New Drugs Smart-Bomb Tumours

New Drugs Smart-Bomb Tumours

ANYONE WHO'S PLAYED a shoot-'em-up video game knows one of the secrets to survival is a powerful and varied arsenal. It's the same with CANCER. There are more than 200 different types affecting humans, and scientists expect no single cure will ever be found. That's why patients need all the bullets they can get, maybe even harnessing ordinary viruses - unlikely allies though they may be.

In 1998, Patrick Lee, working out of the University of Calgary, published a groundbreaking study which showed that a common cold virus, called the reovirus, is capable of killing cancer cells. In the process, he helped open what is fast becoming the newest front in the war against one of the world's most deadly diseases. The plan works because the reovirus hijacks the wayward cell's internal, overstimulated growth cycle and makes copies of itself instead. Once the viral particles reach a critical mass, they burst the cell. Bye-bye cancer. "A tumour cell makes this deal with the devil, as it were, to become immortal," explains John Bell, senior scientist at the Ottawa Regional Cancer Centre. "As such, it also becomes vulnerable to infection by viruses."

The common cold cures cancer - if only things were so simple. The problem is it takes only a small amount of virus to cause a cold, but, to treat cancer, hundreds of millions of viral particles have to be injected into the bloodstream or the tumour itself. "The major hurdle we have to overcome is the body's natural reaction to fight the virus," says Lee, now at Dalhousie University in Halifax. "If we can overcome that problem, then we'd be home free." To date, new viral therapies have been tested extensively only in mice. But in those trials, the reovirus has proved effective against brain, breast, prostate, ovarian and colorectal cancers. Results of early toxicological tests on humans suggest the therapy is safe. The next step is to see if it works in clinical trials.

Get in line. There are countless bright ideas having their day in the lab, but when science closes in, cancer often slips away, says Dr. Elizabeth Eisenhauer, who since 1982 has been director of the Investigational New Drug Program at the National Cancer Institute of Canada Clinical Trials Group in Kingston, Ont. "Every time we think we've pinned something down," says Eisenhauer, "a little twist comes along just because of the genetic variety in human beings."

Take, for example, the now emerging generation of therapies known as targeted drugs. Like the viral approach, they too are aimed directly at messing up the tumour's molecular machinery. Lauded for pinpoint accuracy and generally benign side effects (at least more benign than chemotherapy), targeted drugs have, for some anyway, fallen short of their initial promise. But if they're not the knockout blow everyone was hoping for, they're making enough inroads on such cancers as lung, non-Hodgkin's lymphoma, colon and chronic myeloid leukemia to keep researchers encouraged. "Many would question whether in the long run we will ever 'cure' cancer," says Victor Ling, vice-president of research at the B.C. Cancer Research Centre in Vancouver. "But there's real optimism that we'll be able to control cancer so it becomes another disease we manage, like diabetes."

On the survival front, the broad prognosis today is much improved over a generation ago, especially for women with breast cancer and men with prostate cancer, two of the most common forms of the disease. The same holds true for a variety of other cancers, including melanoma, Hodgkin's disease and cancer of the uterus, cervix, thyroid, testis and male bladder. Others, including cancer of the lung, pancreas, stomach, ovary and brain, as well as leukemia, are a harder go.

Adding concern was last week's report by the American Cancer Society: for the first time, cancer surpassed heart disease as the top killer in the U.S., based on 2002 figures, the most recent available. The report noted that deaths in both disease categories have declined, but they've dropped more quickly for heart disease. Both declines were attributed to fewer people smoking - an addiction that lies behind as many as one-third of all cancers.

Still, there are more reasons for optimism. Recent studies, for example, show that women who appear to have the same so-called node-negative breast cancer actually have tumours that differ genetically. Those differences seem to determine which women respond well to traditional chemotherapy. The expectation is that by genetically screening women in advance, doctors will be able to determine who will benefit from chemo, as well as from the new more targeted treatments. "These traditional chemotherapeutic drugs are toxic and expensive," says Alan Bernstein, president of the Canadian Institutes of Health Research (CIHR), "so why give a toxic drug to a woman who isn't going to respond?" Adds Bernstein: "I think we're looking at the beginnings of a very profound change in cancer treatment - there's a revolution going on."

IF BERNSTEIN is right about the revolution, then Marilyn Michener, a 49-year-old marketing executive in Toronto, is at the barricades. In August 2003, she was diagnosed with incurable lung cancer even though, as she likes to point out, "I've never smoked a day in my life." Within a month of that diagnosis, after a hellish period in and out of hospital ERs, "I was told I better start getting my affairs in order," she says. The disease - known as non-small-cell lung cancer, the most common type - had spread to her stomach. Her first doctor gave her a year to live. In March 2004, after a round of aggressive chemotherapy, another specialist, Dr. Frances Shepherd at Princess Margaret Hospital in Toronto, told Michener her cancer was "active" again. Shepherd suggested Michener consider participating in a clinical trial for Iressa, one of the newest of the targeted drugs.

