Lymphomas are cancers of the immune system. Canadian cancer statistics estimated around 8,100 newly diagnosed cases and 3,300 deaths from lymphoma in 2009. Lymphomas develop as the result of errors, or mutations, in the proteins that regulate the rate of cell division. These types of mutations are found in many different cancer types; however, certain mutations are found only in a specific cancer type. When the same mutation is found in several patients of a specific cancer type, it is likely to be a cancer-causing or cancer-driving mutation. The aim of Dr. Maria Mendez-Lago’s research is to investigate the impact of mutations found in the gene MLL2 on the formation and progression of lymphomas. Her research team discovered mutations in MLL2 by using next-generation sequencing of 127 non-Hodgkin lymphoma cases. Based on the pattern and distribution of the mutations, they believe MLL2 is a new tumour suppressor that might be acting through de-regulation of gene expression. Next-generation sequencing has allowed Dr. Mendez-Lago’s team to do whole genome, exome, and transcription sequencing using limited amounts of DNA from cancer tissues – an approach that was not possible only four years ago. They are applying this technology to different applications, such as the targeted sequencing approach used to detect mutations in MLL2. MLL2 has only recently been linked to cancer, so there is a great need to study the gene in further detail to understand how mutations in this gene promote cancer. To explore the impact of these mutations, Dr. Mendez-Lago’s team will culture and study all lines similar to the cancer cells from patients. Their findings will likely determine new candidates for designing drugs to treat cancers.
Program: Trainee
Investigating anti-arrhythmic inhibition of voltage-gated sodium channels with unnatural amino acids and fluorescence spectroscopy
Cardiac arrhythmias are on the rise in our aging population. They are electrical disturbances in the heart that can cause a wide variety of potentially life-threatening conditions, including an increased chance of stroke or, in the case of heart failure, sudden death. Anti-arrhythmic drugs that target a particular type of protein called an “ion channel” are useful in converting these irregular heart rhythms back to a normal beating. Unfortunately, many available anti-arrhythmic drugs have serious side effects. The basic action mechanisms of anti-arrhythmic drugs are not understood, and the chemical characteristics of good/safe anti-arrhythmic drugs are not known. This makes it difficult to engineer the next generation of life-saving cardiac drugs. Dr. Stephan Pless is aiming to fill crucial gaps in our understanding of how anti-arrhythmic drugs regulate heart function. By combining cutting-edge chemical methods with computer modeling, he has already made significant progress in defining the essential characteristics of what makes a “good” anti-arrhythmic drug. His next goal is even more important, as it aims to define the precise nature of the heart receptor through which anti-arrhythmic drugs modulate electric excitability. For this purpose, he will employ novel artificial amino acids to delineate the precise location of the receptor and will use novel fluorescent probes to give us insights into the atomic-level movements of the receptor during drug binding. All of the technologies used here have been tested in other relevant systems, but never for this application; therefore, it places Dr. Pless in a position to make a substantial contribution to the cardiovascular health of Canadians.
Role of cerebral blood flow in the pathophysiology of central and obstructive sleep apnea
Sleep apnea occurs when a person repeatedly stops breathing for a short period of time while they sleep. This common disorder affects about 20 per cent of Canadians. During sleep apnea episodes, blood oxygen levels fall, resulting in persistent low levels of oxygen, called hypoxia. Consequently, people with sleep apnea commonly experience adverse health outcomes, including high blood pressure, heart attacks and strokes. Preliminary findings from Dr. Philip Ainslie’s research lab have shown that reductions in brain blood flow can worsen sleep apnea, while increases in brain blood flow may reduce it. Dr. Shawnda Morrison’s research will expand on these exciting initial findings by exploring the possibility of treating sleep apnea by manipulating brain blood flow. Dr. Morrison will use sophisticated imaging techniques to examine the effect of an oral medication, which alters brain blood flow, in patients at rest and while they sleep. Her first study will examine patients with and without sleep apnea in a controlled laboratory setting. In her second study, Dr. Morrison will induce sleep apnea in otherwise healthy humans at high altitude (5,000 metres, near the base camp of Mt. Everest, Nepal). In this study, she will also conduct the same experiments on a group of high-altitude residents who do not develop sleep apnea, and compare any differences observed between the two groups. The results of these studies will have major implications for understanding what influences brain blood flow and how these different factors can then affect sleep apnea. Those people who do not develop sleep apnea will provide insight into future sleep apnea treatments. Indeed, these studies will provide a “proof of concept” that an oral medication, which alters brain blood flow, can be an effective treatment for sleep apnea. This will, in turn, dramatically reduce the incidence of heart disease and stroke in patients who have sleep apnea.
