Pursuing the Prostate

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By Tim Lougheed

As if to make modern man feel a little more special, he and the domesticated dog have the largest prostates — relative to their body size — of any mammal on the planet. This dubious distinction is unquestionably linked with the fact that they are also the only mammals to suffer from spontaneous prostatic carcinoma. That may be just one reason why male baby boomers are bound to be looking between their legs with rapt attention over the coming decade and beyond.

With an average age that is now 50 or more, members of this sizeable demographic group are susceptible to an incidence of prostate cancer that mounts with each passing year. One in eight men over that age will have an encounter with the disease, which is already the most commonly diagnosed cancer among North American men. Treatment runs a gamut from radiation and chemotherapy for quelling a tumour to removal of the gland itself or even surgical castration to stop the output of sex hormones that can influence the disease process. Not surprisingly, prostate cancer has become an increasingly high priority for researchers and clinicians seeking to understand and treat this often fatal condition.

These investigators have their work cut out for them. Besides its almost exclusively human aspect, prostate cancer poses puzzles and challenges as significant as those in any other branch of oncology. The most hotly contested points of discussion deal with etiology — the tension between nature and nurture that enters into almost any consideration of cancer. In some cases, such as establishing a link between tobacco and lung cancer or asbestos and liver cancer, environmental factors have been demonstrated as primary causes. Yet even in these clearcut instances, the role of genetic predisposition continues to be weighed. As we continue to refine the biotechnological tools and concepts that we can apply to genetic processes, we find ourselves exploring the “nature” side of the debate at the molecular level, revealing the origin of cancer in some of the most subtle interactions of the body’s proteins.

We may owe some of those interactions to other uniquely human traits. Mel Greaves, PhD points out that we have the longest sex life of any animal, relative to our entire lifespan. Begun as early as the teenage years, sexual activity can continue well into old age, decades after the conceiving and bearing of children is over and done with. For Greaves, who is director of the Leukaemia Research Fund Centre for Cell and Molecular Biology at the Institute of Cancer Research in the U.K., our sexual longevity could put us at risk for problems that were unknown to our forebears.

“Our current lifestyles are not at all those to which we originally adapted,” he says, offering as an example the predominance of diabetes among Canada’s native populations. This phenomenon has been linked with an inherited metabolic ability to cope with sporadic shortages of food, which enabled the body to remain physically active during times of famine. Yet this same ability forms a diabetic response when an individual consistently adopts the regular diet and more sedentary lifestyle of post-industrial society.

Similar changes in lifestyle have been blamed for the rising incidence of breast cancer, which has been linked to women achieving menarche earlier, delaying childbirth, and having fewer children than their evolutionary ancestors. Exposed to higher levels of female sex hormones over the course of a lifetime, these women’s bodies may generate hormonal imbalances with carcinogenic results.

In much the same way, Greaves observes that men’s large prostates may be another evolutionary holdover, a means of having seminal fluid constantly “on tap” to take advantage of the fact that human females can conceive at any time of year rather than in a particular season. This, combined with the large amounts of male sex hormones that are released after orgasm, may be imposing long-term stress on the prostates of men having sex beyond the age of 50 or so — stress that could become carcinogenic.

“There are so many parallels between prostate cancer and breast cancer, in terms of sex hormone dependence of the tumour,” he says. The topic intrigued him enough to write a book, Cancer: The Evolutionary Legacy, which was published in 2000. The fault, he concludes, lies with alleles, variant forms of active genes that become a liability in the modern environment.

“That could really just be an accident of having those alleles that really don’t have an adaptive benefit in evolution,” he notes. “Or it could be that in the past people with those alleles have been more fertile and have been at an advantage.”

Either way, Greaves sees us confronting cancer brought on by our genetic makeup and the contemporary influence of the world around us. Kristan Aronson, PhD agrees with this general notion, but she is not so quick to credit the vagaries of our sex lives for the outcome.

“It’s much more controversial than people think,” says the associate professor with the Department of Community Health and Epidemiology at Queen’s University in Kingston, Ont.

Among other things, she points out, prostate cancer has been linked with high levels of exposure to female sex hormones as well as male sex hormones. Diet might play an important role, or exposure to chemicals such as pesticides or PCBs in a workplace setting. But the most frustrating finding may well be that in as many as 90 per cent of cases, there appears to be no risk factor at all.

With this difficulty in mind, she recently completed a comprehensive study of specific biomarkers, including potentially toxic chemicals, heavy metals such as zinc or cadmium, lipids, vitamins, and of course, sex hormones. This research began in 1997, following the cases of 85 men who were diagnosed with prostate cancer and 400 others who underwent similar diagnostic procedures but did not have the disease. She hopes that this basic scientific approach will shed new light on the biochemical mechanisms that are at play.

“The etiology must be highly complex,” Aronson says. “It probably involves gene-environment interactions. New technology is going to help us figure that out, and so all future research needs to be heading in the direction of assessing gene-environment interactions.”

Nevertheless, the permutations and combinations of those interactions can be mind-boggling. And while the research community regularly celebrates the mapping of a myriad of genes associated with specific disease processes, determining the role and action of those genes remains very much a matter of trial and error. Fortunately, as Aronson suggests, we can marshal ever more robust and powerful hardware to the task of examining gene activity more directly. One of the most outstanding collections of such hardware can be found at the Prostate Centre, part of the Vancouver General Hospital that houses a number of research initiatives to this field, including one of the world’s most sophisticated gene microarray facilities.

