Studies Towards the Total Synthesis of Eleutherobin and Designed Analogues for Cancer Therapy

Cancer is one of the leading causes of death among Canadians, and therefore the identification of new cancer therapies is of great importance. To that end, researchers have found that the structurally diverse defence chemicals provided by sessile marine organisms offer great potential in the fight against cancer. In fact, in the past decade more than 30 natural products isolated from marine sources have entered preclinical and clinical trials as potential treatments for cancer. However, it is rarely ecologically or economically feasible to obtain the active ingredient by harvesting the natural source. Fortunately, synthetic organic chemistry – where molecules are fabricated in the laboratory through a series of chemical transformations – can serve as an alternative source of these compounds. Eleutherobin was originally isolated from a rare soft coral located of the coast of Western Australia in 1997, and in preliminary tests it has shown many promising anti-cancer properties. In fact, taxol, a member of the same class of agents, has already been used to treat more than one million patients suffering from advanced breast and ovarian cancers. Over the past two years, Jeffrey Mowat has spearheaded research centered on the development of a concise synthesis of eleutherobin and analogues of this substance as candidates for cancer treatment. However, so far, eleutherobin's preclinical evaluation has been hampered by lack of material from the natural source or chemical synthesis. Mr. Mowat's current research project addresses this situation through the development of a synthetic strategy that would significantly reduce the number of steps required to access eleutherobin and facilitate its preclinical evaluation. His research also provides a venue for the construction of analogues of eleutherobin, the biological evaluation of which may well lead to the discovery of new, improved antimitotic drugs for cancer therapy.

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.

Targeting the Ras/MAPK pathway for treatment of high-grade pediatric brain tumors

Brain cancer is an extremely aggressive disease that remains difficult to cure and carries a high mortality rate. Every year, more than 3,500 children in North America are diagnosed with this disease. Brain tumours are the most common solid tumours and the second leading cause (after leukemia), of cancer-related deaths in children. The majority of patients (80 percent), with the more aggressive forms of brain tumours will survive less than two years. Surgical removal of brain tumours is challenging for a number of reasons, and complete removal of cancer cells is virtually impossible. The chemotherapeutic agent Temozolomide (TMZ), is used in patients with aggressive brain cancers however, in a subgroup of patients this drug does not work effectively because they are resistant to it. Furthermore, recent research shows that TMZ is not generally very effective at eliminating pediatric brain tumour cells. Consequently, certain ‘survivor’ tumour cells become ‘seeds’, generating more cells that subsequently form a new tumour. Cathy Lee’s research focuses on a protein called PLK1, which is essential to the cell division process in cancer cells. Many researchers have shown that PLK1 levels are higher in cancer cells than in normal cells and that tumour cells require this protein for survival. When this protein is eliminated, cancer cells either die or their growth is suppressed. Importantly, normal cells do not seem to be greatly affected by PLK1. Ms. Lee’s research will provide a deeper understanding of this protein. In related research, Lee will examine the ‘seeds’ of brain tumours, called ‘brain tumour initiating cells’, with a view to determining a way to prevent their expansion and induce cell death. The results of her research will improve our understanding of pediatric brain cancers and allow future design of novel, alternative therapeutic strategies that benefit patients’ health and improve the way we currently treat this devastating disease.

A cross-national evaluation of opioid dependence treatment service systems in Canada and the United States

Methadone maintenance treatment (MMT) is the most effective form of treatment for opioid dependence, a chronic, recurrent disease. However, the availability and means by which MMT is delivered varies greatly, both locally and internationally. Understandably, the resulting accessibility, quality and comprehensiveness of care provided through the various treatment practices have important public health implications, and require careful consideration. Notably, there are vast differences between the drug treatment systems in California and British Columbia. Treatment for opioid dependence remains restricted in California due to regulatory constraints on treatment settings, (i.e. registered drug treatment centres), and physician practice, (i.e. limits on the number of patients per physician). Nonetheless, treatment through drug treatment centres may offer some advantages. In comparison, access to MMT in BC has improved following administrative transfer from the federal government to provincial colleges of physicians and subsequent deregulation through the introduction of community-based treatment (i.e. office-based prescription and dispensation in community-based pharmacies). Community-based treatment may maximize access, albeit at a relatively high cost, although the economic merits of maximizing access are well-established. Building on his earlier research in this area, Mr. Nosyk is working to identify differences in patient characteristics, treatment outcomes and costs of opioid dependence treatment systems in both the countries, with a specific focus on the performance of the treatment systems in terms of effectiveness, efficiency and equity. The knowledge gained from his research can be extended to estimate the health and economic impact of introducing treatment services at the population-level, and corresponds with long-term recommendations to expand services to provide more comprehensive treatment for substance users in BC.

