Research Location: BC Cancer Agency - Vancouver

Cancer is the leading cause of premature death in Canada, and the number of new cases continues to rise as the population grows and ages. Based on current rates, 38 per cent of Canadian women and 44 per cent of Canadian men will develop cancer in their lifetimes, many when they are 70 or older. Traditionally, physicians assess the severity of cancer tumours by removing tissue samples from a patient and assigning a severity score based on what they see under the microscope. This process can be time-consuming and yields limited information. Recent discoveries have identified a number of molecules produced by cancer cells. Gerald Li is working on an optical imaging system to detect and evaluate the presence of these molecules. In particular, his focus will be on the use of specially designed probes that will flag these molecules, allowing a physician to immediately identify malignant cells. This system will make it possible to image various parts of the body to detect cancer earlier, predict which pre-cancerous lesions will become tumours, and image tumours in the operating room to help determine the boundary between healthy and malignant cells. It will also assist in the selection of treatments targeting cells that create these molecules.

Cancer causes six million deaths worldwide each year, and is the second leading cause of death in developed countries. Of 227,000 new cases diagnosed in Canada this year, about 80 per cent will be some type of carcinoma, a malignant tumor that begins in the epithelial cells lining the inner and outer surfaces of our organs. Carcinomas comprise a vast array of cancers, including lung, breast, prostate, colorectal, oral, esophageal and cervical. Although current treatments can be effective, survival rates vary for these different types of cancer. Mutations in genes are responsible for the development of all cancers. But the nature of epithelial cancer cells makes it difficult to distinguish which mutations initiate the process. William Lockwood is using new technology to define patterns of DNA change in people with early stage epithelial cancer and to identify the genes responsible for the progression of the disease. Ultimately, these genes may be used to predict which pre-cancerous lesions are prone to develop into tumours to improve early detection and treatment.

T cells are white blood cells involved in a variety of our immune system responses, including detection and destruction of cancer cells. With T cell therapy, “tumour-reactive” T cells are isolated from a patient’s blood, and large numbers are grown outside the body. These T cells are then infused back into the patient to help the body recognize and destroy cancer cells, a method called adoptive immunotherapy. Michele Martin is studying the potential for using T cell therapy to treat breast cancer. Early results show about 19 per cent of tumours will regress or shrink with this treatment – unprecedented with other types of treatment – while the rest have partial or no regression. Michele is investigating how some of the tumours manage to exclude the T cells and also whether combining T cell therapy with low doses of chemotherapy can facilitate T cell infiltration into these tumours. If successful, this approach could improve breast cancer cure rates and reduce the side effects associated with current treatments.

Therapeutic antibodies are a popular and effective class of cancer drugs, particularly when combined with more traditional treatments. While natural antibodies are found in our blood all the time, they do not recognize cancer. Therapeutic antibodies are designed to recognize special molecules found only on the surface of cancer cells, allowing them to target and kill those cells without harming healthy ones. This results in a dramatic decrease in the side effects of chemotherapy such as nausea, fatigue and hair loss. Little is known about how therapeutic antibodies work, including the reasons why they are ineffective in some cancer patients. This lack of knowledge currently makes it hard to adapt or improve the drugs. Jesse Popov is studying trastuzumab, a therapeutic antibody used to treat aggressive breast cancers. Focusing on revolutionary new theories about the way that cellular membranes function, Jesse is working to determine how trastuzumab works in the body, as well as the basis for trastuzumab resistance. With new insights, he hopes to uncover ways to tailor therapeutic antibody-containing pharmaceuticals to make them more effective in treating different forms of cancer. This research is part of the ongoing Breast Cancer Research Program at the BC Cancer Research Centre, an initiative focused on identifying pharmaceutically viable methods for improving the effectiveness of breast cancer treatment.

Non-Hodgkin’s Lymphoma (NHL) is a cancer of lymphocytes – a type of white blood cell that moves throughout the body as part of its role in immune defense. As a complex disease with both environmental and genetic factors contributing to its development, NHL is incurable and the fourth highest cause of cancer deaths in Canada. Johanna Schinas aims to identify the genetic factors contributing to NHL susceptibility. She is focusing on the role of apoptosis which is a natural process of cell death triggered by genes and carried out by the immune system. When an immune cell originally meant for destruction escapes apoptosis, it becomes an ideal environment for further changes that can cause progression to malignant cancer. By searching for DNA variants in apoptosis genes that are associated with the development of lymphoma, she hopes to identify markers of genetic susceptibility to lymphoma. This will lead to not only a better understanding of the molecular basis of this cancer, but also assist in the design of effective surveillance programs for at-risk individuals.

