Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men of the Westernized world. While early stage disease is frequently curable with surgery or radiotherapy, limited treatment options are currently available for approximately one-third of patients who clinically present with locally advanced or metastatic disease resulting in a poor prognosis for patients with advanced disease. One treatment option that is currently being used for advanced PCa is a medical procedures designed to block androgenic steroids to induce death of prostate cancer since prostate cancer cells typically require these hormones for their growth and integrity. While this treatment is often effective with a response rate of up to 80%, within 1-3 years the tumours inevitably recur as hormone-refractory variants, a condition for which there is no current effective therapy. Thus if we are to have an impact on survival rates of patients with PCa, new therapeutic strategies are required for treating advanced disease. Up to 50% of advanced prostate cancers have acquired mutations in a gene called PTEN that essentially inactivated it. Inactivation of PTEN in prostate cancer is correlated with a poor prognosis. Loss or inactivation of this gene makes prostate cancer cells more resistant to different forms of therapy including chemo-, radiation and hormone-therapy. The development and progression of cancer is dependent on the deregulation of the intricate balance in the rates of cell growth and death. The proposed project addresses how loss of the PTEN gene confers cell with a survival advantage and resistance to therapies. Under ordinary conditions, PTEN keeps growth of normal cells in check by serving as a brake to inhibit cell growth. When PTEN is mutated in cancer, the brakes fail and this confers uncontrolled growth and increased resistance of the cancer cells to chemotherapy and hormone ablation therapy. My lab is actively working on how loss of PTEN protects prostate cancer cells from death signals and we are looking for different ways to block the effects of inactivating PTEN. Results of this study will be directly relevant to development of new therapies aimed at treating the subset of advanced prostate cancers that have lost PTEN.
Year: 2007
Social Determinants of Rural and Northern Community Health
Research has increasingly linked the health of individuals to the integrity of a community’s social fabric, the extent to which residents in a community trust each other and participate in community activities, and on the networks of communication and exchange between community members. However, little research on this “”social capital”” has been conducted in British Columbia. Yet, communities in British Columbia are facing an accelerated pace of structural change due to the effects of globalization, changes over the past 15 years in health and welfare systems, and industrial restructuring. It is imperative, particularly in the Central and Northern Interior of the province, where an unprecedented eco-economic crisis is unfolding due to the pine-beetle infestation, that the impacts of these changes in community structure and functioning and, in turn, their impacts on social capital and the health and the health and educational status of children and adolescents are investigated in a way that may lead to amelioration. Building on the foundation of over a decade of work on the social determinants of workplace and community health and a recently awarded New Emerging Team grant to investigate the social determinants of community health in British Columbia, this program of research will further methodological developments in community health research while strengthening the base for community health research at the University of Victoria, in BC, nationally, and internationally. Given that many other communities in Canada, as well as in other nations, similar challenges, the knowledge, conclusions, and recommendations arising from this program of research will be applicable in other jurisdictions.
Community screening and intervention for high-risk oral premalignancies
Worldwide there are over 300,000 new cases of oral cancer each year with half of these cases dying of the disease; mainly because of late diagnosis. As such, the advanced widespread disease often requires complex and disfiguring treatment, consequently with a huge impact on the quality of life of the patients, at the same time adding stress to the health care system. It is important to prevent and identify the disease at early stages.
In BC, a particular high-risk medically underserved community resides in Vancouver Downtown Eastside (DTES), the location of one of Canada's poorest neighborhood. Residents in this community are at high risk for oral cancer because many are heavy smokers and regular consumers of alcohol, which are the established risk factors for oral cancers. Further aggravating the problem is that many are having complicated immune status; additionally, poor nutrition and oral hygiene and a limited access to dental and medical care.
There is an urgent need to reach this high-risk population to make sure these individuals are equally served. Moreover, a screening program targeted toward such a high-risk community could effectively decrease the suffering and fatal impact attributable to oral cancer. The key focus of my research is to work within high-risk communities to develop a screening strategy targeted towards the hard-to-reach underserved populations where the need is greatest.
The main objective of this study is to establish current research activity in the study of oral cancer and precancers within the context of community-based clinics in a high-risk population in Vancouver. The activities involve: 1) to establish the first oral cancer screening clinic in a high-risk community in BC, 2) to incorporate and evaluate several new visualization tools and molecular markers for the identification of high-risk OPL and early cancer, and 3) to understand the biology of infection and inflammation to OPLs and its role in cancer formation in a high risk community. This work meets the main objectives of the National Cancer Agency, Canada in prevention and early detection of cancers.
Detection of novel microdeletions and microduplications in persons with intellectual disability using whole genome microarrays
Intellectual disability (ID) is a diagnosis given to persons who have life-long cognitive and adaptive impairments that commence in early life. ID affects about 1-3% of the population, thus nearly 1 million Canadians have an ID. The cause of ID is unknown in at least 40% of all cases. Recent reports have suggested that very tiny chromosome changes are the cause of many cases of ID. These tiny chromosome anomalies are usually not seen using routine microscopic analysis. However, recently developed microarray technology provides an opportunity to detect these very small changes.
