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A team effort

A team effort

[A team effort]
Photo by Garrett Elliott

Victoria Hoskin and Lois Mulligan

Most of us know about genetic mutations, like those in the BRCA1 gene inherited by Angelina Jolie, which dramatically increase a woman’s risk of developing breast or ovarian cancer. If you inherit a genetic mutation, you’re more or less stuck with it. But Devon Boyne is doing leading-edge research in cancer and epigenetics, a red-hot field in science that investigates how cells switch genes on and off. Unlike inherited genes, epigenetic processes can be modified by lifestyle, dietary, and environmental factors.

“My research is looking at how lifestyle choices can affect your epigenetics and cancer risk. The aim is to help guide cancer prevention efforts at the population level,” says Mr. Boyne, an MSc student (Epidemiology) in the Queen’s Transdisciplinary Training Program in Cancer Research, an innovative program established in 2002 to produce future leaders in translational cancer research in Canada.

Like all students in this unique program, Mr. Boyne was expected to develop a cancer research question that involves several research areas and he was supervised by multiple mentors
with the different kinds of expertise needed to address the problem.

Moving across diverse fields

For his master’s thesis project, Mr. Boyne asked how certain lifestyle choices might be related to epigenetic changes thought to predispose women to developing cancer. He tackled this key question in a fresh way by drawing on diverse scientific disciplines and experts to help answer it. Mr. Boyne was supervised by Will King, a Queen’s molecular epidemiologist who studies environmental factors in relation to epigenetics and cancer risk and Christine Friedenreich, a University of Calgary researcher who has led pioneering studies showing that physical activity helps prevent and control cancer. He was also assisted by John McIntyre, a molecular biologist at the Tom Baker Cancer Centre in Calgary, and scientists at the McGill University and Génome Québec Innovation Centre who have specialized expertise in epigenetic analysis of DNA from blood samples.

As an undergraduate at Laurentian University, Mr. Boyne had majored in music. But he also chose electives in statistics, medical geography and public health that reflected his avid interest and ability to move easily across diverse fields. “The transdisciplinary program has been a great learning environment, especially for someone new to this field, like me. I’ve been fortunate to have had exposure to various types of cancer research through my interactions with other trainees, mentors and visiting scientists – on everything from the delivery of health services to the cellular pathways that drive tumour development. The program has really helped me to appreciate the importance of communicating and collaborating with researchers from different backgrounds.”

[Devon Boyne]
Devon Boyne (Photo by Garrett Elliott])

Flipping gene switches on and off

For his epigenetics study, Mr. Boyne used information from Dr. Friedenreich’s Alberta Physical Activity and Breast Cancer Prevention (ALPHA) trial, involving 320 post-menopausal women, aged 50 to 74 between 2003 and 2007€. He applied sophisticated data analysis techniques to measure how changes in two known breast cancer factors – body fat and sex hormones – can affect an important epigenetic process, called DNA methylation, that flips gene switches on or off. This mechanism is important because certain changes in DNA methylation – such as turning off a tumour suppressor gene – can lead to cancer.

DNA was collected from the ALPHA trial women’s frozen blood samples, Génome Québec scientists measured the DNA methylation levels and Mr. Boyne had the raw epigenetic data needed for his analysis. “I found associations between body fat, estrogen and changes in DNA methylation. This might help to explain why certain people get cancer while others do not. My research also suggests that, even in older populations, lifestyle can affect epigenetics. This is promising because it suggests that an epigenetic predisposition can be potentially modified or reversed through positive lifestyle changes,” he says.

Mr. Boyne has submitted two papers to academic journals from this initial research and is now working with Drs. King and Friedenreich to investigate directly whether a yearlong aerobic physical activity intervention has an effect on DNA methylation in healthy, inactive, post-menopausal women. “This is a really new topic and being on the cutting edge is exciting. It’s also a huge learning experience, which has helped prepare me to work on a transdisciplinary cancer research team,” he says.

Each student in the program develops a research question that involves several research areas. Each is supervised by multiple mentors with different kinds of expertise.

The changing world of cancer research

The transdisciplinary training program was designed by founding director Lois Mulligan and her colleagues to bring together cancer researchers who would not normally work in the same environment. Dr. Mulligan sees it as an opportunity for young investigators – including graduate students, post-PhD and post-MD fellows – to get a distinctive type of training and hands-on experience that will best prepare them for how cancer research is increasingly being conducted today and the direction in which it’s moving.

“Each of the students has a multidisciplinary, translational experience in what they learn, who they learn it from, and how they take their research forward. The cancer research world has changed. We’re teaching our students how to be part of that world and giving them the tools to contribute to it,” says Dr. Mulligan, a principal investigator in the Cancer Biology and Genetics Division,Queen’s Cancer Research Institute.

