People seem to intuitively understand that this is a long battle that’s going to require a sustained effort.
Timothy Caulfield
20
May
2015
|
16:00
Europe/Amsterdam

Teaming up to Conquer Cancer

Researchers are breaking down boundaries and finding allies in unexpected places, speeding up discovery in the hunt for answers.

By AMIE FILKOW

Editor's note: Tanya Prochazka passed away May 12, 2015, after living with ovarian cancer for nine years. She gave one of her final interviews for this story.

Everyone Has a Cancer Story

“Everyone has a cancer story. When I was first diagnosed, every person I met told me theirs.”

Tanya Prochazka’s own cancer story involves nearly a decade of hope in the face of daunting odds and repeated disappointment. It’s about holding on to that hope, even beyond her own life.

An internationally acclaimed cellist who has performed everywhere from Carnegie Hall to the wedding ceremony for Wayne Gretzky, ’00 LLD (Honorary), Prochazka’s life in the past few years has been full of weddings, births, laughter and milestones. Back when she was first diagnosed with Stage 3 ovarian cancer, she never thought she’d be around to see any of these milestones, but this mother of three grown children and four young grandchildren has defied the odds.

Few ovarian cancer patients live more than five years after diagnosis; she’s on year nine. (“I’m not even in the data,” she says.) With the support of family, friends and a phalanx of dedicated health practitioners, the former University of Alberta music professor has endured three surgeries, four gruelling rounds of chemotherapy plus one of radiation. “It all gets very hazy because you just leap from one treatment to the next. You forget what it’s like to be normal.”

Even after chemotherapy proved ineffective, Prochazka kept trying. She participated in a clinical trial in Seattle and explored other experimental treatments, including nitroglycerine. She donated a biopsy sample of her cancer to the provincial tumour bank for a U of A research project.

“I just wanted to be there to see my children go through their lives and help them with their children,” she said a year ago. But nothing has halted her cancer, and there are no more treatments to try.

Research Roadblocks

Few understand the complexities of the disease better than cancer researchers. Strategies to target treatment to certain cancers have saved lives, while other cancers, such as pancreatic and brain cancer, remain a mystery.

In the quest to understand, diagnose and treat cancers, scientists, physicians, universities and funding agencies are coming to realize something that patients such as Prochazka have known all along: when it comes to cancer, you can’t do it alone.

There is a growing realization that a “race to be first” model of research, the romantic image of a lone researcher in a lab finding “the cure,” will not work. The best approach to tackling cancer now appears to lie in more — and better — collaboration from the moment a research project is conceived.

This is the crux of what’s known as “translational research.” It involves, in part, breaking down disciplinary barriers to build teams of experts from different fields who share ideas, resources and results. Translational research also refers to “translating” scientific discoveries from the laboratory to the treatment of patients, sometimes called “bench to bedside.” It’s a feedback loop of discovery and treatment, in which basic cancer research leads to new treatments and better patient outcomes, which, in turn, help direct further avenues of research.

When a biochemist, an oncologist, a biomedical engineer, a nutritional scientist and a biostatistician work on a research project together, they bring different questions, expertise, insights and points of view to bear on the problem. This makes the research process more effective, ideally shortening the time it takes for new discoveries to move through the research pipeline from an experiment at the lab bench to detection or treatment at the cancer patient’s bedside.

At its core, translation is about clearing roadblocks on the twisting and expensive pathway from basic scientific discovery to patient care.

In an academic setting, this means breaking out of departmental silos and separate buildings. It means establishing ways for scientists in the lab to share what they know with health practitioners who treat patients — and vice versa. It means creating opportunities for collaborative research projects that tap into a research university’s greatest strength: its wealth of expertise in diverse disciplines.

“As a basic scientist I can do amazing things in the lab and have breakthroughs that get published in Nature, but they may have no impact on patients because I don’t have the knowledge or resources to bring it to the clinical next step,” says John Lewis, who holds the Frank and Carla Sojonky Chair in Prostate Cancer Research at the U of A and leads a team in translational prostate cancer research.