Dr. Evica Rajcan-Separovic has used this technology to look for such abnormalities in 200 subjects with ID and have detected very small genetic changes in 16% cases. Some of the genetic abnormalities were seen in more than one individual. Her team plans to extend their array study to 400 more ID individuals in the next 6 years and to examine using molecular methods another 2000 subjects with ID to see if they can find additional individuals with the same abnormalities. By studying a larger number of individuals with the same chromosome change, they will be able to determine what physical features and medical issues are due to that genetic change.
Rajcan-Separovic's next step will be to develop Health Care Watches for each new condition identified. These will describe expected health issues, so that families and physicians can be better prepared to care for individuals with these new genetic syndromes. This approach will eliminate costly multiple testing and searching for answers, and should allow optimal care and health for persons with ID.
The British Columbia Adolescent Substance Use Survey
The use of tobacco, alcohol and marijuana by teenagers continues to pose a significant threat to the health of many young Canadians. Recent national surveys indicate that 18 per cent of Canadian teens smoke tobacco daily or occasionally and one-third of all teens have tried marijuana more than once, with about eight per cent of teens using it at least once a week. Just over 44 per cent of teens reported drinking one to three times each month, with an additional 17 per cent of teens aged 15 to 17 drinking one to three times a week or more. Despite extensive prevention efforts, the use of these substances appears to have become a somewhat normalized part of adolescence. The goal of Dr. Richardsonâs program of research is to improve our understanding of why adolescents are using these substances, and in so doing, facilitate the development of more effective interventions. For example, Dr. Richardson will be using an internet-based web survey to collect information every six months from a large group of adolescents to examine how the influence of known risk factors for substance use, such as peer influences and psychological characteristics related to risk taking, change as the studentsâ progress through high school. Dr. Richardson hopes this research will enable researchers to identify specific longitudinal patterns (i.e., trajectories) of alcohol, tobacco and marijuana use and examine how the influence of known risk factors change as adolescents progress through the secondary school system. In addition to improving our understanding of the different patterns of substance use, this research will contribute to the development of individually tailored prevention and harm reduction interventions that can be delivered over the internet.
Nervous System Regeneration and Repair: Lessons From the Olfactory System
The brain or central nervous system (CNS) is especially vulnerable to permanent injury and loss of function following stroke, trauma and seizure or the onset of genetic disorders such as Huntington or Parkinson disease costing billions of dollars in health care every year and long-term loss of productivity. Despite major advances in understanding of neural development in recent years, a major challenge facing neuroscientists today is how to use this knowledge to help direct repair and rebuild the CNS after it becomes damaged. Dr. Jane Roskams uses the mouse olfactory system (nose) to study CNS repair because cells in the system have a remarkable ability to remodel, repair and regenerate, compared to other regions of the CNS. Olfactory system repair is driven by two types of cells â one that replaces lost neurons (specialized olfactory stem cells) and another that guides these replacement cells to their target (olfactory glial cells). As part of the only team in the world focused on these complementary research areas, Dr. Roskams has developed a series of tools and approaches to determine which specific cells are activated to replace damaged neurons, and to test the signals that drive this activity. She is also working to determine the unique ways that these cells contribute to repair following spinal cord injury and stroke. While transplanting either of these types of cells into injured or damaged CNS tissue could help with repair. Dr. Roskamsâ work is focused on understanding how repair mechanisms work at the molecular level, with the goal of discovering if there are ways that injured cells might be manipulated into repairing themselves â a potential new way of addressing or preventing long-term CNS damage.
Improving youth sexual health in British Columbia
In spite of prevention programs that target risky sexual behaviours in youth, many BC teens continue to experience serious health and social problems related to sexually transmitted infections (STIs) and unplanned pregnancies. While untreated STIs can lead to pelvic inflammatory disease, infertility and increased risk of HIV, early maternal age can result in decreased future educational and employment opportunities for young mothers. As a Scholar, Dr. Jean Shoveller investigated the factors that play a role in the increased incidence of teen pregnancy and STIs among rural and remote BC communities. Now, Dr. Shoveller is working to reduce gaps in public health interventions related to youth sexual health by focusing on policy and program intervention research related to the health and social impacts of STIs and unwanted pregnancies amongst youth. Dr. Shovellerâs research will integrate participatory approaches to research (where youth are directly involved in the planning and implementation of research projects) with an analytical framework that examines how features of youth’s social contexts (e.g., gender, place, culture) affect youth’s sexual lives. Also, data that illustrate how context affects young people’s sexual health will be mapped to reveal how strengths and weaknesses in the health, education and social service systems affect youth’s sexual health. This research will provide researchers with new tools that can be used in new and unique participatory research opportunities that actively involve youth in research into this complex and sensitive topic and will provide public health policy makers and program planners with information to help inform decisions regarding improving and promoting youth sexual health.
