Cancer. The word stirs fear in all of us. According to the National Cancer Institute of Canada, approximately 38% of Canadian women and 43% of men will develop cancer in the course of their lifetimes. About 1 in 4 Canadians will die of the disease.
Although the numbers are staggering,they are partly due to population growth and aging, not to increased individual risk of cancer. And in the past two decades, researchers have made tremendous advances in various areas of fundamental research, advances that are increasingly being applied in the clinic in the form of new cancer treatments. With support from AHFMR, many Alberta-based researchers continue to add to the growing body of knowledge—adding piece by piece to the cancer puzzle.
Reprogramming cancer cells
One of those researchers is AHFMR Scholar Dr. Michael Hendzel. His work at the University of Alberta involves epigenetics—the study of changes in the activity of the gene that occur without a change in its DNA structure (the molecules that carry genetic information and pass changes on from one generation to the next). Researchers recently demonstrated that a cancer cell nucleus could be reprogrammed; in other words, the event that led to the onset of cancer could be undone while all the cell’s DNA changes that preceded the onset remain intact. “That tells you there is an epigenetic component to cancer,” explains Dr. Hendzel. “This is good news because, unlike changes in DNA sequence, epigenetic changes can be reversed.”Changes
It’s now estimated that at least as many changes in gene expression occur through epigenetic processes as through mutations in the DNA; deactivation of cancer tumour suppressors is a case in point. In the past, cancer researchers have focused on changes in the DNA sequence. Epigenetic changes hold new potential because of their reversibility. “If we had a full understanding of how epigenetic processes work, in theory we could reprogram the genome to behave the way we want,” says Dr. Hendzel. Along with two University of Alberta colleagues, experimental oncologist Dr. Gordon Chan and Heritage researcher and medical geneticist Dr. Alan Underhill, Dr. Hendzel studies a particular epigenetic modification that may facilitate rapid cell evolution—a major concern in cancer, where cells divide and grow very quickly.
Dr. Hendzel points out that the first generation of drugs targeting epigenetic processes is now coming to the clinic: non-toxic drugs that have great potential as chemotherapy. “There is real hope that these drugs can directly target cancer cell growth without having adverse effects on other processes,” says Dr. Hendzel. “They have great potential for both treatment and prevention of cancers.”
New tools
Potential is also a word that drives the work of Heritage Scholar Dr. David Schriemer—the potential to use new tools in the study of cancer. An analytical chemist at the University of Calgary, Dr. Schriemer applies the tools of his field to cancer research. More specifically, he uses mass spectrometry to study the structure and function of proteins (the workhorses of a cell). A mass spectrometer is an instrument used to measure the mass of molecules. “Think of it as a very sensitive bathroom scale for really, really small things,” says Dr. Schriemer. He explains that there may be proteins in a cancerous sample that do not appear in normal tissue. Learning how these proteins interact with one another and what sort of problems in interaction lead to dysfunction could provide insight into how to better treat disease. “We want to see how a healthy person and a diseased person look on a molecular level,” he explains. “Our tools are designed to quantify that difference.”Microtubules
One of Dr. Schriemer’s projects involves the analysis of microtubules, hollow tubes in every cell system that play a role in cell division. Since cancer cells divide at a faster rate than other cells, microtubules are an important target for cancer drugs aiming to slow down their cell division function—drugs such as Taxol (Paclitaxel), which is mainly used to treat breast and ovarian cancer tumours. Microtubules are very complex structures and relatively little is known about them. “If we can study their structure and function, maybe we can come up with a better drug to target microtubules,” says Dr. Schriemer, “one with fewer side effects and better outcomes.”
Diagnosis in the palm of your hand
While Dr. Schriemer conducts his work on the basic end of the research spectrum, Dr. Linda Pilarski’s research bridges the gap between the lab and the clinical setting. A University of Alberta researcher working at the Cross Cancer Institute, Dr. Pilarski studies multiple myeloma, a particularly deadly type of cancer which affects plasma cells in the bone marrow. Part of her research looks at the early-stage cells that lead to this type of cancer. “These cells don’t go away with any current type of cancer therapy,” she explains. “Treatments such as chemotherapy target only the later-stage cells, which do not appear able to regenerate themselves. We also have to get rid of the early-stage cells that maintain the disease process, or the cancer will keep coming back.” Dr. Pilarski has identified two genes which help these early-stage cells survive and is now testing a treatment to target these genes.Lab on a chip
Her second line of investigation focuses on technology that could one day be applied in the clinic to help diagnose cancer patients. As leader of the Alberta Cancer Diagnostic Consortium, Dr. Pilarski collaborates with engineer Dr. Chris Backhouse and medical geneticists and Heritage researchers Dr. Moira Glerum and Dr. Susan Andrew to develop a handheld diagnostic device—“a lab on a chip”—to analyze these early-stage cancer cells. The device could revolutionize cancer diagnostic testing, which is currently time-consuming and expensive, and requires specific expertise, whereas almost anyone could use the lab-on-a-chip. It could also be used in many other fields of study. Dr. Pilarski was recently invited to Washington, DC, to give a symposium to members of the FBI on use of the technology for genetic testing in forensics.