Resistance to cancer and infectious diseases relies on complex responses in our immune system. Natural killer (NK) cells provide a first line of defence, recognizing and killing infected and tumour cells, while sparing normal cells. NK cells use an intricate system of proteins, found on their surface, to either activate or inhibit their “natural killer” activity. However, the mechanisms by which these proteins induce this action are not completely understood. Dr. Valeria Alcón is studying two cellular proteins (CD72 and CD100) that are involved in the activation of several immune cells to determine how these proteins regulate natural killer cell activity. She is also examining how NK cells interact with other immune system cells to induce immune responses. Her research could explain how to activate natural killer cells, leading to the development of more effective treatments for infectious disease and cancer.

Neurofibromatosis 1 (NF1) is a genetic disease associated with a variety of skin abnormalities and an increased risk of developing cardiovascular disease and cancer. About one third of people with NF1 die before age 45; usually from one of these complications. However, the risk of developing cardiovascular disease and cancer is not the same in all NF1 patients, with some people at higher risk of developing these complications. These differences are seen both between families with different mutations of the gene that causes NF1 and within families with the same mutation. Alessandro De Luca is exploring whether certain specific alterations of the NF1 gene and differences in other genes that interact with the NF1 gene are linked to an increased risk of cardiovascular disease and cancer. Alessandro is studying the frequency of particular NF1 mutations and variants of interacting genes in NF1 patients with and without cancer and cardiovascular disease. The ultimate aim of his research is to develop a panel of genetic markers that can be used to predict the risk of developing cardiovascular disease or cancer in patients with NF1.

A serious, chronic condition facing 28 per cent of women who have received treatment for breast cancer is breast cancer-related lymphedema (BCRL)—a painful swelling of the hand or arm. Typically resulting from the removal of a patient’s lymph nodes and/or radiation treatment, BCRL is characterized by an impaired lymphatic system, which is no longer able to properly drain fluid from tissues. In addition to pain, women with BCRL live with side effects such as restricted movement in the affected arm, increased risk of infection and reduced quality of life. Although exercise was initially believed to aggravate BCRL, current research suggests that exercise may actually help in reducing the severity of lymphedema and alleviating symptoms. MSFHR previously funded Kirstin Lane for her PhD research to develop a test that uses nuclear medicine in combination with exercise to measure lymphatic function in women with BCRL. Now, as an MSFHR Post Doctoral Fellow, Kirstin is applying this test to evaluate and compare lymphatic function in women with BCRL before and after a three-month program of supervised upper extremity exercises. The results of this research may confirm exercise as a safe, positive treatment option for BCRL. This information could be used to create exercise programs for preventing and treating the condition, thereby improving the health and quality of life for women living with BCRL.

Myelodysplastic syndromes (MDS) are a family of disorders primarily associated with decreased production of blood cells in the bone marrow. The blood cells of people with MDS die before maturity, causing a shortage of functional blood cells. Patients with MDS are at a significantly increased risk of developing acute myeloid leukemia (AML). Dr. Daniel Starczynowski is studying whether genetic alterations in a protein known as TRAF6 may be implicated in both of these related diseases. This protein simultaneously regulates cell death and cell growth signaling pathways, and has been shown to be abnormally activated in some patients with MDS. He hopes that an increased understanding of the molecular events in MDS will reveal new targets for therapy.

Sepsis is a life-threatening medical condition caused by a severe bacterial infection. It is a leading cause of death in critically ill patients, with mortality rates reaching greater than 60 per cent in its most critical forms. Endothelial cells, the layer of cells that line the inside wall of blood vessels, are a primary target for bacteria during infection. Major components present on the surface of some types of bacteria are recognized by molecules on the surface of the endothelial cell and can trigger the cells to release a class of chemicals that initiate an inflammatory response, characterized by redness, heat, swelling and pain. Under normal conditions, the body will protect itself by initiating this response. However, sepsis occurs when there is hyperactivation of the inflammatory response and the body fails to resolve the infection. This can result in endothelial cell damage, leading to major organ failure and death. Lipopolysaccharide (LPS) is a large molecule that forms an integral part of the outer wall of some bacteria. Exposure to this molecule signals cells to activate the inflammatory response and, in the case of endothelial cells, leads to cell death. Shauna Dauphinee is investigating whether a protein called FADD (Fas associated death domain) decreases the signalling ability of LPS, thereby reducing the inflammatory response and causing cell death. The results of this research could ultimately lead to new ways to treat sepsis.