Defining Immune Abnormalities And Their Consequences In The HIV Exposed But Uninfected Child

The primary route of infection for human immunodeficiency virus (HIV), in infants is from mother to child. Following the introduction of ‘Prevention of Mother To Child Transmission’ (PMTCT), programs, HIV infection rates in newborns from mother to child (vertical transmission), have been reduced from 30 percent to less than five percent. As a result, the number of ‘HIV Exposed but Uninfected’ infants (HEU) has steadily risen. In South Africa, where 30 percent of all women of childbearing age are HIV infected, 300,000 HEU births occur per year. Recently, infection and death rates among HEU infants have been determined to be much higher than those in HIV unexposed (UE) infants. Consequently, there is an urgent need to understand why HEU infants are so vulnerable to infections. Briefly, when a person is exposed to an infecting microbe, two major arms of the immune system respond: innate immunity, which keeps the microbe at bay, and adaptive immunity, which eventually clears the infection. While it is now known that alterations in the adaptive immune system of HEU infants do take place, there is little known about how the innate immune system of HEU compared to that of the UE infant. Mr. Brian Reikie, working in collaboration with Stellenbosch University, South Africa, is conducting a pilot study to determine whether exposure to HIV, in the womb or around birth, activates the innate immune system, which then causes damage to the adaptive immune system. As well, he will explore the HIV-innate-adaptive interaction to help explain why HEU infants are so susceptible to infections. Beyond the study of HEU, this will be the first demonstration of how innate immune responsiveness correlates with development of either normal or altered adaptive vaccine immune responses over time. The findings from this project will provide the essential groundwork for urgently needed guidelines for appropriate treatment and clinical follow-up of this vulnerable population.

Exit Strategies: The Timing and Impacts of Physician Retirements

Much has been made over the past fifteen years about the actual or impending shortage of physicians in Canada. The aging of the patient population increases the need, while the aging of the physician population reduces the supply. Recent dramatic increases in the number of medical students being trained in Canada should go some distance in addressing supply concerns. Less well-understood is the potential effect of changes in physicians’ decisions about when, and how quickly, to retire. Despite the fact that retirement decisions can have a large influence on the total available supply of physicians, surprisingly little is known about those decisions. The purpose of this project is to fill in some of those gaps in our understanding.

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Development of Clinical Standards of Care for Huntington disease Intermediate Allele Predictive Test Results

Predictive testing for Huntington disease (HD) has been available since 1986. This genetic test has the ability to ‘predict’ whether individuals will develop HD in their lifetime and possibly pass the disease onto their children. Some individuals who undergo predictive testing receive an unusual test result, called an ‘intermediate allele’ (IA), which differs from a gene positive or negative result. While individuals with an IA will never develop HD themselves, there remains a risk that their children or grandchildren could subsequently develop the disorder. Currently, knowledge gaps exist with respect to IA for HD. Specifically, the current International Predictive Testing Guidelines do not address the possibility of this result, nor are the complexities surrounding this result acknowledged in the literature. Alicia Semaka’s research, which is the largest empirical study on HD IAs to date, will not only address these gaps, but also inform the development of clinical standards of care for communicating IA results during predictive testing. The specific objectives of Ms. Semaka’s research are to determine the prevalence of IAs in British Columbia’s general population; determine quantified risk estimates for the likelihood that an individual with an IA will have a child who will develop the disease in their lifetime; and lastly, describe the psychological and social impact of receiving an IA result. Collectively, the three objectives of this unique, multidisciplinary study will provide the foundation for the development of clinical standards and practice recommendations for IA predictive test results. These standards will help ensure that this subset of patients receive appropriate information, support, education and counselling throughout the predictive testing process.

