Targeting androgen receptor dimerization as a potential therapy for prostate cancer

Prostate cancer is a leading cause of death in men. Treatment involves reducing production of di-hydro-testosterone (DHT) or blocking the interaction of this hormone with the androgen receptor (AR), a transcription factor responsible to drive expression of genes responsible for tumour growth. This treatment is unfortunately temporary and tumours eventually undergo genetic changes to become castration-resistant and able to grow in the absence of DHT.

This research project aims to use drugs to block AR activity in castration-resistant prostate cancer. Within the nucleus, two androgen receptor molecules must self-associate (“dimerize”) before binding DNA and initiating transcription. Dr. Dalal hypothesizes that slowing tumour growth can be achieved by preventing the AR-DNA interaction directly or by interfering with AR dimerization.

Cell biology and biochemistry approaches will allow Dr. Dalal to study the molecular mechanism of DNA-blocking or dimer-interfering compounds. Several compounds targeting both processes have been optimized to show potent and specific inhibition of the androgen receptor in cultured prostate cancer cells. Gel shift assays, calorimetry methods and confocal microscopy are now being used to gauge the effects of drugs on both DNA binding and AR dimerization. Site-directed mutagenesis of amino acids on the AR protein surface will validate the binding location of inhibitors. Promising compounds will be tested in mice to show effects on the size of prostate tumours.

Targeting transcription factor dimerization and DNA binding is a novel strategy that holds great promise to treat advanced forms of prostate and other cancers.

Examining executive functions as mediators of a mental and social enrichment intervention for older adults with chronic stroke

Significant proportions of stroke survivors suffer long-term physical disability and are predisposed to sedentary lifestyles. This limits their performance of activities necessary for independent living in the community and contributes to increased risk for recurrent stroke and heart disease. Dr. John Best recognizes that intervention strategies are needed to motivate stroke survivors to engage in routine physical activity and to optimize their physical and motor functions.

Best’s research will examine executive functions (EFs) as mediators of a mental and social enrichment intervention for older adults with chronic stroke. Broadly speaking, EFs refer to the cognitive processes that allow for adaptive behavior and self-control.

One promising strategy targets EFs by engaging stroke survivors in complex mental and social activities. Best’s research will evaluate the importance of improving EFs within the context of a mental and social enrichment intervention in order to have a meaningful impact on physical and motor functions, the ability to perform daily activities, and routine engagement in physical activity.

The information garnered from Best’s research will be crucial for improving stroke rehabilitation for older Canadians who suffer chronic disability from stroke.

Practice experiences of rural GP surgeons in British Columbia

The recruitment and retention of health care professionals is one of the most pressing challenges currently facing the Canadian health care system. In rural communities, the number of obstetricians and general surgeons is diminishing for a number of reasons, including difficulties in recruitment, an aging workforce, resistance to a demanding call schedule, and an increase in sub-specialization resulting in fewer ‘general’ surgeons. In some rural communities, maternity care is provided by general surgeons with enhanced obstetrical skills.

There are approximately 4,000 pregnant women in BC living in rural communities whose maternity care comes from these general practice (GP) surgeons. Despite the important role these practitioners play in sustaining rural maternity care in BC, to date, there has been no systematic research into their current experiences, and no official policy regarding guidelines for the practice, training, and maintenance of skills. Dr. Jude Kornelsen is investigating the role of these practitioners in rural health care in BC and their contribution to sustainable maternity care in these communities from a multi-disciplinary perspective.

Primarily through in-depth interviews, she will detail the experiences of GP surgeons in providing obstetrical care to rural communities including understanding their motivation, the nature of support received, and identifying any barriers to practice. She will describe the relationship between GP surgeons and specialists in their local community and in referral facilities, and determine how they receive ongoing training, mentoring and education. Ultimately, this research will provide a greater understanding of the culture of GP surgeons’ role in rural maternity service delivery in rural BC, and will help to inform policy guidelines regarding the practice, training, and maintenance of skills.