There are only a handful of these medications approved for clinical use in Canada, though others are being tested in trials. What makes them different from traditional chemo or radiation is that they are designed to home in on the cancer cell's peculiar makeup and attack that directly. Iressa, as well as earlier drugs like Gleevec (for chronic myeloid leukemia), target a chemical receptor called EGFR that helps the cancerous cell grow and spread.

Approved only for non-small-cell lung cancer, though it's being tested on others, Iressa has been known to shrink tumours by more than 50 per cent, and extend lives sometimes by years - welcome news against the world's worst cancer killer. Unfortunately, Iressa works in only 10 per cent of patients - those whose cancer cells appear to have a particular genetic imprint - and costs up to $3,000 a month. It's not yet possible to predict conclusively who will respond to treatment.

Michener, though, took the plunge. She signed up for the trial and was randomly selected by computer to start taking a single Iressa pill daily. She started last June and continues today. "It wouldn't be exaggerating to say that within three or four days there was some sort of change going on," she says. "All of a sudden, my breathing was easier, the pain wasn't there anymore." On one of Michener's follow-up exams, her lung capacity had improved so dramatically that the technician thought the machine had malfunctioned. A nurse handed her a report with similarly stunning results. "She said, 'You might want to frame this because it says the stomach cancer is gone,'" recalls Michener, her voice catching. "To me, it's been unbelievable."

Michener is one of the lucky ones. In December, Iressa's manufacturer, London-based drug giant AstraZeneca, released a disappointing study that said the drug "failed to significantly prolong survival" in a trial of 1,692 patients with advanced lung cancer. The study showed significant tumour shrinkage but not "a statistically significant survival benefit." Further tests are planned. Meantime, AstraZeneca said it would discuss the results with Health Canada, suspend Iressa promotions, but continue supplying patients already on the drug.

Shepherd, one of Canada's top cancer researchers, remains a strong Iressa defender. She notes that patients taking Iressa lowered their risk of death from the disease by 11 per cent, but researchers couldn't say for sure whether the improvement was due to the drug, or simply chance. "For patients who respond, this is a wonderful drug," says Shepherd. "They are definitely going to have a survival benefit."

Still, the study didn't offer the news researchers were hoping for, and it pointed to the need for a reality check. Gleevec, first approved by Health Canada in 2001 to treat chronic myeloid leukemia, was the original darling of targeted drugs. "Gleevec looked, for all the world, like the wonder drug when it was first developed," says Michael Wosnick, executive director of the Canadian Cancer Society's research arm. "And now, we're starting to see that maybe it's not quite as spectacular as we had hoped."

It turned out some patients relapsed over time. Still, says Wosnick, "we're far from abandoning this kind of approach." Gleevec was important in showing that cancer can be fought at the molecular level by taking advantage of the cell's biological hubris. Typically, cancer treatment takes a shotgun approach - physicians blast away, largely with radiation and chemo, and hope they somehow open the door to a cure. Now, says Wosnick, "we're actually looking at how to pick the lock - that's what drugs like Gleevec have shown us."

Sometimes, though, it can seem like a pretty desperate attempt at a break-in. Under its accelerated approval program, the U.S. Federal Drug Administration gave Erbitux the green light last February for treatment of advanced colorectal cancer. Made by New Jersey-based ImClone Systems (of Martha Stewart fame), Erbitux was shown to shrink tumours and delay the onset of others. But there's been no indication it helps patients live longer. Serious but rare side effects included difficulty breathing and a sudden drop in blood pressure. What's more, the medication costs about US$17,000 a month. Like Iressa and Gleevec, Erbitux also targets the EGF receptor. Erbitux, however, is what's called a monoclonal antibody, a molecular foot soldier of the immune system, one that's been genetically engineered to attack a single target linked to cancer cells. Monoclonal antibodies have been held out as a cancer cure since the 1980s.

Herceptin, also a targeted monoclonal antibody, is used to treat breast cancer. The FDA approved it in 1998, and it's been available in Canada since 1999. However, in 2000, Genentech, Herceptin's manufacturer, wrote health-care providers to warn them of 62 post-marketing reports of serious adverse reactions, including 15 patients who died, some after experiencing an acute reaction in their lungs. At the time of the warning, about 25,000 patients had taken Herceptin.

Yet another monoclonal antibody, this one called Avastin, is used to treat colon cancer that has metastasized, or spread, to other organs. Also made by Genentech, Avastin is different from the other targeted drugs: it is the first treatment approved to block the formation of blood vessels required by cancer cells to survive - what scientists call an angiogenesis inhibitor. Health Canada has yet to approve Avastin, but the FDA allowed its use in early 2004. Then, in July last year, another warning letter from the company to doctors: it said patients taking Avastin doubled their risk of serious heart and stroke problems.

