Science & Research

Old drugs, new treatments

A new research centre at the U of M - the first of its kind in Canada - will investigate whether drugs developed for specific maladies such as headaches or arthritis can also be used to prevent cancer

Dr. Salah Mahmud holds three pills that may contain properties that could be helpful in preventing certain types of cancer
Dr. Salah Mahmud holds three pills that may contain properties that could be helpful in preventing certain types of cancer.
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Bio: Dr. Salah Mahmud

Drugs with potential

Winnipeg Health Region
Wave, Summer 2013

It doesn't look like much now - cubicles, desks and chairs spread over about 600 square feet of office space.

But that's about to change.

In a few short months, this space, along with two other small offices located on the third floor of the Apotex Centre at the University of Manitoba's Bannatyne Campus, will be transformed into a new centre for research into potential treatments for a variety of cancers, including prostate, colon and cervical.

"It's really a work in progress," says Dr. Salah Mahmud, who is heading up the fledgling centre. "We haven't even been formally inaugurated."

In fact, the centre is so new it doesn't even have an official name. "The centre is provisionally named: Centre for Pharmacoepidemiology and Vaccine Research," says Mahmud, an assistant professor in the Faculty of Medicine's Department of Community Health Sciences and the Faculty of Pharmacy at the University of Manitoba. "We're still looking for a catchier name, so let me know if you have any suggestions."

Once the ribbon is cut and the doors open, the new Faculty of Medicine centre will be home to a 10-member team dedicated to investigating whether medications developed to treat one problem - say a headache or arthritis - possess properties that could be used to treat various forms of cancer.

Mahmud is a leading expert in this type of research, a fact that has not gone unnoticed. In March, he was appointed Canada Research Chair in Pharmacoepidemiology and Vaccine Evaluation. The appointment was made under the Canada Research Chairs program, which was established by Ottawa 13 years ago to invest in top-flight research in Canada. It carries a $500,000 grant, which will be used to help Mahmud focus on the research program. In addition, the Canadian Foundation for Innovation (CFI), the provincial government and the University of Manitoba are providing $400,000 to help launch the centre, which will be the first of its kind in Canada.

The investment into this type of research is important. Cancer remains one of the leading causes of death in Canada, and identifying an existing drug with the potential to treat or prevent the disease will not only help the patient, it will also help save the health-care system money.

But the work is not easy. As Mahmud explains, he and his team are essentially miners of data. They sort through mountains of medical information collected by provincial health-care systems, looking for clues that suggest a potential new use for an old drug.

In essence, this is what pharmacoepidemiology is about, says Mahmud. "Pharmacoepidemiology is the study of the intended and unintended consequences of using drugs and vaccines."

At the top of the list of drugs under review is Aspirin.

Initially created as a pain control medication used mostly for headaches, researchers soon discovered that Aspirin had other benefits, most notably as a blood thinner to help prevent heart attack and stroke.

That the medication could also possess cancer-fighting potential is not a new theory. Mahmud says many researchers have hypothesized that its anti-inflammatory properties may make it a first line of defence in cancer prevention. That's because new research shows that inflammation is a primary cause of several different forms of cancer. "The theory is when you have an environment that causes inflammation, that you have an environment that is pro-cancer, so to speak."

Inflammation in the body is an immune system response from injury or infection from a virus, bacteria or fungus. The symptoms - redness, pain and swelling - are not in and of themselves bad things. Acute inflammation is actually a sign of a healthy immune response. "These types of inflammation are good ones," he says. "When you have a small cut, there's inflammation from the immune response and it heals in a few days."

But emerging research suggests that chronic inflammation is unhealthy, potentially leading to life-threatening illnesses. "The problem with chronic inflammation is that it doesn't end," he says.

For example, smoking cigarettes damages the mucosa - the inner lining of the respiratory tract. This regular assault on the body causes non-stop inflammation that eventually can lead to cancerous growth in the lungs.

"Cells are dying and growing all the time, which increases the chance that something will go wrong in the generation of the DNA in the cell, and, at the end of the day, that's what cancer is," he says. "It's an error in the genetic material when a cell is reproducing that causes it to replicate itself in an out-of-control way."

In theory, drugs like Aspirin that prevent inflammation should also help prevent cancer - at least the forms of the disease that result from chronic inflammation. Yet a theory is only an educated hunch. Proof is required.