As well as collaborating with senior cancer research mentors from multiple fields, students doing research in diverse areas work closely with each other for weekly journal clubs and seminars. “Students learn to feel comfortable talking about their own narrow field of study to wider audiences. This will be helpful and important when they communicate their research to the public, the media, funders, or future employers and collaborators,” says Dr. Mulligan.

About 100 students have completed the program and following their training they have become clinician-scientists, academic researchers, data analysts or found positions in the pharmaceutical industry, where there is a big demand for graduates with translational research skills and knowledge. “This program is a great stepping stone for students in their future careers,” says Dr.Mulligan.

A fast track to discovery

For post-doctoral fellow Victoria Hoskin, the Queen’s Transdisciplinary Training Program has opened up a fast track to translating her basic findings in cell biology into an important discovery with promising clinical applications for cancer patients. As a PhD student in the program with a cell biology background, Dr. Hoskin was interested in studying proteins involved in metastasis, the spread of cancer cells from one part of the body to another.

“A lot of cancer patients don’t die because of the primary tumour but from the spread of the disease. About ‚90 per cent of cancer deaths are due to metastasis and the ultimate goal of my research is to find better ways to stop the spread of cancer,” she says.

As a trainee, Dr. Hoskin has benefitted immensely from Queen’s cancer research mentors who span multiple disciplines. This has led to fruitful transdisciplinary collaborations on the metastasis problem, and these have progressed in exciting and, at times, unexpected directions. Her primary supervisor is cancer biologist Bruce Elliott, an expert in studying proteins involved in cancer metastasis. Her collaborations with pathologists Sonal Varma and Sandip SenGupta and medical oncologist Yolanda Madarnas gave Dr. Hoskin access to breast cancer patient samples and an anonymized medical database containing information such as breast cancer sub-type and treatment regimens, as well as invaluable guidance from a clinical perspective.

“The program is fantastic for students because it fosters a collaborative network between basic scientists and clinicians. It opens up your mind to think about research questions from new angles, leading to different areas of research that a trainee may not have ventured into without that type of collaboration,” she says.

The importance of a protein

As a basic scientist, Dr. Hoskin began studying a protein called ezrin and showed, at the molecular level, how it plays an important role in promoting the spread of breast cancer to other parts of the body. On the pre-clinical side of her research, she has found that estrogen receptor-positive breast cancer cells with higher levels of ezrin are more resistant to anthracycline drugs, a traditional chemotherapy for breast cancer patients. Clinically, she discovered a link between high ezrin levels and poor outcome in patients with estrogen-positive breast cancer.

“I’ve developed an appreciation for the clinical challenges that face cancer patients. Clinical science questions are now driving basic science questions for me as a result of the cross-talk between basic scientists and clinical research scientists,” she says.

As part of her post-doctoral studies in the program, Dr. Hoskin is now using pre-clinical models to test the effectiveness of a new commercially available drug that blocks ezrin to treat breast cancer cells with high levels of that protein. “You have to go down the road where the science takes you – we want to investigate whether using ezrin inhibitors in combination with traditional chemotherapy can help overcome resistance to treatment.”

One promising possible clinical application of Dr. Hoskin’s research would be to use ezrin as a predictive biomarker. “We want to know if ezrin can predict relapse and if so, patients at high risk of relapse could benefit from being treated more aggressively initially. We also want to find out if ezrin can predict a patient’s response to treatment, whether it will be poor or good,” she says.

You have to go down the road where science takes you.

From one collaboration to another

Like all trainees in the program, Dr. Hoskin is expected to present a seminar on her research to a broader audience of students and faculty beyond her own narrow field of study. When she presented her findings on ezrin as a potential highrisk biomarker for the spread of breast cancer at the Queen'sQueen’s Cancer Research Institute retreat, her work caught the attention of David Berman, a prostate cancer scientist and director of the Queen’s Cancer Research Institute. That cross-disciplinary exchange of ideas led to a new collaboration with Dr. Hoskin’s supervisor, Dr. Elliott, and Dr. Berman.

"Dr. Berman was interested in looking at ezrin in a prostate cancer model after hearing my presentation. Now the Elliott lab and the Berman lab are working together on that," says Dr. Hoskin.

That’s the kind of synergy Lois Mulligan likes to see. “The work Victoria has done, bringing together the combined expertise of biologists, pathologists and oncologists, is not only advancing our knowledge of breast cancer but can be translated to other forms of cancer. It will spur on new lines of inquiry, and new collaborations.”

Dr. Mulligan has high hopes that, with continued funding of the program in the next few years, these young investigators and their mentors will transform Canadian cancer research.

[cover of Alumni Review 2016 Issue 3]