PCFA Research

Prostate cancer is the most common type of cancer that afflicts Australian men and the second highest cause of cancer deaths in men.

Recently, the PCFA approved nearly $6 million of funding for Australian research projects ranging from investigations into genetic susceptibility and the role of cholesterol, to new immunotherapies, ways to slow down and prevent tumour growth and better methods of predicting who will and who won’t need surgery. The PCFA is proud to be supporting these researchers as they work to reduce the impact of prostate cancer on men and their families around Australia. This funding has only been made possible thanks to our generous donors – especially everyone who has supported Movember.

We would like to take this opportunity to introduce some of these important research projects to you, along with the men and women with the knowledge and determination to help sufferers by ridding the world of prostate cancer.

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PROJECT: Cholesterol, statins and prostate cancer

The link between cholesterol and heart disease is well-established. Now new evidence is forging an intriguing link between cholesterol and cancer. A high-fat diet is a well-known, but poorly understood risk factor for prostate cancer, which may involve increased levels of cholesterol in the blood.

Researchers have recently discovered a connection between a major player involved in maintaining cholesterol balance in human cells and a key proliferative pathway that is overactive in many cancers, including prostate cancer. There is also growing evidence that statins, commonly-prescribed cholesterol-lowering drugs, hold promise for the treatment of prostate cancer. However this area remains controversial and solid basic research is needed to support or challenge the use of statins in this way.

The researchers will conduct a series of experiments in prostate cancer cells which firstly explore the link between cholesterol metabolism and a key pathway involved in cell proliferation and hence the development of cancer. Then they will investigate statin drugs as possible anti-cancer agents, determining if and how they work.

Finally, they will investigate a new drug target that they have good grounds to believe may be superior to statins in terms of anti-cancer effects, especially for the treatment of men with prostate cancer.

Dr Andrew Brown is a Senior Lecturer at the University of New South Wales in the School of Biotechnology and Biomolecular Sciences. He has a PhD in the biochemistry of heart disease from the University of Sydney and continued to work on heart disease at the University of Edinburgh in Scotland before returning to Sydney to work at The Heart Research Institute. In 2000, he commenced two years in the laboratory of Nobel laureates, Drs Joe Goldstein and Mike Brown, at the University of Texas, Southwestern Medical Center, Dallas, before taking up his current appointment.

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PROJECT: New ways to diagnose, understand and treat prostate cancer

Some 20 to 30 per cent of men who receive the best early treatment options for prostate cancer (eg radical surgery, radiation therapy or brachytherapy) relapse with life threatening disease within five to seven years.

Because it is known that the androgen hormone testosterone elicits the genetic signals essential for continued prostate tumour growth, this pathway is targeted by hormone therapy / androgen ablation. This is initially a very effective treatment strategy. However, many advanced prostate cancers will eventually become resistant and continue to grow.

The problem with designing more effective approaches is that androgen/testosterone signalling acts to increase or decrease many hundreds, if not thousands, of genes in prostate cancer cells. Until recently only a small number of these genes were known, and it has been impractical to analyse more than one or two in a given project. Researchers have recently identified a gene called PCARC that acts as a master braking system for androgen effects in prostate cancer cells. Importantly, the PCARC gene appears to cease functioning effectively as prostate cancers progress, resulting in amplification of the androgen signalling system.

Initially, researchers will analyse a large number of human prostate cancer samples in order to document the role of PCARC in disease progression and survival. This may be very important in the diagnosis of life-threatening disease. Next, they will couple their capacity to increase or decrease PCARC levels in cancer cells, effectively ‘applying the brake’ or ‘accelerating’ androgen signalling respectively, using powerful new genome-wide techniques. This will allow the researchers to precisely define the complete set of androgen target genes in prostate cancer cells, including those below the previous threshold of detection, and the global consequence of altered PCARC levels.

Finally, they will use a computer-controlled automated biological screening system to scan a library of some 300,000 unique compounds for inhibitors or activators of PCARC. Promising compounds will be tested further as potentially new prostate cancer treatments.

Dr Grant Buchanan (PhD ’02 Flinders in prostate cancer research). Received postdoctoral training at the Universities of Adelaide and Southern California and mentoring from internationally renowned leaders in prostate cancer. He has held a postdoctoral fellowship from the Cancer Council of South Australia, a Young Investigator Award from the US Department of Defense, and an NHMRC CJ Martin Biomedical Fellowship. Dr Buchanan works within the Freemasons Foundation Centre for Mens Health at the Univesity of Adelaide.

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PROJECT: Tumour metastasis in prostate cancer

Prostate cancer is often curable if detected at an early stage, when the cancerous cells are restricted to the prostate. Complexities arise if the cancer that originates in the prostate, metastasises or spreads to other parts of the body, sometimes making the prostate cancer incurable.