Mahmud actually started working a decade ago to determine if there was epidemiological evidence to support the theory that Aspirin could help prevent cancer.

At the time, research into Aspirin's anti-cancer properties had already yielded promising results. In the 1990s, researchers found a connection between its use and a lower incidence of colon cancer. But Mahmud wanted to know if it could help prevent other cancers, especially prostate cancer.

"Prostate cancer is very common; men over the age of 50 have a 30 per cent to 40 per cent chance of having it, and we don't really know why," he says, noting that there are no obvious risk factors, like sun exposure for skin cancer, or smoking for lung cancer.

"The solution becomes asking, 'Can we take something to prevent prostate cancer?' Because chronic inflammation plays a role in cancer in general, and prostate cancer is just another form of cancer, that was the hypothesis."

Yet the challenge for many researchers regarding a widely used drug like Aspirin is how do you create a study using broad samples of the population that is cost-effective and can sort through millions of pieces of data in a meaningful way?

It's no small feat, says Mahmud. Aspirin is widely manufactured under its generic name, acetylsalicylic acid, or ASA for short. The patent on the medicine has long expired. Clinical trials to test the theory would be too costly, and no company is willing to spend money on a hunch. A solid lead based on evidence is first required to move onto clinical research and long-term trials with patients.

Mahmud says he and his team have already completed much of the study, leveraging the vast amount of information gathered by Canada's healthcare system, including prescriptions, and then mining the data for evidence to support or disprove the theory. They will conduct similar reviews with other common medications.

"Every time you go to fill a prescription, that information is stored because the government needs to know about it for accounting purposes," he says. "We are using the information for millions of prescriptions to see if we can try to find new uses for these drugs."

It's a daunting task, one that would be impossible without advanced computers. And, by and large, computer programming makes up a large part of the research.

The team first determines what kind of information they need to establish whether a drug has cancer-fighting potential. "Then we develop software tools," he says. "We have a number of them that we use to extract pertinent information from databases."

Much of their technology funding comes from the CFI, but their relationship with the organization provides them with more than money to purchase computers. "Besides the funding, we also get access to CFI-funded information technology projects," he says. "And that includes the High Performance Computing Centre, which is located at the University of Manitoba's Fort Garry Campus."

Mahmud's research has a need for computing speed - a requirement that is much too expensive for his centre's limited budget. The U of M computing centre is the ideal match, home to one of the fastest computers in Canada. And its role in facilitating the kind of research Mahmud does is essential. Instead of days to process data, the U of M super computer gets the job done in a few hours.

Of course, the computer is only the workhorse. The research team still must design the studies determining what information is relevant and what's not.

With Aspirin, Mahmud and his team focused on data related to its use by men who developed prostate cancer. "We use different calculations, different groups of people and different study designs to see if we can get consistent results, and that's what happened with Aspirin and prostate cancer," he says. "We found people who were using Aspirin in 1990, for example, and then we would see if they developed prostate cancer in the year 2012."

This group was compared to men who didn't take Aspirin regularly, measuring their prostate cancer rates over the same period. "The other approach is to look at men who have prostate cancer right now and compare them with men who did not have prostate cancer, and we asked them about their Aspirin use," he says. "Sure enough, we found that there's a small benefit from using Aspirin, about a 10 per cent reduction in the chance of getting prostate cancer. That's our best estimate right now."

The next step is a clinical trial because, while exciting, the results are not concrete. "We're working with very noisy data. We're not in a situation where we have full control over an experiment, so how do we even ensure that we're not coming to the wrong conclusion?" he says. Clinical trials will provide a much more definitive answer.

Questions still to be answered include: How often would someone have to take Aspirin in order to achieve a benefit? Could the risk-reduction rate exceed 10 per cent?

"That is a part of what I am trying to ascertain," says Mahmud.

Meantime, he emphasizes that Aspirin does have the potential for harmful side-effects, such as bleeding from the stomach. As a result, he says people should not take Aspirin to help prevent prostate cancer until the research is completed. Even then, he says, people should not take Aspirin without considering all the pros and cons and talking to their doctor.

Through its research, the centre will continue to unearth evidence about drugs that will help pharmaceutical companies and government agencies determine whether spending money on a clinical trial is warranted.

