A killer begins to spill its secrets

Cancer researchers are feeling upbeat these days as advances in molecular medicine offer an unprecedented understanding of how the disease develops — and how it might be defeated.

by Daniel McCabe, BA’89

Michel Tremblay recently stepped down as the director of of McGill’s Rosalind and Morris Goodman Cancer Research Centre (Photo: Claudio Calligaris) What would you say is the scariest word in the English language? Chances are most of us would settle on “cancer,” the two syllables that no one ever wants to hear uttered in their doctor’s office.

There are reasons for that. For one thing, cancer continues to stalk us with deadlier precision than any other disease. It’s this country’s number one killer. According to the Canadian Cancer Society, cancer claimed the lives of close to 30 percent of all Canadians who died in 2007.

It killed Jack Layton. It killed Steve Jobs. It’s killed people that each of us has loved - parents, siblings, cherished friends. In one way or another, no one escapes cancer completely. Five hundred Canadians are diagnosed with some form of it every day.

Oncologist Siddhartha Mukherjee, author of the Pulitzer Prize-winning >A Biography of Cancer<, described cancer cells as “more perfect versions of ourselves.” They grow faster than normal cells and they’re more aggressive. They can be fiercely, maddeningly adaptable, often nimbly resisting the best efforts of medical science to curb their lethal colonization of our bodies. Scientists suspect that some, given the right set of circumstances, might even be immortal.

Cause for hope

One could excuse a certain degree of gloom then, or at least resignation, among those who are actively searching for new ways to thwart such a formidable opponent, but that isn’t the case. There is a widespread sense that the tide is turning in a profound way. Researchers are busily developing a far more detailed understanding of cancer’s molecular roots than they’ve ever had before.

In the past, the treatments devised to combat cancer, even the ones that proved to be effective were formulated without this depth of knowledge. Now, medical scientists have a much firmer grip on what they need to zero in on and they have a wider and more sophisticated array of tools to bolster that pursuit. Gerald Batist is the director of the Jewish General Hospital’s Segal Cancer Centre (Photo: Claudio Calligaris)

“This is a really exciting time in cancer research,” declares Morag Park, McGill’s Diane and Sal Guerrera Chair in Cancer Genetics. “Things are moving very fast.” Gerald Batist, MDCM’77, director of the Jewish General Hospital’s Segal Cancer Centre, concurs. “We are in the midst of sweeping advances.”

“We are starting to see cancer become more of a chronic disease,” says Michel Tremblay, who recently stepped down as the director of McGill’s Rosalind and Morris Goodman Cancer Research Centre (GCRC). Out-and-out cures might be elusive, he says, but those who are diagnosed with cancer will, in many cases, live longer lives, and they’ll enjoy a better quality of life than was often possible in the past. It’s already happening, he says.

He points to new data released in May by the Canadian Cancer Society, which indicates that cancer death rates are dropping. Between the years 1988 and 2007, the death rate for cancer patients decreased by 21 percent in men and nine percent in women. The decline in smoking is an important factor, notes Tremblay, as is the increased emphasis on the early detection of some cancers. But he believes that part of the credit should go to the improved treatments that have already resulted from our better understanding of how cancer develops.

For decades, many scientists mused that cancer was caused by some sort of outside agent (and they were half-right—certainly carcinogens like cigarettes play an instrumental role). In the late seventies, though, scientists began to conclude that the potential for cancer already existed within our generally well-behaved cells.

Sometimes the genes that direct cellular activity become mutated by exposure to carcinogens. Anti-oncogenes, which place limits on cell division, stop functioning properly. Proto-oncogenes, which promote cell growth, start to encourage a runaway rampage. The traffic lights that regulate proper cell activity malfunction. The green light never switches off and the red light never switches on.

A disease of many diseases

More recently, the advent of molecular medicine, heralded by the Human Genome Project, has offered scientists the tools and techniques required to put these insights to good use. The mutated genes that trigger different forms of cancer are being catalogued. The behavioural patterns of cancer cells—and their potential vulnerabilities=are being carefully assessed. And the realization that cancer was even more complicated than we thought it was began to settle in.

Cancer has never been a single disease, of course. The different types of cancer all have basic things in common, but they aren’t the same illness and they can’t be treated through exactly the same methods. Researchers now realize that each form of cancer itself comprises a subset of diseases, each with its own unique characteristics. This wasn’t a complete surprise clinicians who specialized in one form of cancer had long been noting marked dissimilarities in the tumours they treated but the degree of variation that is being uncovered is a game-changer. Scientists from the B.C. Cancer Agency, for instance, recently concluded that there are 10 distinct forms of breast cancer.

There can be a world of difference, for instance, between cancers that attack adults and those that attack children. A team of McGill University Health Centre researchers led by Nada Jabado, an associate professor of pediatrics, recently identified two genetic mutations that are responsible for up to 40 percent of all cases of a deadly form of brain cancer known as glioblastomas in children. Treatment usually does little good and Jabado thinks her team has uncovered an important reason. Her research proves that the molecular mechanisms associated with childhood cases differ from those that affect adults, so the treatments that might benefit some adults, wouldn’t necessarily work for children. Pediatric oncologists now know that they need to look elsewhere for solutions and the two recently revealed mutations are a good place to start.