The mechanism by which SOCS3 mediates IL-10 inhibition of macrophage activation

Inflammation is a protective response generated by immune cells against infection. However, when inflammation becomes unregulated within the body, it can cause diseases. A key anti-inflammatory regulator of immune cells is a cytokine (a type of hormone), called interleukin-10 (IL-10). The importance of IL-10 in regulating immune cell function is illustrated by the fact that many tumour cells and intracellular pathogens produce or elicit production of IL-10 for their survival. A main target of IL-10 is macrophages. Activation of macrophages by interferons, or bacterial cell products such as lipopolysaccharide (LPS), induces a number of immunologic responses including production of pro-inflammatory mediators such as the cytokine TNF. IL-10 is able to suppress these events by interfering with pathways utilized by LPS, but its mechanism is unclear. Previous research on the intracellular signal transduction pathways utilized by IL-10 has shown that an important component is a protein called SOCS3 which is thought to target specific proteins for degradation. In order to understand how IL-10 uses SOCS3 to inhibit macrophage activation, Tsz Ying Sylvia Cheung’s research is focusing on proteins that interact with SOCS3 in cells stimulated with IL-10. Identification of these proteins will allow for a further research focus on understanding the role they play in macrophage activation and why they are targeted by IL-10. Developing a clear understanding of the mechanism by which IL-10 regulates the network of intracellular signal transduction pathways will better enable the development of therapeutics mimicking the beneficial anti-inflammatory effects of IL-10, and allow for the development of strategies to counter the immunosuppressive effects of certain tumours and immune cell pathogens.

Structural analysis of proteins involved in bacterial cell wall biosynthesis

Antibiotics play an essential role in the treatment of bacterial infections. However, the overuse of antibiotics has resulted in the emergence of numerous drug resistant strains of important human pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE). These, and related bacteria, represent major threats to human health if tools cannot be developed to combat these so called “”superbugs””. Potential targets for the development of these new antibacterial treatments include the enzymes involved in the production of the bacterial cell wall. Robert Gruninger’s research is focused on characterizing distinct aspects of cell-wall biogenesis. By clarifying the three dimensional structure of these enzymes, it will be possible to design drugs that will block their function, and combat the development and spread of “superbugs”.

Seasonal plasticity in brain estrogen signaling mechanisms regulating aggression

While estradiol, a kind of estrogen, is often considered a “”female”” hormone, it is fundamentally important for both female and male brain function. It is a hormone with a wide range of effects on the brain and human behaviour. In early life, estradiol plays an important role in the growth of brain cells and in the establishment of differences between male and female brains. In adulthood, estradiol activates both male and female reproductive behaviour. Studies also implicate estradiol in the regulation of aggression, learning and memory, muscle control and the perception of pain. Furthermore, estradiol has been shown to influence depression, recovery from stroke and brain injury, Parkinson’s disease and Alzheimer’s disease. Because estradiol is involved in a vast array of brain functions, many of which are critical to human health, it is important to understand how estradiol affects brain cells. Dr. Sarah Heimovics’ research explores the degree to which there is plasticity in how estradiol affects the brain and behaviour. Specifically, she is investigating the effect of environmental factors, such as photoperiod, on estradiol signalling mechanisms the brain. Traditionally, estradiol has been understood to influence brain and behaviour genomically, via changes in gene expression over a relatively long timescale (days to weeks). However, a growing body of research suggestes that estradiol also has rapid (within 30 minutes), non-genomic effects. Dr. Heimovics will compare the role of genomic and non-genomic estradiol signalling mechanisms in the neural regulation of aggressive behaviour on short and long photoperiods. She is testing the hypothesis that non-genomic estradiol signalling is more pronounced on short photoperiod (as during the winter in BC), which may have implications relative to depression. The results of this research will contribute to the greater understanding of how estradiol acts on the brain, which is a critical issue for the health of British Columbians.