Imaging studies: towards understanding the complications related to advanced monoaminergic disease and treatment
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, estimated to affect 100,000 Canadians and is characterized by deficiency of the neurotransmitter dopamine (DA) as a consequence of dopaminergic neuronal death. Existing treatments ameliorate the symptoms, but they do not seem to alter disease progression. Furthermore, treatment often induces undesired side-effects such as motor complications and high risk taking behavior such as compulsive gambling. Positron emission tomography (PET) is a non-invasive imaging modality that uses radioactive tracers to obtain information about biological function in-vivo; depending on their chemical form, radiotracers tag different biochemical processes. PET is thus ideally suited to investigate the complex neurochemical changes associated with neurodegeneration. Using PET we have already provided significant insights into the motor aspects of disease-induced complications; an alteration in the pattern of the neuronal release of DA has been identified as being involved in the occurrence of motor complication. The main goal of this research program is to further develop and use novel imaging techniques to gain insights into the impact of different treatment strategies on motor complications and into treatment-induced psychiatric complications. Studies on human volunteers will be performed on a new, state-of-the art human PET brain scanner. This scanner, existing only in 15 PET centers worldwide, while providing and unprecedented amount of information, requires development of accurate data manipulation and interpretation algorithms, which are another part of this research program. A very important aspect in medical research is the ability to develop and investigate animal models of disease to be able to investigate disease in further detail in a more controlled environment. A third important part of this research program will be the in-vivo investigation of rodent models of PD and their relation to other diseases such as, for example, Alzheimer’s, since there is evidence of some clinical and pathological overlap between neurodegenerative diseases. A unique strength of this program is its ability to bridge advancement of knowledge with the advancement of methodological approaches. This aspect will contribute towards the establishment of a more comprehensive imaging environment aimed at the investigation of neurodegenerative and related disease, which is the program long term goal.
The MaMS Study. Malignancy and Multiple Sclerosis: incidence and impact of beta-interferon treatment
Multiple sclerosis (MS) is thought to be a chronic autoimmune disease of the central nervous system, which attacks myelin, a protective material that insulates nerve fibers in the brain and spinal cord. Over time, MS can cause loss of balance, impaired speech, extreme fatigue and problems with vision. Currently there is no cure, but treatment with beta-interferons (IFNBs) is available to reduce the frequency of MS attacks. Recent research suggests that the use of IFNBs may increase the risk of cancer. Given the estimated 75,000 Canadians with MS and the increasing popularity of the MS drugs, even a moderate increase in cancer risk could translate into a substantial number of new cancer cases.
Dr. Helen Tremlett is conducting the first study in North America to investigate the effect of IFNB on cancer risk in an MS population. Dr. Tremlett will examine more than two decades of BC data created by linking the BC Multiple Sclerosis Research Groups’ database with the BC Cancer Agency's Registry to determine the overall risk of cancer in the MS population, and the risk among MS patients treated with beta-interferon compared to the general population. Dr. Tremlett’s research will help to determine the background risk of cancer among MS patients, whether widely used treatments are associated with increased risk of cancer, and will also facilitate researchers in evaluating future drugs licensed for MS.
Apolipoproteins and Autoimmunity to Lipid Antigens
The immune system is designed to rid the body of infections and unwanted cells, such as tumor cells or virally infected cells. The decision to target a certain agent for elimination is made by recognizing that a component (antigen) of a bacteria or virally infected cell is «foreign» to the body. Sometimes, however, the immune system can mistakenly target «self» components in healthy tissue, which leads to autoimmune diseases such as multiple sclerosis (MS). White blood cells called T cells are the central players in this decision making and are classically known to target protein components. Recently, however, it has been found that lipid components (ie. fats) can also be targeted by T cells, which is a new paradigm in immune recognition. We have been studying how T cells recognize lipids, and found that a major blood protein, apolipoprotein E (apoE), which was previously known to carry lipids for metabolic purposes, is also playing a role in the immune system to promote the recognition of lipids. ApoE has been known to play a role in many diseases, including MS and atherosclerosis (the disease of blood vessels which leads to heart disease and strokes). These two diseases also share common features in that there is immune system involvement which causes harm, in MS directed against the fatty insulation of nerves (myelin), and in atherosclerosis, immunity against unknown agents, possibly lipids found circulating in the blood. Our findings integrating lipid metabolism by apoE and the immune system thus open up a new area of research of direct relevance to MS and atherosclerosis, and we will set out to demonstrate that lipids are targeted in these diseases, and how apoE is involved to promote this mistaken targeting. Understanding these mechanisms will allow us to better monitor these disease using blood samples from patients, and also point to new strategies to treat disease by dampening or altering the immune response to lipids.