As molecular medicine offers a more definitive understanding of cancer, it’s also supplying a more detailed road map of our overall genetic makeup and that’s essential, because our unique genetic characteristics are an important part of the cancer puzzle. “Right now, what we’re discovering is that everybody is different. No two people are exactly alike, not even in their tumours,” says Nathalie Johnson, an assistant professor of medicine and oncology at McGill.

That’s opened the door for treatments that focus more narrowly on specific forms of cancer and on the specific genetic traits of patients. One well-known example is Herceptin, a drug that has proven to be effective for women with a certain type of HER2-positive tumours that affects about 20 percent of all breast cancer patients. McGill’s Gerald Bronfman Centre for Clinical Research in Oncology played an important role in the clinical trials that paved the way for Herceptin’s use.

Morag Park heads the GCRC’s Breast Cancer Functional Genomics Group (Photo: Claudio Calligaris)

Apart from his responsibilities at the Segal Centre, Gerald Batist is also the director of the McGill Centre for Translational Research in Cancer, and he has long focused on finding ways to increase the speed with which promising new treatments make their way from lab benches to patients’ bedsides.

“In the past, if a pharmaceutical company developed a medication that only seemed to benefit 15 percent of the patients with the cancer it was targeting, they might not have been too enthusiastic about pursuing that drug,” Batist explains. “But now, if we can help them identify the 15 percent of patients that the drug does work on, things get a lot more interesting for those companies.” A drug with proven effectiveness is also more likely to move quickly through the regulatory process.

“The guiding philosophy [at the Segal Centre] has always been to be able to say to our patients, ‘We left no stone unturned,’” says Batist. “Even when the outcome isn’t what we were hoping for, patients take comfort from that.” Molecular medicine now offers oncologists much more detailed information about their patients and the types of tumours they have. “We can turn over more stones,” says Batist. He looks forward to the addition of a new molecular pathology centre, capable of performing highly detailed genetic analyses of cancer tumours, which is scheduled to open at the Segal Centre this fall.

The GCRC also offers researchers access to a range of technologies and services a metabolomics facility, for instance, that analyzes molecules extracted from tissues or blood samples. “One of our primary goals is to make sure that the infrastructure is there, to facilitate the lives of our scientists and to support their research programs,” says Tremblay.

The McGill University and Genome Quebec Innovation Centre, which frequently collaborates with McGill cancer researchers, provides expert assistance in areas like genotyping, proteomics and bioinformatics.

“To a large extent, the technology is driving the science,” says Tremblay. “The problem is that funding is often what drives the technology.”

Among other things, technological advances offer the prospect of improved techniques for diagnosing cancer.

One of McGill’s most heralded contributions to cancer research was made in the sixties by Phil Gold, BSc’57, MDCM’61, MSc’61, PhD’65, and Samuel Freedman, BSc’49, MDCM’53, DipIntMed’58, DSc’92, when they identified carcinoembryonic antigen (CEA), a protein associated with many cancers, and one of the first widely used biomarkers to detect the presence of cancer.

CEA has its limitations; it can be found in some perfectly healthy people, for instance—but it’s still widely used around the world as a “warning system” to detect the reoccurrence of cancer. “The market sale of all CEA kits together was estimated to be well over a billion dollars a year,” notes Tremblay.

Working with bioinformatics specialists from the GCRC, David Juncker, McGill’s Canada Research Chair in Micro- and Nanobioengineering, recently demonstrated the viability of a more precise method for detecting cancer, one that was capable of simultaneously hunting for the presence of six different proteins, all associated with a single form of breast cancer. Finding such multiple proteins lowers the risk of a misleading result.

Juncker’s lab is currently perfecting this technique, which could result in a handheld test that would swiftly scour a drop of blood for danger signs of cancer.

Driven for answers

As important new technologies might be, the most crucial factor continues to be the quality of the people who are attracted to cancer research. According to Eduardo Franco, interim chair of the Department of Oncology and director of the Division of Cancer Epidemiology, cancer researchers often already have a familiarity with the disease they are studying. For many of them, it’s personal.

“It’s not uncommon that their lives have been touched by cancer in some way. There is nothing like seeing someone you care for suffer.&rdquo

Of all the various experts involved in cancer research, Batist says one group plays a particularly important role. “The most valuable players in all this are the clinician-scientists, because they’re the ones who see patients, and see what they need, and that informs the work that they do in the lab.”

One such clinician-scientist is Nathalie Johnson, MedResident’05, the director of a Quebec lymphoma tissue bank located at the Jewish General Hospital.

Most forms of lymphoma, a cancer that affects immune system cells, are treatable, Johnson says, so the disease is curable for most of the patients she sees. “That helps me cope with the fact that other patients won’t make it.”