“We have to start using a broad spectrum of experts with diverse skills to tackle this in a very different way,” says Stephen Robbins, scientific director of the Institute of Cancer Research in the Canadian Institutes of Health Research (CIHR), which funds more than a quarter of all cancer research in the country — the single largest investor.

It’s not that collaboration is new. What is new is how broadly the network of collaboration stretches, the diversity of the collaborators and how early in the process the connections are formed. Funding models, research facilities and even purpose-built buildings are shifting to support this integrated, team-based approach.

Cancer physician John Mackey (left) and biochemist Ing Swie Goping are studying why some breast and ovarian cancer tumours respond to treatment while others show resistance. [Photo: John Ulan]

Skating with Gretzky

“I’m tired of seeing my patients die,” says cancer physican John Mackey, ’90 MD, a fierce advocate for research, who links patient care back to the lab bench.

Mackey is a medical oncologist who treats breast cancer patients and a professor of oncology in the U of A’s Faculty of Medicine & Dentistry. He serves as director of clinical trials at the Cross Cancer Institute in Edmonton and is co-founder of Alberta’s pioneering provincial tumour bank, now part of the Alberta Cancer Research Biorepository.

Sitting in his clinical office at the Cross, fishing through a stack of papers for a journal article, he laughs, “I’m a jack of all trades and a master of none.” In fact, it’s difficult for Mackey to choose just one of his projects to talk about. He begins describing one, then interrupts himself to mention another. He falls silent for a moment, mentally flipping through all of the projects he wants to share.

One of Mackey’s most promising lines of inquiry is a collaboration with U of A associate professor of biochemistry Ing Swie Goping. They’re striving to understand why some patients respond to chemotherapy while others show resistance. Specifically, they are looking into taxanes, aggressive chemotherapy drugs used in the treatment of breast and ovarian cancers. Despite the highly toxic therapy, cancer relapses in nearly 40 per cent of breast cancer patients and 70 per cent of ovarian cancer patients.

When Goping proposed a collaboration, Mackey was eager to be involved, having seen his patients suffer from the harmful side-effects of taxane therapy, which in some cases can even cause death. “As doctors, if we don’t understand the biology, our treatment strategies will simply be empiric, like randomly throwing darts at a wall without knowing the direction to aim,” he says.

The team is developing an antibody-based diagnostic kit that will help breast cancer patients and their doctors determine whether the difficult treatment might be beneficial.

Goping discovered that a protein called BAD (Bcl-2-associated death promoter) acts as a predictive biological marker that indicates whether a patient will respond to taxane treatment. Since taxanes require BAD in order to eliminate the cancer cell, patients with the protein in their tumours respond better to the therapy.

The team is continuing to test its hypothesis in larger numbers of tumour specimens but, based on the findings, the biomarker could potentially spare hundreds of Albertans from having to undergo this difficult treatment without any benefit. For patients whose tumours have high levels of the BAD protein, the hope is that they will be more willing to soldier through the taxane therapy with the odds in their favour. Knowing they have the biomarker would give them a reason to hope.

The project demonstrates what basic research and clinical medicine can achieve through collaboration, when people from different disciplines contribute a variety of insights and approaches. “Collaboration was absolutely necessary for this project to move forward, for us to expand our knowledge and reach our conclusion,” Goping says.

As a medical oncologist who sees patients on a daily basis, Mackey recognized the need for a diagnostic tool to help target treatment. The tumour bank he co-founded provided samples for the research on taxanes. (Open to all researchers, the biorepository has blood and tissue samples of more than 40 types of cancer from more than 20,000 participants.) Pathologist Judith Hugh, another key member of the translational team, can “read” each tumour sample and determine its grade and diagnosis. Cancer surgeon Todd McMullen, ’91 BSc(Spec), ’97 PhD, who also has a background in biochemistry, provides surgical input to help acquire specimens. Biostatistician John Hanson, ’64 BSc, ’68 MSc, analyzes vast amounts of research data and interprets the results.

Mackey is enthusiastic about the depth and breadth of talent with which he works.

“Most of what I do is like skating with Gretzky,” he says. “You get a few goals, but most are because of the talented people you’re collaborating with. I work with people who know things I don’t know and that’s really where the sparks fly and the advances happen. When people approach the same problem from different directions, patients win.”