The lab-on-a-chip project is supported through the Alberta Cancer Diagnostic Consortium, a unique collaboration between the universities of Alberta and Calgary and the Alberta Cancer Board, funded by Western Economic Diversification Canada, CIHR, NSERC and other agencies. This support has allowed scientists from a variety of backgrounds to work together in the same lab—an absolutely critical factor, according to Dr. Pilarski. “Things are going really well right now,” she says of the project. “Having biomedical and engineering staff working in close proximity allows us to work more effectively, to make the device more efficient.”
Life after treatment
Dr. Jana Rieger focuses on how patients cope following cancer treatment. For the approximately 400 people diagnosed with head or neck cancer in Alberta each year, even treatment considered successful can mean a serious reduction in their quality of life. Patients who undergo radiation treatment often experience dry mouth due to the destruction of their salivary glands. The condition sounds minor, but it can have devastating effects. Without saliva, patients can develop cavities in their teeth and sores in their mouths; eating and speaking can become very difficult; and wearing dentures or other prostheses in the mouth may be problematic. Patients who speak for a living, such as teachers, might lose their jobs because they can no longer communicate very well. And society often judges them very harshly. A recent study found that people listening to recordings of the voices of patients who had undergone surgery for oral cancer tended to rate the speakers as less intelligent, less attractive, and less employable than average.“A lot of people don’t realize that when the capacity for either speech or eating has been taken away, the consequences are far-reaching,” says Dr. Rieger, a Heritage Population Health Investigator and speech pathologist at the University of Alberta. “These people tend not to socialize with their friends or eat dinner with their families. They can feel very isolated and often become reclusive.”
Dry mouth
Dr. Rieger wants to help. She studies two different types of treatments to prevent dry mouth: a surgical treatment to transfer one of the salivary glands before radiation, and a drug treatment patients receive while undergoing radiation. To understand whether one method works better than the other, Dr. Rieger collects information about the patients’ speech, chewing and swallowing, and general quality of life before and after the treatments. She works with a unique multidisciplinary team of surgeons, oncologists, speech therapists, and prosthodontists (specially trained dentists who make replacements for missing teeth or other structures in the mouth) at Edmonton’s COMPRU facility—the Craniofacial Osseointegration and Maxillofacial Prosthetic Rehabilitation Unit—an internationally recognized centre of excellence for head and neck reconstruction. Here Dr. Rieger’s work allows her to assess patients so that surgeons can change their tactics when something is not working well.
“We want to plan surgeries better, not just in terms of curing the cancer, but also for optimal function and quality of life for the patient,” she says.
Colon cancer screening
Heritage Population Health Investigator Dr. Robert Hilsden focuses on screening patients early to prevent them from developing colon cancer. The third most common type of cancer in Canada, colon cancer may also be the least talked about; many people are embarrassed to discuss symptoms which include changes in bowel movements. Colon cancer develops from polyps or tumours in the large intestine, which are harmless at first and develop into cancer only if not removed. Without early detection, about 45% of people diagnosed with colon cancer die; but it can be cured if caught early. This is where Dr. Hilsden hopes to make a difference.Colon cancer testing has received greater attention recently, partly because of the involvement of former hockey great Daryl Sittler as a spokesperson to raise awareness of the disease. In addition, a colon cancer task force recently established guidelines suggesting that screening should begin at age 50.
Action
“The real problem is: how do you put that into action?” says Dr. Hilsden, a University of Calgary researcher as well as a practising gastroenterologist. “Which test should be used, and how should it be implemented? There are also questions about cost. We want to understand the factors that influence people’s decision-making in choosing a particular type of test; things like effectiveness, invasiveness, and whether or not they have to travel to have it done.”
One of his research projects, in collaboration with AHFMR researchers Dr. Elizabeth McGregor and Dr. Gillian Currie, is an economic analysis of the various types of colon cancer tests. Dr. Hilsden also wants to determine the complication rate for colonoscopy, a test which uses a tiny camera to examine the inside of the large intestine. A third project involves the fecal occult blood test—how often it is used, and whether people receive appropriate follow-up afterwards.
“This cancer is treatable,” emphasizes Dr. Hilsden, “but we need to figure out the best way to catch it in its early stages.”
Brain cancer While Dr. Hilsden focuses on a type of cancer that is deadly but treatable, AHFMR Clinical Investigator Dr. Ian Parney is
preoccupied with a type that has a much poorer prognosis: brain cancer. A brain surgeon as well as a researcher at the University of Calgary, Dr. Parney studies glioblastomas—the most malignant type of brain tumour. What causes these tumours is still a mystery for the most part, but the end results are all too well known. Average survival time for a patient with this type of tumour is only about a year to 16 months; without treatment that time drops to 3 to 4 months. And despite advances in radiation and chemotherapy, those survival rates have not improved a great deal over the past 30 years.