Generation of a humanized mouse xenotransplant model of myelodysplastic syndrome
Myelodysplastic syndromes (MDS) are diseases of the blood and bone marrow. MDS originate when a stem cell, from which all other blood cells originate, becomes mutated and then overgrows and crowds out other cells. This results in reduced numbers of red cells (anemia), white cells (leukopenia) and platelets (thrombocytopenia) circulating in the blood. As the disease progresses, bone marrow may completely fail to produce normal cells, and the myelodysplastic stem cell may develop into cancer, Acute myeloid leukemia (AML). The exact molecular causes for MDS are unknown; however, a common feature of MDS is chromosomal abnormality, the loss of the long arm (q) of the chromosome 5 being one of the most common in a subtype of MDS called 5q- syndrome. This lost region of 5q likely harbors several important genes, which may prevent MDS.
Dr. Joanna Wegrzyn Woltosz's research project will decipher the molecular mechanism of the disease and identify targets of a new drug (lenalidomide) currently used in MDS treatment. She is studying two important factors that are located on the 5q arm and are involved in the development of MDS (1) the RPS14 gene, which is thought to be responsible for the anemia seen in MDS patients, and (2) microRNAs, whose loss allows the abnormal MDS stem cells to survive and grow more than the other bone marrow cells. Since lenalidomide reverses symptoms resulting from loss of the microRNAs, she will also study whether lenalidomide increases the expression of these microRNAs. Currently, the only treatment for MDS is high-dose chemotherapy with stem cell transplantation, which is risky and challenging for patients to endure.
The information Dr. Wegrzyn Woltosz expects to obtain from this study will not only help to better understand the molecular mechanism underlying MDS, but will suggest novel steps towards the development of better therapies that will improve treatment and quality of life and increase survival for MDS patients.
Survival and Cause of Death in the British Columbian Multiple Sclerosis Population
Multiple sclerosis (MS) is a relatively common neurological disease. Because of its chronic nature and because it typically first appears in people in their mid 20s to 30s, people with MS are usually expected to live for many years following disease onset. Little is known about survival expectations, predictors of long-term survival, how survival is influenced by MS drug therapies, and causes of death in this population. Ever since immunomodulatory therapies first became available to Canadian MS patients in the mid 1990s, there has been a rapid uptake of these drugs. These medications appear to be at least partially effective in modifying some aspects of the disease, such as relapses, but they are associated with significant side effects, require frequent injections, and are expensive. The long-term impact of treatment is unknown and opportunities to study treatment-naïve patients have diminished over the years, as there are fewer patients with MS who have not taken these therapies. In British Columbia, we have a valuable data resource that includes both unexposed (untreated) and treated MS patients.
Dr. Elaine Kingwell is combining several large, powerful, clinical and administrative longitudinal datasets, including the population-based BC MS clinical database (containing data from approximately 7,000 MS patients over a 30-year period), BC Ministry of Health medical services plan registration data, BC Vital Statistics death data and BC Cancer Agency data. She will use this data set to determine the long-term health impacts of MS and how they are influenced by immunomodulatory drugs. She will specifically compare the causes of death (including cancer, suicide, heart disease and infection) between people with MS and the general population.