This facility features microinstrumention spun off from the semiconductor industry, which makes it possible to prepare “chips” looking much like overgrown microscopic slides, containing well-ordered, imprinted information from as many as 30,000 separate genes. A computer can read the data on the chip in much the same way as it reads a floppy disk or a CD-ROM, quickly indicating whether the genes had been activated at the time they were sampled. Such technology can match even the strictest demands of bioinformatics, assembling details about the participation of genes in particular disease states and the impact various therapies have had on those genes.

“This has taken our abilities in cancer research to a whole new level,” says Colleen Nelson, PhD, director of the facility. She has seen the precision and speed of the robotics controlling the process yield complete reports on the activity of these thousands of genes in as little as 24 to 48 hours, with an efficiency and cost that would have been unimaginable a decade ago.

The roots of the Prostate Centre go back to the early 1980s, when the Vancouver General began assembling a specialized team of urologists and oncologists. By the early 1990s, they had laid the foundation for a comprehensive clinical research and patient-care institute that could translate basic research into new therapeutic applications. In 1998, the National Cancer Institute of Canada and the Terry Fox Foundation awarded the first ever peer-reviewed program grant to a team at the Prostate Centre.

Starting with that support, the facility has since acquired nearly $40 million in support, half of it coming from local business tycoon Jimmy Pattison. In 1999, Health Canada provided a grant of $10 million, and the hospital has established other private donor endowments. In addition to facilities dedicated to functional genomics and bioinformatics, the Prostate Centre’s research components are home to a clinical research team that has been participating in multi-centre, international studies for more than 15 years. The centre also investigates complementary and alternative medical approaches to prostate cancer, including Asian techniques, relaxation therapy, healing touch and modifications to an individual’s environment. Finally, the centre also fulfils an educational mandate, mounting continuing education programs for clinicians and scientists, along with information and updates directed at the public.

The concentration of these considerable resources has made it possible to attract young, enthusiastic scientists like Nelson, a 39-year-old American whose devotion to cancer began as a teenager, when she babysat a child who died from the disease at age five.

“Cancer is by no means a simple disease,” she says. “Cancer will respond and change and it’s very plastic in its nature. It’s inadequate to try to describe it on a gene-by-gene basis. It’s happening in a whole context of aberrant gene expression, mutations and other features that can be quite different from person to person, even though they have clinically the same cancer.”

This context defines her search for a baseline description of what might be happening in prostate cancer, both before and after remission, as well as before and after treatment. More specifically, she and her colleagues are concentrating on genes that appear to be regulated by androgen, the hormone that appears to be so necessary to the initial disease process. That process sometimes progresses to the point where androgen no longer plays a key role, thus defeating the efficacy of treatments designed to reduce hormone levels and keep the cancer at bay.

Nelson’s laboratory also examines dietary elements and environmental contaminants which influence steroid hormone action, analysing compounds that interfere directly with molecular receptors on these steroids. By sorting out the specific DNA-binding action that is related to the genes taking part in the development of prostate cancer, her research is looking for those genes that might be “knocked out” in order to stop that development in its tracks. Such neutralization is achieved with antisense nucleotides, strands of RNA that have been designed to fit neatly onto the active section of the gene, thereby complementing and cancelling out the sequence responsible for its activity.

“Unlike small molecules and antibodies that inhibit their product or target based on structure, antisense inhibits its target based on sequence,” says Dr. Martin Gleave, director of Clinical Research for the Prostate Centre. “You design an antisense based on the known sequence of its gene. There is some other art to it, in terms of just knowing and testing what sequence is the most potent, but that’s all part of drug development.”

Gleave and his colleagues have polished this art to the point where they have created antisense to inhibit several gene products linked directly with prostate cancer, including IGF binding proteins, PCL-2, and clusterin, a key protein that makes prostate cancer tumours resistant to conventional treatments. This intellectual property formed the basis for a new company, OncoGenex Technologies Inc. (Vancouver, BC), which was founded in 2000 by Gleave, who serves as its chief scientific officer.

One of these antisense products, a material named OGX-011 that inhibits clusterin, had reached the point of Phase I clinical trials by the end of 2002. In collaboration with California-based Isis Pharmaceuticals Inc., OncoGenex will conduct a trial on about 60 patients who will receive OGX-011 as part of their overall treatment. In some cases the drug will be given prior to surgical removal of a cancerous prostate, while in other cases the drug will be delivered along with standard chemotherapy.

Much of the study is being supported by the U.S. government, specifically the Department of Defense, which had sponsored earlier work on OGX-011 after expressing concerns over the significant number of veterans being diagnosed with prostate cancer.

“This is OncoGenex’s first drug candidate to enter clinical trials, and we are optimistic about its potential as a treatment for prostate cancer and other tumour types,” Gleave says.

He notes that antisense drugs could prove valuable in dealing with other forms of cancer, and perhaps even other types of disease. But he says the Prostate Centre’s philosophy remains one of taking its work from the lab bench to the hospital bedside, making it important to follow through with the potential of OGX-011.

“This is an exceedingly complex, work-intensive, time-intensive, cash-intensive process,” Gleave says. “It’s important to stay with your strengths and stay focused, and our strengths are targeted cancer therapeutics.”