"Usually what happens is once you find a drug like Aspirin where it reduces the risk of cancer, the drug companies jump on and try and find similar chemicals that do the same thing," he says. "It is what is called rational drug design, where they look at the molecules of the substance to figure out how it works inside the cell. Then, they try to find similar molecules, which then they could patent, protect and market."

But even with strong scientific evidence, funding from the private sector for clinical trials isn't a foregone conclusion. Preventive applications for drugs are generally of less interest to pharmaceutical companies because testing their efficacy in a clinical setting can take longer than drugs that treat illness, Mahmud says. In many cases, government agencies ante up the financial support. "Many of these prevention-style trials are funded by public money, mostly in the United States."

Fortunately for the new centre, Mahmud's team has plenty of support from the province and the federal government - and even the Centers for Disease Control in the U.S. - to carry out research, including studies on vaccines.

In fact, next to Mahmud's research on Aspirin, the largest study that will take place at the centre will investigate the Human papillomavirus (HPV) vaccine's role in cancer prevention.

In the wake of strong evidence from clinical trials a few years ago, the province launched a widespread program to vaccinate girls in their early teens to prevent cervical and other cancers.

A study published in June suggests the vaccine has helped cut in half the rate of HPV infections among teenage girls in the United States since 2006.

Mahmud and his team will be carrying out long-term surveillance in Manitoba to learn more about the vaccine's effectiveness and how it might be used in the future. Among other things, the team will look at dosage and compliance rates and how long the vaccine lasts.

Answering these questions will take years of research. But for the study's major funder, Manitoba Health, the research will not only provide local insight into the vaccine's effectiveness in preventing cancers specific to women, it may also help health officials decide whether to recommend widespread vaccination for early teen males, too, because HPV is also thought to cause other cancers that affect both men and women.

In addition to looking for the unintended benefits of commonly prescribed drugs, Mahmud and his team will also be on the lookout for negative side-effects of various products on the market today.

The importance of this type of research is illustrated by the case of Thalidomide, a drug developed in the 1950s.

Initially developed as a sleep medication, the drug was also found to be an effective treatment for nausea and was prescribed to women for morning sickness in the late 1950s and early 1960s.

As it turned out, the drug had the unintended side-effect of causing severe birth defects.

"This is the poster child of why you don't want to just release a drug in the market and then forget about it," Mahmud says.

Rofecoxib, known as Vioxx, is a more recent drug that later turned out to have dangerous side-effects. "Vioxx relieves the pain of arthritis, but it's also been known to cause death."

Like most modern drugs, Vioxx was rigorously tested first in the lab and then on people. "Tests are usually done on a relatively small sample of a very selective group of people, so they exclude kids, pregnant women, the elderly and the very sick."

If the new medication works as planned, the government approves its use for its target population. The entire process is costly. Drug firms spend billions annually on research and development, and bringing a new drug to market takes years. But the testing process is not without its warts, Mahmud says. "When the drugs are actually used in the real world, and they get used by the very sick, the elderly, pregnant women and children, we are always surprised to find out there are side-effects that we didn't really anticipate."

And that's where experts in pharmacoepidemiology like Mahmud apply their skills. They conduct post-marketing studies and surveillance. Unlike testing prior to a drug hitting the market, this research continues over decades, looking at the outcomes for large numbers of people who have taken the medication.

"We go through hundreds of drugs that have been in use for many years and look at them after they've been used by hundreds of thousands of people, which allows us to detect very rare outcomes - things that you can't detect in a clinical trial."

As it searches for the unintended benefits and negative side-effects of commonly prescribed drugs, the Centre for Pharmacoepidemiology and Vaccine Research will play a significant role in shaping public health policy not just in Canada, but around the globe.

Mahmud is particularly excited about the opportunity to discover new preventive treatments. "I'm a public health person, so my interest is always in prevention," Mahmud says. "Most pharmaceuticals are aimed at treating conditions - people who are already sick."

And for the health-care system, it's just what the doctor ordered. "Considering the climate of fiscal restraint we're living in now, one way to manage health-care costs is to prevent disease from happening in the first place. So not only does preventive medicine reduce the amount of pain and suffering from disease, it also helps with the sustainability of our health-care system."

Joel Schlesinger is a Winnipeg writer.

Wave: Summer 2013

About Wave

Wave is published six times a year by the Winnipeg Health Region in cooperation with the Winnipeg Free Press. It is available at newsstands, hospitals and clinics throughout Winnipeg, as well as McNally Robinson Books.

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