Dr. Kingwell will also investigate cancer survival of MS patients in comparison to the general population, which is an area of some controversy. She will determine how frequently MS is listed as an underlying or contributing cause of death, which will help to facilitate planning and interpretation of population-based studies of MS mortality trends. Findings from this study will further our understanding of the role that MS plays in long-term health outcomes, such as cancer survival, and will broaden our existing knowledge of factors associated with longevity in MS. These results will also provide a vital estimate of the impact of immunomodulatory therapy on survival and specific causes of death for MS. The findings from this research will have a profound impact on the care, monitoring and treatment of the disease.
Identification and characterization of leukemia stem cells in T-cell acute lymphoblastic leukemia (T-ALL)
The traditional view of cancer is that tumours are composed of identical cells, and thus the goal of treatment is to kill every one of those cancer cells in the body. In a tumour, it is estimated that a very small fraction of cells (perhaps 1 in 10,000) are ""cancer stem cells"", which are the cells that have the capacity to self-renew or to create progeny that carry the same properties as the parent cell. A new cancer treatment theory hypothesizes that to treat cancer, the only cells that need to be killed off are these cancer stem cells, and once they are gone the rest of the tumour should regress on its own. The challenge becomes to first identify the cancer stem cells and then design a drug that would specifically kill those cancer stem cells only. Dr. Vincenzo Giambra's lab has recently shown that cancer stem cells exist in a particular type of blood cancer called T-cell acute lymphoblastic leukemia (T-ALL). Although T-ALL is not a common form of cancer, it is unique in that more than 50 per cent of cases carry mutations that inappropriately activate a gene called Notch1, which plays an important role in normal stem cell maintenance. Dr. Giambra's research objectives are to identify how cancer stem cells are able to evade the immune system and thrive in T-ALL, and to design a drug that specifically kills those cancer stem cells. He will be isolating cancer stem cells from a unique mouse model that has Notch1-induced T-ALL, using specific molecules on the surface of cancer stem cells. He will also compare leukemias generated from mice of different ages to see if they express different genes, with the goal of using this information to design new drugs that may help to cure more patients with leukemia. These studies will allow Dr. Giambra to define the genetic programs and pathways that are responsible for conferring self-renewal upon the leukemia stem cells; they will also provide rationale for the design of new therapies that specifically target the stem cells. In focusing his efforts toward killing only the cancer stem cells, Dr. Giambra expects these therapies will be more effective for achieving a cure and less toxic to the patient. Finally, he anticipates that some of the genetic programs and pathways he will identify will be critical for self-renewal of Notch T-ALL stem cells and may be important for self-renewal of all cancer stem cells in general. Thus, these results may prove useful to investigators studying other cancers as well.
Investigating clinical outcomes from highly active antiretroviral therapy (HAART) among HIV-seropositive Aboriginal people in British Columbia
The development of effective HIV/AIDS treatment has resulted in dramatic improvements in the health of people infected with the virus. Taken regularly, highly active antiretroviral therapy (HAART) interrupts the viral life cycle, suppresses the level of HIV in a patient's bloodstream, and promotes health improvements. The recent finding that individuals undergoing effective treatment are far less likely to transmit the virus to others has spurred the development of a new strategy aimed at preventing new HIV infections. Dubbed "Seek, Test and Treat", the goal of this initiative is to increase the number of people on HIV treatment in Prince George and in Vancouver's Downtown Eastside.
Dr. M-J Milloy is specifically focusing on the expansion of HIV treatment among people of Aboriginal ancestry who use illicit drugs. In Canada, young Aboriginal people are a growing sector of the HIV/AIDS pandemic, and Aboriginal people are highly over-represented among HIV-positive drug users. Dr. Milloy’s research will look at treatment for HIV and health outcomes for Aboriginal drug users and, in light of increasing calls by Aboriginal leaders for research that focuses on health and wellness among Aboriginal people, will try to identify the characteristics of successful treatment.
Dr. Milloy's research will address a number of outstanding concerns:
- Are Aboriginal individuals who are HIV-positive and use illicit drugs being effectively treated with HAART?
- What are some of the broader factors, such as stable housing or employment, that promote effective treatment?