Unlike other types of cancer, brain tumours seldom spread to other parts of the body; but they tend to return after surgery, in spite of the long hours surgeons like Dr. Parney spend removing them. “We need to learn more about how the immune system interacts with these tumours,” he states. “We want to learn how to stimulate the immune system to fight back.”
White blood cells
Dr. Parney has been concentrating on trying to stimulate white blood cells called lymphocytes and macrophages to fight the tumours. While there are few lymphocytes in the tumours, macrophages are found in abundance. They act as housekeeping cells, chewing up debris such as tumours. Yet these macrophages seem to be subverted by the tumour to do its own dirty work—they may even be killing the lymphocytes. “My research is focused on how we can change this. How can we turn those macrophages on so they attack the tumour?”
After several years in San Francisco, Dr. Parney returned recently to his hometown of Calgary, drawn by AHFMR funding as well as by Alberta’s strong research environment. “Heritage has been a big part of my research training,” he says, pointing out that his career began with an AHFMR Summer Studentship. “And there has been such phenomenal growth in neuroscience, neuro-oncology, and neurosurgery here that we have one of the best, if not the best, groups of people to work with in the world. Alberta is the place to be.”
Credentials and publications
Dr. Michael Hendzel, an AHFMR Scholar, is an associate professor in the University of Alberta Department of Oncology. He receives funding from the Canadian Institutes of Health Research (CIHR), the Alberta Cancer Board, and the Alberta Cancer Foundation.
Dr. David Schriemer is an AHFMR Scholar and an assistant professor in the University of Calgary departments of Biochemistry and Molecular Biology; Oncology; and Pharmacology and Therapeutics; and an adjunct assistant professor in the Department of Chemistry. He is the Canada Research Chair in Pharmaceutical Proteomics and receives funding from the CFI, CIHR, Alberta Ingenuity (AHFMR’s sister foundation for science and engineering research), and MDS Sciex. He is the director of the Southern Alberta Mass Spectrometry Centre for Proteomics and a principal investigator of the Alberta Ingenuity Centre for Carbohydrate Science.
Dr. Linda Pilarski is a professor in the University of Alberta Department of Oncology and holds the Canada Research Chair in Biomedical Nanotechnology. She also receives funding from the US National Institutes of Health (NIH), CIHR, the Natural Sciences and Engineering Research Council of Canada (NSERC), the Alberta Cancer Board, and the National Cancer Institute of Canada. The lab-on-a-chip project receives support through the Alberta Cancer Diagnostic Consortium, funded by Western Economic Diversification Canada; the CIHR New Emerging Teams (NET) Program; and NSERC.
Dr. Jana Rieger is an AHFMR Population Health Investigator and an assistant professor in the University of Alberta Department of Speech Pathology and Audiology, part of the Faculty of Rehabilitation Medicine.
Dr. Robert Hilsden is an AHFMR Population Health Investigator and an assistant professor in the University of Calgary departments of Medicine and Community Health Sciences. He also receives funding from the National Cancer Institute of Canada, CIHR, the MSI (Medical Services Incorporated) Foundation, and Calgary Laboratory Services.
Dr. Ian Parney is an AHFMR Clinical Investigator and an assistant professor in the departments of Clinical Neurosciences and Oncology at the University of Calgary.
Selected publications
McManus KJ, Hendzel MJ. Quantitative analysis of CBP- and P300-induced histone acetylations in vivo using native chromatin. Molecular and Cellular Biology 2003 Nov;23(21):7611-7627.
Chik JK, Schriemer DC. Hydrogen/deuterium exchange mass spectrometry of actin in various biochemical contexts. Journal of Molecular Biology 2003 Nov 28;334(3):373-385.
Adamia S, Reiman T, Crainie M, Mant MJ, Belch AR, Pilarski LM. Intronic splicing of hyaluronan synthase 1 (HAS1): a biologically relevant indicator of poor outcome in multiple myeloma. Blood. Prepublished online 2005 Feb 24;DOI:10.1182/blood-2004-10-3825.
Rieger J, Seikaly H, Jha N, Harris J, Williams D, Liu R, McGaw T, Wolfaardt J. Submandibular gland transfer for prevention of xerostomia after radiation therapy: swallowing outcomes. Archives of Otolaryngology—Head & Neck Surgery 2005 Feb;131(2):140-145.
Verhoef MJ, Rapchuk I, Liew T, Weir V, Hilsden RJ. Complementary practitioners' views of treatment for inflammatory bowel disease. Canadian Journal of Gastroenterology 2002 Feb;16(2):95-100.
Laws ER, Parney IF, Huang W, Anderson F, Morris AM, Asher A, Lillehei KO, Bernstein M, Brem H, Sloan A, Berger MS, Chang S. Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project. Journal of Neurosurgery 2003 Sep;99(3):467-473.