Developing innovative nanopharmaceuticals for the treatment of relapsed breast cancer

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.

Genetic Variation in Apoptotic Genes and Susceptibility to Non-Hodgkin Lymphoma

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.

The role of CD72/CD100 interactions in NK cell activation

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.

Development of a genetic-based prediction model for cardiovascular disease and cancer risk assessment in neurofibromatosis type 1

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.

The Effect of Chronic Exercise on Lymphatic Function in Breast Cancer Survivors with Lymphedema

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.

Characterization of TRAF6 in normal and malignant hematopoietic cell processes: a focus on Myelodysplastic Syndromes

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.

Genome-scale variation in health and disease

The sophisticated approaches of genomics are increasingly being used to analyze the majority of the genetic material contained within cells. The tools of genomics have catalyzed remarkable developments in health and disease research. These tools continue to evolve at a rapid pace, making possible additional health research opportunities that are increasingly comprehensive. Dr. Marco Marra is Director of the British Columbia Cancer Agency Genome Sciences Centre. Dr. Marra was funded as an MSFHR Scholar in 2001, with a specific focus of using genomics to comprehensively search for genes that play roles in cancer. In 2003, Dr. Marra also distinguished himself as leading the team that cracked the genetic code for SARS. In addition to his continuing work in cancer genomics, Dr. Marra is also working to identify and analyze DNA mutations correlated with, or causing, mental retardation. A consistent theme in Dr. Marra’s research is the identification and analysis of new genes and new gene products to determine their potential for use as new therapies or vaccines to combat cancer, infectious diseases, and other disorders.

Characterization of the role of the Fas-associated death domain (FADD) protein in lipopolysaccharide signalling in endothelial cells

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.

Biological pathways disrupted in mantle cell lymphoma pathogenesis

Mantle cell lymphoma (MCL) is an aggressive, incurable non-Hodgkin lymphoma with a median survival of three years. In order to find new, more effective treatments for MCL, researchers are working to better understand how the disease develops and progresses. MCL is characterized by a specific gene translocation, which prompts an unregulated growth signal. However, this translocation is believed to be only the first event in a stream of genetic alterations required to cause the disease. Using a recently-developed test capable of pinpointing previously undetectable genetic alterations, Ronald deLeeuw is compiling a more complete catalog of the secondary genomic alterations associated with MCL. By uncovering the role of secondary genes within the progression of MCL, Ronald hopes to uncover new targets for disrupting these pathways and halting the disease.

Identification of regulatory mutations involved in cancer by gene expression analysis and bioinformatics approaches

Regulatory DNA sequences determine the leveI, location and timing of gene expression. These sequences are important in nearly all biological processes and many disease conditions. In some cases, the onset of cancer is related to changes in these sequences, such as when gene translocation results in the production of a protein that prevents normal cell death. Expanding on his previous MSFHR-funded work, Obi Griffith will make use of public gene expression data and novel computational approaches to identify genes believed to have undergone a change in regulation leading to cancer. Once these genes have been identified, further analysis will investigate the mechanism responsible for the change in regulatory control. Then, Obi will obtain specific tumour samples and validate the predicted changes in the laboratory. Obi hopes to increase understanding of how genes are controlled under normal conditions and how the loss of this control leads to cancer. Such identified genes could make suitable targets for therapeutic intervention as well as having prognostic and diagnostic value.