Researchers have been investigating the molecular mechanisms that allow cancer cells to metastasise. They have been analysing how a gene known as E-cadherin is ‘switched off’ in cancerous cells. E-cadherin is a cell surface adhesive protein that ensures cells remain stuck in their rightful location. The ‘switching off’ of the E-cadherin gene is known to allow migration and to contribute to the metastasis of cancerous prostate cells.

Researchers have identified regulatory proteins which act in combination to ‘switch off’ the E-cadherin gene. Testing the contribution of these proteins to prostate cancer metastasis and knowing how they cooperate should inform the design of therapeutic drugs to combat prostate cancer. Drugs which inhibit these proteins could reactivate the E-cadherin gene and prevent metastasis of prostate cancer cells.

Professor Merlin Crossley (genetics and microbiology Melbourne, PhD molecular genetics of haemophilia Oxford). Professor Crossley’s doctoral work was supported by a Rhodes Scholarship. He then went on to work at Harvard Medical School and in 1995 he joined the University of Sydney. His research has been recognised by numerous awards, including the Gottschalk Medal from the Australian Academy of Science. In 2004 he was Acting Dean of Science and is currently Acting Deputy Vice-Chancellor (Research) at the University of Sydney.

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PROJECT: A new target for prostate cancer immunotherapy

Researchers at Brisbane’s Mater Medical Research Institute (MMRI) will investigate the potential of a novel prostate cancer protein in generating a stronger immune response in patients with prostate cancer to more effectively destroy the disease.

Early research findings were very encouraging. Immunotherapy is a promising new, non-toxic treatment for prostate cancer that works by training the body’s natural defences against infection, the immune system, to recognise and destroy cancer.

The researchers will aim to conclusively prove the therapeutic power of stimulating the immune system to attack prostate cancer, with a more effective response than ever before.

In 2005 the researchers commenced a phase I clinical trial for an immunotherapy vaccine for prostate cancer, due to be completed this year. The vaccine is created by extracting dendritic cells (DC), the cells responsible for initiating the body’s immune response, from the patient’s blood and priming the cells to order an attack on proteins which are found on cancer cells.

The success of this strategy was dependent on the identification of new proteins which were expressed only on prostate cancer cells, and not normal tissue. These can serve as targets to eradicate the cancer without harming healthy tissue.

This is a highly targeted, individualised approach to treatment which the researchers hope will be more effective and will avoid the harmful impacts on patients commonly associated with prostate cancer treatment. If successful, the team’s findings can be rapidly translated into clinical practice to offer better outcomes for patients by incorporating the new target into the MMRI’s existing vaccine trials.

Dr Kristen Radford, lead researcher, (cancer immunology Newcastle, PhD melanoma mestastisis). Her PhD work led to her award as Young Researcher of the Year by the Leo and Jenny Cancer and Leukaemia Foundation NSW and several other awards. From 1998 until 2001 she worked as a postdoctoral fellow at the Molecular Oncology Unit, Imperial Cancer Research Fund (now Cancer Research UK) in London, focused on developing a novel vaccine strategy for cancer using dendritic cells and Ecoli. She now leads the Dendritic Cell Cancer Team at the MMRI which aims to develop new vaccine strategies for the treatment of a variety of malignancies, but in particular prostate cancers.

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PROJECT: LightCycler 480 real-time
PCR system

Over the past decade researchers have been building resources in Australia, along with local and international scientific collaborators, to enable them to find and characterise prostate cancer (PC) susceptibility genes. This work will lead to an improved understanding of the genetic basis of PC susceptibility and progression.

These researchers have made significant contributions to PC genetics research by planning and performing genome-wide scans on a large number of PC cases and unaffected controls – resulting in the identification of many common genetic variants that are candidates associated with PC risk.

They will now validate these candidate PC risk-associated genetic variants. Due to the small risks associated with these common genetic variants, a very large number of PC cases and unaffected controls are required to validate the findings. These PC studies have a further 8,000 cases and controls (that were not involved in the early phase genome-wide scan) to include in the international collaborative effort to validate the top 50 candidate genes/variants.

To continue these studies and to more precisely measure the cancer risk associated with carrying these genetic variants, molecular analyses must be performed which, because this is a validation study and not a discovery study, and the DNA resources available vary greatly in quality, cannot be carried out commercially.

PCFA funding in this case will go towards the purchase of a LightCycler® 480 Real-Time PCR System from Roche Diagnostics to perform the necessary analyses. This instrument can be interfaced with robotics, such as those already housed in the Genetic Epidemiology Laboratory, to create an automated high-throughput solution.

Associate Professor Melissa Southey is a Molecular Geneticist with a strong background in molecular pathology, genetic epidemiology and cancer genetics. She has been Head of the Genetic Epidemiology Laboratory, University of Melbourne, since 2000 and has recently returned from the International Agency for Research on Cancer (IARC), Lyon, France, where she led a team investigating the genetic predisposition to common cancers. She is an active member of the Genetics Advisory Committee – Hereditary Bowel Cancer Group and The Medical and Scientific Committee, Cancer Council Victoria.

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