An investigation of cognitive behavioural therapy, mindfulness, and predictors of psychological treatment response among women with provoked vestibulodynia

Provoked vestibulodynia (PVD) is severe pain at the vaginal opening and the most common form of chronic genital pain in women. Although as many as 14 per cent of Canadian women and 20 per cent of adolescents are affected by this condition, it is frequently underdiagnosed and undertreated, and as a result, many women experience sexual difficulties, emotional distress, and multiple medical visits. Although different types of treatment exist, ranging from medication to psychological therapy, the best treatments to reduce PVD pain and distress, and which patients will benefit the most, are not known. Evidence indicates that psychological therapies such as cognitive behavioural therapy (CBT) and mindfulness-based therapy (MBT) are effective at reducing pain and sex-related distress for women with PVD. CBT is designed to challenge thoughts and uses active strategies (e.g. progressive muscle relaxation to decrease muscle tension) to change one’s experience, whereas MBT teaches individuals to be nonjudgmental and accepting of their experience and to learn to live without reacting to pain. Dr. Kelly Smith’s aim is to determine whether CBT or MBT is the most effective approach for reducing PVD pain and improving women’s quality of life, and she will determine which patient characteristics are associated with better responses to these treatments. She will be examining personal and medical characteristics for women with PVD who participated in the Multidisciplinary Vulvodynia Program, a treatment program based at Vancouver General Hospital for women with chronic genital pain. She will then study whether CBT or MBT is related to greater pain reduction and improvements in sexual function/emotional distress in a group of 70 women participating in an 8-session CBT or MBT group program. At the end of the study, women will be interviewed to assess their satisfaction with the program and provide feedback on how to improve the program. Dr. Smith’s studies will be the first to provide information on which of these psychological treatments works best for specific types of women with PVD. This information will provide clinicians with evidence-based guidance regarding potential treatment recommendations and will be essential in helping to reduce the health and economic burdens associated with PVD. Dr. Smith’s final results will be communicated to physicians and other health providers in British Columbia, and her findings will be submitted for publication in professional, wide-reaching health journals.

Elucidating the functions of MCL-1 in DNA repair

Mammalian cells have developed elaborate DNA damage response (DDR) and DNA repair systems in order when to protect and repair their DNA encountering toxic agents. In tumour cells, activation of these molecular events can make tumour cells resistant to chemotherapy or radiotherapy-induced DNA damage. Therefore, decoding how the DDR and DNA repair mechanisms are controlled is very important for understanding how cells become resistant to chemotherapy and to find ways to improve conventional cancer therapies. MCL-1 is a pro-survival protein that has multiple roles within the cell and has been shown to protect cells from death. It can interact with multiple important nuclear proteins involved in DDR response. Loss of MCL-1 increases genome instability after DNA damage. These studies indicate that MCL-1 may be an important component of the DDR machinery to regulate the repair of DNA lesions. Dr. Yemin Wang is investigating how MCL-1 regulates DDR and DNA repair. He is taking an intracellular approach to understand how MCL-1 is delivered into the nucleus after DNA damage and will also use this approach to investigate how MCL-1 regulates crucial events in DDR and DNA repair machinery. Dr. Wang will also examine whether the presence of MCL-1 in the nucleus affects how the cell responds to chemotherapy and whether the role of MCL-1 in DDR affects tumor development. The results of Dr. Wang’s work will provide us with a better understanding of MCL-1 in DDR and DNA repair processes, explain its essential function in vertebrate development, and help us to design improved therapeutic interventions for cancer treatment.

Drug impaired driving: Evaluating the threat to traffic safety

Motor vehicle crashes cause 15,000 serious injuries and over 2,000 deaths in Canada annually. The contribution of drug-impaired driving to these tragedies is unknown, but suspected to be significant. This lack of knowledge hinders the development of effective traffic safety policies to prevent drug-impaired driving.

The research of Dr. Jeffrey Brubacher aims to prevent injuries and fatalities resulting from motor vehicle crashes. His research program consists of three inter-related themes:

  1. Cannabis and motor vehicle crashes. This five- year study will examine 3,000 injured drivers from five BC trauma centres to determine whether there was recent marijuana use before their crashes and whether or not the driver caused the crash. The study will provide important information about the role played by marijuana in causing car crashes.
  2. Prescription medications and motor vehicle crashes. This project will involve combining BC prescription data with BC driver records, including traffic accident reports, to determine whether or not drivers are more likely to be involved in a crash when they are taking prescription medications such as sleeping pills or pain medications.
  3. The Injured Driver Platform. This study will provide information on the motor vehicle crash risk associated with recreational drug use. Over an initial three-year period, medical data will be collected and interviews will be conducted with injured drivers at five BC trauma centres, and drivers will then be followed for two years after their original crash to determine how often they are responsible in other accidents or drive while impaired.

This project will help to identify risk factors for impaired driving which may be used to develop targeted interventions to prevent this risky behaviour. Dr. Brubacher's research will contribute to an international effort to understand the role played by prescription medications, marijuana, and other illegal drugs in causing motor vehicle accidents. He will present his findings to government officials so they are better able to develop effective road safety policy and public education campaigns targeting impaired drivers and, by doing so, to improve safety on our roads.