Uncertainty often follows new research, cautions Eisenhauer. Asked about the warning letters issued for Herceptin, Avastin and other cancer drugs, Eisenhauer was frank. "What's fair to say - with some very rare exceptions so far - is so-called targeted therapies have made a difference, but it isn't a dramatic difference," she said. "And the other thing that everybody said about some targeted therapies is that they'd be completely free of side effects. Again, not true."

While many new therapies work, often it's only in a select few, those "lucky" enough to be genetically predisposed to the available treatments. Iressa is a good example. "I know everybody likes to trash pharmaceutical companies," says Michener, "but I want people to know that this drug gave me hope, and that I'm living a virtually normal life right now."

The Canadian Cancer Society tells us one Canadian is diagnosed with cancer every 3 ½ minutes, while one dies every 7 ½ minutes - or about 68,300 Canadians this year. To put a dent in those numbers, the agency last week joined more than 30 cancer organizations to demand Ottawa and the provinces implement a national cancer-control strategy similar to those in the U.S., Britain and Australia.

A national plan, says Wosnick, would cost about $50 million a year, and would include:

- a centralized database listing best clinical practices;

- a database to track health-care workers to avoid staff shortages;

- national screening programs that include tests for colorectal and cervical cancers.

"I don't want to make this a competition between cancer and AIDS, or cancer and diabetes - Lord knows those are significant problems and they deserve the funding they get," says Wosnick. "But cancer as a federal imperative gets a pittance compared to those diseases. When you think about the economic and health burden of cancer, we're out of kilter."

For the broad group of sufferers, the next real advance in the war against cancer will probably come from the knowledge gained in the Human Genome Project - the growing understanding of what makes seemingly similar patients so genetically different from each other that only certain therapies, or the right cocktail of medications, actually work. Better screening technologies and improved understanding of genetic nuances are key, says Philip Branton, the scientific director at the CIHR's Institute of Cancer Research. He also holds out hope that the next wave of targeted drugs will be "much more dramatic" than what is available now.

The broad prognosis is that, sometime over the next decade, a patient's tumour will be run through a series of genetic and biochemical tests. The physician will then administer a tailor-made, targeted treatment suitable to the type of cancer and that patient's cellular receptors. "It doesn't even have to mean that this will be more expensive," says Branton, "because right now, they throw the whole kitchen sink at you, whether it's truly effective or not." In the war on cancer, there will probably never be a magic bullet. For patients and physicians alike, the hope is to find enough weapons to cut the Big C down to size.

THE ODDS

At current rates, 38 per cent of Canadian women and 43 per cent of men will develop some form of cancer. Most likely this will happen later in life.

About 23 per cent of women and 28 per cent of men - or almost one in four Canadians - will die from the disease.

THE BIG ONES

Along with prostate cancer in men and breast cancer in women, lung and colorectal cancers in both sexes comprise 50 per cent of all new cases each year. Breast and prostate are the most common cancers, but lung cancer remains the most frequent cause of death. For women, the mortality rate is growing at three times what it was in 1975, a result of the huge increase in women smokers from the 1960s to early '80s.

Others that are difficult to cure: leukemia, multiple myeloma, and pancreatic, stomach, ovary, brain and esophageal cancer.

TREND SPOTTING

The good news: a small but steady decline in the mortality rate for all cancers since 1988, especially for men. Male deaths from lung and prostate cancer have declined noticeably since the early 1990s. For women, the mortality rate rose a bit in the early '90s before starting back down; of the major cancers, only the death rates from lung, non-Hodgkin's lymphoma and melanoma are increasing among females. Also, the most recent data shows the mortality rate for breast cancer to be the lowest since 1950, a result of early detection.

Source: National Cancer Institute of Canada

TRACKING TUMOURS WITH A FORENSIC MIND

SCIENTISTS CALL IT gene chip technology. But the rest of us might view it as the CSI approach to fighting cancer: analyze the suspect (tumour) and then follow the evidence to determine how the culprit might be taken down. Cancer's an ingenious foe. The same disease takes root differently in different people, depending on their genetic makeup or maybe the way the original tumour first started to develop. To destroy it, doctors need strong weapons, but they also need an appropriate database from which to match a tumour's genetic fingerprint with the right therapy. That's where Wan Lam steps in.

A senior scientist at the B.C. Cancer Institute in Vancouver, Lam and his team have developed gene chips with more than 32,000 DNA fragments, a huge increase in what has so far been available. The idea is elegantly simple: biopsy a tumour and spread its DNA across a glass slide or chip; then run a chemical reaction, analyze that tumour's genetic signature and compare it to healthy tissue.

It's a field in which Canada has taken a lead role. Some of Lam's work centres on identifying changes in gene activity, meaning which chemicals and enzymes come to the fore - becoming potential targets for drugs - as certain cancers progress. Four hospital labs - one in Vancouver, another in Edmonton, and two in Toronto - are now testing Lam's chips to determine whether they're practical in a hectic lab environment. It's the first step in high-tech screening. "If we knew patients had a certain genetic alteration that makes them resistant to a drug," says Lam, "then we wouldn't give them that drug in the first place."

Maclean's January 31, 2005