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From Petri Dish to Patient

For centuries, doctors have also often been scientists — treating patients, examining specimens, dissecting cadavers, writing up their discoveries, finding cures. Some of the biggest medical breakthroughs of the 20th century were made by physicians who lived double lives as scientific investigators. Jonas Salk was a trained medical doctor who branched out into virology research and discovered the polio vaccine. Canadian Frederick Banting was an orthopedic surgeon who co-discovered insulin and won the Nobel Prize. The Harvard pathologist Sidney Farber experimented with antifolate drugs as anticancer agents in the 1940s to develop the first chemotherapy and ran a clinical trial for children with leukemia.

In recent decades, however, a great divide has grown between scientists in the lab and health practitioners who see patients in the clinics. Like travellers in parallel universes, they are searching for similar answers but often their paths only rarely and randomly intersect. Why is there such a disconnect between scientific discovery and its application?

For one thing, each is busy with their own work: busy caring for patients, busy writing papers and grant applications, busy teaching and busy doing the research that will help them renew their funding — the crucial financial backing that can make or break a research program. Funding models have, until relatively recently, generally backed a project’s principal investigator, not his or her collaborators from different fields. University faculties and departments have tended to be silos of distinct disciplines with experts focused on advancing knowledge in highly specialized areas. Finally, doctors and scientists, nurses and pathologists, nutritionists and statisticians don’t speak the same language, and that can create hurdles to collaboration.

“Until you put the framework in place for collaboration to occur, and provide drivers to encourage it, it doesn’t happen as often as it should,” says prostate cancer researcher Lewis.

Talk of interdisciplinary collaboration and translational science has been around for 20 years, but the idea is only now gaining widespread traction in Canada and shifting the culture of science. “We’re speaking in language now that we couldn’t speak before,” says the CIHR’s Robbins. Funding models now often encourage and even require this model of research. Federal initiatives such as the Networks of Centres of Excellence and CIHR — which has a mission to “create new scientific knowledge and to enable its translation into improved health” — are focused on helping bridge the gap between basic and clinical science.

The U of A is doubling down on collaboration by creating a research centre and initiative — to support cross-disciplinary teams and accelerate research — the new Cancer Research Institute of Northern Alberta, or CRINA. The goal is to connect hundreds of cancer specialists (Mackey, Goping and Lewis are among them) on campus and at affiliated institutions. These connections facilitate teamwork, streamline research and push clinical trials forward. Collaborators from medicine can connect with their colleagues in engineering, science, nursing, nutrition, public health and law, simply by walking across the pedway. Multiple disciplines can contribute their expertise to navigate the policy, ethics and economics involved in getting a new drug from the petri dish to the patient. Even buildings and infrastructure are being purpose-built to encourage collaboration. The Edmonton Clinic Health Academy, built on the U of A’s North Campus in 2011, for example, is an attempt to dissolve physical boundaries between health-care disciplines.

“More and more universities and research centres are working in this translational space and trying to bring transformative groups together,” says Robbins. “In every case the focus is on helping patients much faster.”

It takes an average of 17 years for potential treatments to go from drug discovery to delivery, says Deborah James, former executive director of CRINA. That’s an excruciatingly long wait for anyone living with cancer. “Across Canada, universities and governments are working to create programs that are going to facilitate translation much better.”

Perhaps the greatest value in a translational approach, from a health perspective, comes from the increased focus on the patient, says James. “It’s starting with a different question — one from the patient perspective, from the clinical perspective.”

Patients are part of the collaboration in other key ways. In 2013, looking for ways to help his wife, Prochazka’s husband, Arthur, read about the work of U of A cancer biologist Lynne-Marie Postovit, a co-director of CRINA, and contacted her. Postovit — who holds three endowed chairs in the Faculty of Medicine & Dentistry — leads a translational research team that has identified a cellular biomarker that could one day be detected in blood for early screening of ovarian cancer. Prochazka agreed to donate a biopsy sample of her cancer to the provincial tumour bank, which contributed to Postovit’s research. “Patients don’t realize it, but they can really help push research forward,” says Postovit.