Air pollution and asthma: Modifying factors in a public health context

In reaction to air pollutants, asthmatics may experience an “”asthma exacerbation”” characterized by the narrowing of their airways. This may lead to a shortness of breath that may require urgent medical attention. One source of air pollution associated with asthma exacerbations is diesel exhaust. How and why diesel exhaust causes exacerbations is unclear, but one hypothesis is that it causes “”oxidative stress””, which is damage to cells and body tissues due to certain chemical characteristics. Ongoing exposure to traffic-related air pollution can also result in new asthma in previously healthy individuals. Dr. Christopher Carlsten is working to understand how different air pollutants, particularly diesel exhaust, influence asthma. He is trying to determine whether diesel exhaust creates oxidative stress, and, if so, if that stress is responsible for airway narrowing in human asthmatics. In his laboratory, diesel exhaust is generated in concentrations typically found in mining operations or in busy bus terminals. Volunteer subjects inhale the exhaust for two hours – a short exposure time has no permanent effects but does produce mild, temporary changes – and changes in oxidative stress and airway narrowing are measured. In some subjects, other typical environmental allergens such as tree and grass pollen are added to see if they worsen the effect of diesel exhaust. In addition to this work, Dr. Carlsten and colleagues are following a group of more than 20,000 children from birth to see how their exposure to such pollution may lead to new asthma. Dr. Carlsten’s research will lead to a better understanding of diesel exhaust-related airways disease and will lead to measures to protect Canadians exposed to traffic-related pollution. This research aims to inform recommendations for or against changes in fuel composition and/or personal measures to bolster anti-oxidant levels. Dr. Carlsten’s work to understand the effects of air pollution on asthma development should inform interventions regarding pollutant exposure in children.

Finding a cure for tendinopathy: a translational biology approach

Repetitive-use tendinopathy, formerly known as tendonitis, is a major cause of repetitive strain injury (RSI). The occupational costs of RSI are enormous: work-related injuries cost Canada $8.6 billion annually and an estimated one-third of workers' compensation costs in industry are due to RSI of soft tissues, particularly tendons. In 2001, 2.3 million Canadians reported an RSI, and the average time lost from work per case of tendon-related injuries was 79 days (Source: StatsCanada 2001). Despite the enormous clinical, societal, and economic significance of RSIs, there is only limited understanding of the mechanisms that cause them.

In order to establish new treatments for RSI, Dr. Alexander Scott has established an innovative tendinopathy research program. He is incorporating a multi-disciplinary approach from basic to clinical science, which integrates a number of different methods, including molecular and cell biology, biomechanics, and rehabilitation science. His work will focus on the role of new blood vessel formation as a feature of chronic tendon injury. This work promises basic insight into the biology of RSI as well as directly applicable knowledge to develop new therapeutic strategies. This will be the first research program in Canada to have a primary focus on the biology of work-related tendon overuse injuries using a multidisciplinary approach. The ultimate vision of this program is to find better treatments for work-related tendon injuries.

Borrelidin: a novel therapeutic agent for treatment of inflammatory diseases

Inflammation is the body's normal physiological response to injury, infection or foreign substances. While the ability to mount an inflammatory response is essential for survival, the ability to control inflammation is also necessary for health. Inflammatory diseases such as rheumatoid arthritis, osteoarthritis, Chrohn's disease, ulcerative colitis, inflammatory bowel disease, asthma, allergies, septic shock, atherosclerosis and many others are a group of disorders characterized by uncontrolled or excessive inflammatory responses. Often, clinical intervention is required to prevent tissue damage and organ dysfunction in these disorders. While there have been advances in anti-inflammatory therapies over the years, long term use of steroidal and non-steroidal anti-inflammatory drugs (NSAIDS,) is limited due to drug-induced toxicities such as stomach ulcer, gastric erosion, exacerbation of asthma and nephrotoxicity. Therefore, the identification of novel agents that can effectively suppress inflammatory responses without associated long term toxicities represent a major unmet medical need. One of the key ways that the body controls inflammation is through the expression of immunoregulatory enzymes. An example of this natural immunoregulation occurs in pregnant mammals: cells of the placenta that surround the fetus express an immunoregulatory enzyme called indoleamine 2,3-dioxygenase (IDO). IDO expression protects the fetus from being attacked by the mother's immune system. Earlier research has revealed that the small molecule drug, borrelidin, could be used to specifically mimic the signalling effects induced by IDO expression and suppress the action of inflammatory cells. Nadya Ogloff's research builds on this evidence by providing pre-clinical proof-of-principle data to support further development of borrelidin as a potent immunosuppresive agent for treatment of inflammatory diseases.