- What is the level of viral resistance to HIV medications among Aboriginal drug users?
Much of the data for this study will come from the AIDS Care Cohort to Evaluate access to Survival Services, an ongoing study of approximately 750 HIV-positive drug users in Vancouver. The research will be supervised by Dr. Evan Adams, Physician Advisor to the First Nations Health Council, who will ensure that the research is respectful and responsible to Aboriginal participants and communities.
The information gained could be used to improve existing systems to provide HAART as well as inform new Aboriginal-led efforts to improve health and wellness. By improving HAART delivery and expanding the number of people receiving effective care for HIV infection, it is hoped that the number of new infections will also drop.
Investigation of steroidogenesis mechanisms in prostate cancer progression: Effects of cytochrome P450 17A1 and steroid 5 alpha-reductase inhibitors
One in every eight Canadian men will be diagnosed with prostate cancer in their lifetime. Androgens, which are male sex hormones, are the primary driving force behind the development of prostate cancer and are synthesized in the testes, prostate, and in the prostate cancer tumour itself. Although once the standard of care, orchiectomy is rarely performed; continuous androgen deprivation is necessary when the cancer is very advanced. In these cases, the cancer becomes more aggressive and progresses to a stage called castration-resistant prostate cancer, which does not respond to hormonal agents. Dutasteride and abiraterone acetate are two current treatments for prostate cancer. The actions of these therapies are complementary, targeting different androgen metabolizing enzymes. Currently, dutasteride is successfully used for benign prostate hyperplasia, which is non-cancerous enlargement of the prostate. Abiraterone acetate, which was been approved in April 2011, is a promising treatment option for advanced prostate cancer patients. Clinical studies have shown that a subset of prostate cancer patients manifested resistance to abiraterone, and this suggests that there are compensatory mechanisms at work, either by supplying androgens via alternative biosynthetic pathways and/or by altering the signaling pathways involved in prostate cancer progression. The purpose of Dr. Subrata Deb’s research is to investigate the effects of abiraterone and dutasteride on pathways of androgen biosynthesis in castration-resistant prostate cancer. Mouse models of human prostate cancer, human prostate cancer cells, and human prostate tissues will be used to determine the effect of dutasteride and abiraterone acetate, either alone or in combination, on androgen formation during castration-resistant prostate cancer or in resistance to abiraterone. The aim of this research is to find the potential reasons for treatment failure in prostate cancer and aid in the development of potential treatment strategies.
Integrative analysis of epigenetic signatures in stem cells
The billions of cells in your body share the same DNA sequence and yet display a vast array of morphologies and functions. Understanding how this same genetic material is interpreted in diverse cell types remains a challenge. Epigenetic modifications are those that change how DNA is expressed without altering the genome sequence. For example, chemical modification of histones, the proteins that bind DNA into the large chromosome structures, can influence how genes are expressed.
In a related process, DNA itself can become methylated, which is typically thought to be a gene-silencing signal. Understanding how epigenetic modification influences gene expression has significant therapeutic potential and may provide us with insights into how we can disrupt abnormal cell divisions in cancer or promote self-renewal in stem cells for clinical use in repairing damaged or diseased tissue.
Dr. Cydney Nielsen aims to characterize epigenetic changes of stem cells, from which all other cells in the body arise. Stem cells can either self-renew to form identical daughter cells or can divide and differentiate into specialized cell types. Dr. Nielsen will use next-generation sequencing technologies and develop new data analysis techniques to examine the epigenetic changes and determine gene expression patterns in stem cells before and after differentiation.
Using these data sets, she will determine if characteristic epigenetic modification patterns exist for self-renewing cells. She will also use this information to determine if certain therapeutics are able to induce self-renewal in stem cells, to determine what the epigenetic changes are in this case, and if this ''reprogramming'' of cellular state opens up promising therapeutic applications. Such an approach will be valuable in evaluating the extent to which chemically induced cells have been reprogrammed and are appropriate for therapeutic use for regenerative medicine.
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.