Much of her research focuses on particularly aggressive forms of lymphoma that target adolescents and young adults. While most lymphomas respond well to chemotherapy, these don’t.

“The main question driving my research is, why won’t these [cancer] cells die after chemotherapy,” says Johnson. “The basic definition of an incurable disease is that its cells won’t die.” She suspects that in some forms of lymphoma, mutated genes and their proteins have become particularly resistant to chemotherapy and inhibit its effects.

The lymphoma tissue bank is central to her work. Samples taken from patients that aren’t required for diagnostic purposes are preserved for study. “We want to find out how [lymphoma survivors] are winning their war so we can better treat the patients that don’t win these battles,” Johnson explains. “That’s why I do research,” she adds. “I’m comforted by the fact that my work might help the next patient.”

Assistant Professor of Medicine and Oncology Nathalie Johnson is the director of a Quebec lymphoma tissue bank located at the Jewish General Hospital (Photo: Claudio Calligaris)

Morag Park, who heads the GCRC’s Breast Cancer Functional Genomics Group, also relies on a tumour bank, one that focuses on breast cancer tissue. She examines tumour microenvironments. Cancer cells don’t develop in a vacuum, she says. They rely on their surroundings for the nutrients and oxygen they need to grow. These microenvironments can provide essential clues about the nature of the tumours in their midst, Park and her collaborators have found, including how well they are likely to respond to treatment.

“The fact is, I work very closely with clinicians and with our informatics group [experts skilled at using technological approaches to pore through reams of medical data]. None of us could do this alone,” says Park.

According to The Emperor of All Maladies, that kind of teamwork didn’t always characterize the approach to cancer research or treatments, a field in which professional rivalries abounded.

“There are reasons for that,” says Franco. Imagine the years of intensive training required to become a top-flight surgeon or a first-rate radiation oncologist. Specialists tend to become so focused on their own disciplines, they become wary of other forms of expertise. Successful collaborative efforts that made headway against certain forms of childhood cancers helped ease those tensions, Franco believes. “When a child’s life was at stake, people put their pride aside.”

While Tremblay believes that McGill has a good track record in terms of encouraging partnerships among the clinicians and scientists in its cancer centres and teaching hospitals, he says that the University is currently exploring ways to promote even closer collaborations. Batist says that the advances in molecular medicine are a powerful spur for crossdisciplinary cooperation. “Even the surgeonsare talking about molecular pathology as much as they are about cutting.”

A cancer we can beat

If cancer treatments are making exciting progress in places like Canada, that isn’t always the case in developing countries. Improved screening programs, for instance, have enabled doctors to detect many potential cases of cervical cancer at an early precancerous stage, when it’s easily treatable. This isn’t true in many poorer parts of the world, where women don’t have easy access to doctors

“With some cancers, at least you die with dignity,” Franco says. “This type of cancer rots you from the inside. The pain is unbearable.” Franco has become a leading expert on cervical cancer. More specifically, his expertise relates to human papillomavirus (HPV), a sexually transmitted virus that causes almost all cases of cervical cancer.

While a HPV infection can begin a chain of events leading to a potentially deadly outcome, the ability to spot the virus’s presence can also save lives, says Franco. His research has pointed to HPV testing as an even more effective technique than Pap smears for detecting cervical cancer at its earliest stage. Franco envisions mobile medical clinics equipped with battery-operated HPV tests that could visit remote rural villages. If test results are positive, women could be treated immediately and potentially dangerous lesions could be frozen and destroyed by portable cryosurgical tools.

Eduardo Franco is the director of McGill's Division of Cancer Epidemiology (Photo: Claudio Calligaris)

Franco led one Canadian study that indicated that 44 percent of young adults involved in new romantic relationships were infected with the form of HPV that causes cervical cancer. Because these infections are so ubiquitous, he has become a leading proponent of the HPV vaccines that are becoming more widely used. When some expressed fears that the vaccines might be linked to a handful of deaths, Franco did a careful analysis of the existing U.S. data for the vaccinations that have death rate for young women who hadn’t received the vaccinations actually proved to be seven times greater than for those who had been vaccinated.

Franco doesn’t think the vaccines themselves play a role in this discrepancy, since cervical cancer typically occurs in women who are much older than the age group that was examined (he suspects that the young women who received vaccinations might generally adopt safer practices in how they live their lives). But he does believe that the vaccines have been proven to be both safe and effective. That’s why it frustrates him when HPV vaccines are opposed for spurious reasons, such as the notion put forward by some religious leaders that the use of the vaccines might somehow promote sexual activity.

“There is an opportunity here to actually eradicate a type of cancer,” says Franco.

It’s a bold goal, but one that’s well within the realm of the possible. With every piece of new knowledge that cancer researchers bring to light, the diseases that have long terrified us become a little less frightening. Cancer continues to be a formidable opponent for the scientists who seek to defeat it, but it no longer holds its mysteries quite so well.