Lost in Translation

Not all are won over by the promises of collaboration and translational research. Some see risks to the kind of unfettered research they consider critical to scientific advancement.

There is some concern this model might increase the push toward commercialization and the expectation that universities should be economic drivers. The worry is that pressure to translate scientific discoveries and show a “return on investment” could create bias and put research teams in danger of exaggerating results and initiating a premature rush to market.

In reality, biomedical science moves forward in tiny, unsteady (and often retraced and highly regulated) steps, according to health law professor Caulfield, a member of CRINA who has worked on translational projects in genomics and stem cell research. Pressure to accelerate this process can lead to hype, he says, which can skew results and also risk damaging public trust in academic research.

“We need to be careful about over-promising. The problem is a lot of these translational projects are big science projects with huge teams, so you need those big dollars,” says Caulfield. “And in order to get those big dollars, you need to promise big. It’s a real policy challenge, trying to frame this in a way that talks about the big solutions so you can get the long-term big money to do this research. You need sustained funding to fulfil these promises.”

Yet, Caulfield adds, having a group of experts working together can also be a powerful way to limit research hype. “When you’re a lone researcher and you’re trying to raise your hand above everyone else, you’re more likely to have biases than if you’re in a big research team where there’s internal validation.”

Another criticism of translation gets at the heart of what science is all about: curiosity and experimentation. A funding-based translation timeline could limit the freedom of scientists to ask pure research questions and have experiments fail, perhaps preventing the serendipitous discoveries that have sometimes resulted in groundbreaking treatments — from the penicillin mould in Alexander Fleming’s petri dishes that proved to be a powerful antibiotic, to a dangerous explosive called nitroglycerine that was patented as dynamite by Alfred Nobel but was later found to treat heart disease.

“Every discovery that we make in the lab is a true discovery from the cell point of view, but it might not have an impact on cancer treatment,” explains biochemist Goping. “It might, however, have an impact on how the eye develops in a baby, or on whether Alzheimer’s is going to progress slowly or quickly. In 25 years we might say, ‘Oh, that’s really interesting for another disease,’ but because the focus now is on translation, it will force that discovery into the cancer translation pipeline.”

Despite the potential risks, the popular consensus among doctors, scientists and health researchers seems to be that the trend toward collaboration and translation is on the right track.

“You need interdisciplinary teams because basic researchers are not experts on clinical outcomes,” says Caulfield. “Scientists may have some new exciting invention in the laboratory, but how it plays out in the clinic is pretty complicated. Is it really better than what’s available, long term? What is the real value of this for patients and for the health-care system? What are the benefits of this new invention from a health policy or health economic perspective?”

“We can achieve much more than the sum of the parts by doing this,” says Robbins. “It’s much better working with 10 great minds than one great mind.”

Inventing and Reinventing

If cancer research has a story to tell, it’s one of epic victories and heartrending setbacks. The ending remains uncertain, but the central theme might best be summed up by author and oncologist Mukherjee: to keep pace with this malady, research needs to keep inventing and reinventing, learning and unlearning strategies.

Tanya Prochazka’s cancer story is still unfolding. She has stopped treatment and is in palliative care at her home in Edmonton. Still, she has found reasons to hope. She hopes for a day when her children and grandchildren do not have to live in fear of a cancer diagnosis. A day when research and medicine, working together, will have found early detection techniques and targeted therapies for many cancers.

“I’m making sure my daughter gets screened every year. She’s only 30, but she’s not going to do what I’m doing. No way,” Prochazka says. “My hope is that ovarian will follow in the footsteps of breast cancer, where more women survive than not.”

That’s the hope that drives researchers and clinicians, patients and caregivers alike. By attacking cancer from multiple perspectives, disciplines and entry points along the spectrum of research, by asking probing questions from every vantage point, perhaps researchers can help more people survive — or better yet avoid — a cancer diagnosis.

Since they first met nearly two years ago, cancer biologist Postovit has stayed in touch with Prochazka. “When I interact with cancer patients and survivors, I’m humbled, but I’m also driven even more to make a difference,” she says. “I may not be able to change that patient’s life in the moment, but they are always in the back of my mind, inspiring me to go further.”


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