The main objective of my research is to understand the molecular basis of how cancer progresses and to use the knowledge to identify new cancer therapies. To achieve this, my research team is studying receptors found on the surface of most cells that cause them to attach to other cells. We want to determine how the receptors communicate information they detect on the outside of the cell to the inside of the cell. We have identified proteins that interact with these receptors on the inside of the cell and are responsible for transmitting information to other parts of the cell to control cell division, cell death, cell differentiation and cell movement. We are focusing on one protein – Integrin Linked Kinase (ILK) – whose function is tightly regulated in normal cells, where its activity rapidly turns on and off. But in cancer cells, ILK is on all the time, leading to increased cell division, decreased cell death and increased cell movement. We have determined that ILK is at least partly responsible for the abnormal behaviour of cancer cells, and ILK activity is considerably elevated in many types of cancer. We have also identified specific chemical inhibitors of ILK activity, which are currently being evaluated in pre-clinical trials. The results to date show these inhibitors are effective in blocking growth and spread of tumours. ILK is present in many tissue types, and it is likely that it plays a critical role in the development and function of these tissues, and in other diseases of chronic inflammation such as arthritis, asthma, kidney disease and heart disease. To investigate this further we are using genetic techniques to alter ILK expression and function in a tissue-specific manner. Such studies will lead to a better understanding of the role of ILK and related proteins in nomal and diseased tissues.
Research Location: Vancouver General Hospital
Aminophylline bolus in bradyasystolic cardiac arrest: a randomized placebo-controlled trial
Cardiac arrest occurs when the heart stops pumping blood effectively. Without blood flow, no oxygen circulates and brain damage can occur within minutes. Bradyasystole, a type of cardiac arrest where the heart beats very slowly or not at all, accounts for more than half of cardiac arrests. Less than three out of every 100 people who experience this type of cardiac arrest survive. Bradyasystolic cardiac arrest may be caused or worsened by adenosine, a chemical that exists in our bodies and is released by cells when the heart is under stress. The drug aminophylline has been used to treat asthma for years, and may also counteract the adverse effects of adenosine during cardiac arrest. My research will evaluate the effectiveness of aminophylline in improving survival from bradyasystolic cardiac arrest. All advanced life support ambulances in Greater Vancouver and Chilliwack are participating in this double-blind, randomized study. Patients will receive either aminophylline or a placebo in addition to standard resuscitative care. The patient, paramedics, physicians and nurses will not know what the patient received. If the therapy proves beneficial, numerous lives could be saved. About 1,000 people experience cardiac arrest in North America every day, and the majority would be eligible for this treatment.
Genetic studies in common, complex diseases with special emphasis on Multiple Sclerosis
Multiple sclerosis (MS) is one of the most common neurological diseases, usually striking people between the ages of 20 and 40. My research focuses on understanding genetic epidemiological, molecular genetic and environmental factors that increase susceptibility for MS and other common complex diseases that begin in adulthood. As part of my work in the Canadian Project on Genetic Susceptibility to MS, a BC and Canada-wide database on MS has been established. This is the largest database of information on family histories of MS in the world. Using this information, we have shown that both hereditary and environmental factors do have a role in causing susceptibility to MS. Now we are focusing on identifying the genes and non-genetic factors responsible for MS. This research will help identify people at high risk of developing MS, and possibly contribute to treatments that slow down or prevent the onset of the disease. In addition, the results of this research are relevant for addressing other common adult onset diseases such as Alzheimer’s disease, breast cancer and diabetes.
Key signaling pathways controlling survival and death of hemopoietic cells
All cells are programmed to die eventually. If cells don’t die normally, they can become harmful. For example, cancer can result when cells that should die keep growing instead. Each cell produces 10 to 15,000 proteins, with approximately 25 to 50 per cent of these involved in transmitting signals from the outside to the inside of the cell. My research is investigating how signals are sent within individual cells during the process of cell death. Signalling proteins bind to receptors on the cell surface to regulate growth and determine whether a cell lives or dies. The function of many signal proteins is to keep cells from undergoing apoptosis (cell suicide). My research team has deciphered the function of some key proteins and is continuing to study how proteins determine whether cells live or die. Our goal is to find ways to stimulate or block cell growth or death, which could lead, for example, to the ability to force cancer cells to die. We are also examining macrophages, scavenger cells that clean up debris and are important in the development of atherosclerosis (narrowing of the arteries), and the function of inflammatory cells in the immune system that respond to infection. This research will increase understanding of cell death and may lead to the development of new drug therapies for cancer, cardiovascular disease or inflammatory conditions such as asthma.
Analysis of prostate cancer progression using functional genomic approaches
In the early stages of prostate cancer, tumour growth is regulated by male sex hormones, called androgens. In treatment, androgens are removed to shrink the prostate tumour. However, the results of this therapy are usually temporary as surviving tumour cells become independent of androgens for growth and survival. I am investigating the genes responsible for this transition. To analyze these genes in a high throughput manner, I have created a Microarray Facility, the second of its kind in Canada. In the Facility, we can put up to tens of thousands of genes at a time on a single microscope slide. With this technology, we can now do experiments in a few days that would have taken years not long ago. We are comparing normal tissue to early and late tumours, and examining which genes are associated with tumour development. This research will identify the genes that cause prostate cancer, and how genes are turned on and off as the cancer progresses. We can use the information to predict when prostate cancer will occur, prevent its onset and develop new treatments that target the cancer-causing genes. In addition, we are investigating the effects environmental contaminants and dietary factors may have on the development and progression of prostate cancer.