C, Russell PJ, Molloy PL, Clark SJ.  Detailed methylation analysis of the glutathione S-transferase p (GSTPI) gene in prostate cancer.  Oncogene, 1999; 18(6):1313-1324.

• Yu Y, Yang, J-L Markovic B, Jackson P, Yardley G, Barrett J, Russell PJ.  Loss of KAI 1 messenger RNA expression in both high grade and invasive human bladder cancers.  Clin Cancer Res, 1997; 3:1045-1050.

• Raghavan D, Shipley WU, Garnick MB, Russell PJ, Richie JP.  Biology and management of bladder cancer: advances and innovations.  N Eng J Med, 1990; 322(16):1129-38.

• Russell PJ, Raghavan D, Gregory P, Philips J, Wills EJ, Jelbart M, Wass J, Zbroja R, Vincent PC.  Bladder cancer xenografts: a model of tumor cell heterogeneity.  Cancer Res, 1986; 46(4 Pt2):2035‑40.                             

• Miller JFAP, Brunner KT, Sprent JS, Russell PJ,  Mitchell GF.  Thymus‑derived cells as killer cells in cell‑mediated immunity.  Transplant Proc 1971; 3(1):915‑7.

• Diener E, Shortman K, Russell PJ.  Induction of immunity and tolerance in vitro in the absence of phagocytic cells.  Nature, 1970; 225(5234):731‑2.

• Russell PJ, Hicks JD, Burnet FM.  Cyclophosphamide treatment of kidney disease in (NZB x NZW)F1 mice.  Lancet, 1966; June 11, 287(7450):1279‑84 (Leading article).