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.
Research Pillar: Biomedical
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.
Promotion of metastasis by hypoxic tumour cells
Nine out of ten Canadians who are killed by cancer die because their tumour has metastasized, or spread, to other parts of their body. Metastasis occurs when tumour cells escape from the original, or primary, tumour and then grow into life-threatening metastatic tumours in other organs. Despite the fact that thousands of tumour cells can escape from a primary tumour every day, most cells do not live long enough to grow into metastatic tumours. As well, metastatic tumour cells can only grow in specific organs. Most primary tumours contain cells at lower oxygen levels than normal tissues, and these low-oxygen tumour cells make tumours more aggressive and metastatic.
Based on these facts, Dr. Bennewith's team is developing new approaches to help identify tumours that contain low-oxygen tumour cells in patients. In addition, Dr. Bennewith and his colleagues have recently discovered that proteins made by low-oxygen tumour cells cause the body's normal bone marrow cells to enter the bloodstream and build up in specific organs. These cells create an environment where metastasizing tumour cells can survive and grow into metastatic tumours. Dr. Bennewith’s team intends to identify the specific proteins that control bone marrow cell behavior in order to develop targeted therapies that will prevent the build-up of bone marrow cells in organs and thus inhibit metastatic tumour growth. Metastatic tumours are very difficult to treat, but by studying how tumour cells spread and grow into tumour metastases, more effective cancer treatments can be designed. Dr. Bennewith's expertise in metastasis research combined with his unique research program will improve our understanding of how low-oxygen tumour cells promote metastasis. Importantly, his work will help to create more effective methods to both detect and to treat metastatic cancer in the clinic.
Innate immunity and its influence on cardiovascular function
In Canada, severe infection, or sepsis, is the most common acute illness causing death. Patients with severe infections can go into shock as a result of progressive cardiac collapse and can die within 24 to 48 hours. The mortality rate of sepsis is 40%. The fact that this rate has not changed in the last 30 years illustrates that very little is known about how infection causes cardiovascular dysfunction and that very little is known about the best ways to prevent this from occurring.
Dr. John Boyd's research program is using a two-pronged approach to understand how sepsis causes progressive cardiac collapse. The objective of his clinical research program is to identify prognostic factors and to characterize the cardiac response to infection in patients with sepsis. Specifically, he is focusing on very early enrollment of acutely ill patients with infection presenting to the St. Paul's Hospital emergency department in order to identify prognostic factors such as new biomarkers and the presence of emerging infections. He will characterize their cardiovascular response to infection using a bedside cardiac ultrasound. Although previous work in this area has been done, patients were recruited from critical care units 24 to 36 hours following admission, too late to identify prognostic markers and intervene to improve outcome.
As a complementary approach, Dr. Boyd's pre-clinical (basic) research program is taking a molecular approach and using the immune system as a tool in the fight against cardiovascular collapse. He has identified a "counter-regulatory" receptor which appears able to reverse the heart damage induced by other receptors in the same family. The identification of this receptor will hopefully lead to the development of a targeted intervention for sepsis-related cardiovascular dysfunction. Dr. Boyd's clinical research program aims to answer simple but as-yet unstudied questions such as the optimal volume of IV fluid and how one can reliably diagnose infection. Although the results of his laboratory work are not yet close to reaching the bedside, they may potentially lead to therapies in the future.
New synthetic methods and strategies: Enabling natural product drug discovery
Natural products are chemicals produced by living organisms that encompass a fascinating range of structural diversity and potentially useful pharmaceutical activities. Some of the better-known natural products include anti-bacterial compounds derived from fungi (e.g., penicillin), analgesics such as salicylic acid, derived from the bark of willow trees, and paclitaxel, an anti-cancer compound isolated from the Pacific Yew tree. In fact, over half of the drugs approved by the FDA in the past 25 years are derived from or inspired by natural products, and the near-doubling of the average Canadian’s life expectancy in the 20th century is largely attributed to medical advances based on these compounds.
Recent advances in biochemistry and molecular biology have guided the discovery of many new natural products. However, the limited quantities of natural source materials and environmental concerns associated with harvesting the producing organism highlight the importance of using alternate methods to synthesize these biologically active compounds in the laboratory. Thus, through a total synthesis approach, organic chemists are able to provide a renewable source of the natural product and generate sufficient quantities for extensive biological testing.
The focus of Dr. Robert Britton's Natural Product Research Program is the total synthesis of natural products that represent potential lead candidates for the treatment of human diseases. In particular, his group is focusing on developing novel synthetic pathways to manufacture sufficient quantities of eleutherobin and biselide A, two natural products that hold potential for the treatment of cancer, as well as a family of imminosugars that represent leads for the treatment of diabetes, viral diseases, and lyposomal storage disorders. The work of his team involves the development of innovative synthetic reactions that will allow them to construct complex natural products in a straightforward manner from simple chemical building blocks. The synthesis of these molecules will also enable the discovery of new substances that are similar in structure to these natural products but with potentially improved pharmaceutical properties.
Understanding the mechanisms of experience and injury based cortical plasticity
Strokes are caused by the interruption of blood flow or the rupture of blood vessels to the brain. This sudden loss of brain function can damage the brain centers that sense or move parts our body, profoundly impacting both physical and mental functions. As a result, stroke is the number one cause of acquired disability in adults around the world. Some stroke survivors are able to recover more quickly and more completely than others. Although recovery is influenced by the location of damage in the brain and the extent of the damage, recovery is also influenced by the brain's innate ability to initiate repair and re-wire damaged blood vessels and neuronal circuits in surviving regions. At the present time, we do not yet know why this re-wiring takes place in some patients but not others, nor do we know how to manipulate this process. What we do know is that this repair process can vary between patients and that some patients, such as diabetics, have a poorer prognosis following stroke.
Dr. Craig Brown's lab will use advanced imaging technologies to assess brain structure and function to understand how the brain is able to repair itself following a stroke and to understand why this is such a variable process between different patients. His research program is focused on three distinct yet complimentary lines of research, including: 1) understanding the impact of diabetes on recovery from stroke; 2) using electrical nerve stimulation to improve stroke recovery; and 3) elucidating the cellular/molecular mechanisms of learning or experience-based brain "plasticity".
As a result of this innovative research, Dr. Brown hopes to better understand the brain's plasticity associated with normal (learning/memory) and pathological (diabetes/stroke) brain states. His intent is that this work will stimulate new therapies for improving brain function both in normal situations and after stroke, particularly in patients who have previously had a poor prognosis.
Endothelial cell regulation of T cell responses
Organ transplantation is a life-saving procedure for many individuals. Unfortunately, the long-term success of this procedure is compromised by the rejection of the transplanted organ(s) by the recipient's immune system. T cells are specialized cells of the immune system that protect against infections but that recognize and damage transplanted organs. Understanding how T cell responses are controlled will help to develop new methods to increase the long-term and specific acceptance of transplanted organs.
Dr. Jonathan Choy's research is focused on understanding how T cell survival and persistence is regulated and how these processes contribute to organ transplant rejection. By understanding this, Dr. Choy intends to find new ways of controlling the immune response against transplanted organs. Preventing rejection will improve outcomes for the approximately 2,000 Canadians who receive solid organ transplants each year, as well as for the many Canadians who are already living with transplants.
Auto-inhibited regulatory proteins: New approaches to characterize and identify these important switches in cell communication
The impact of cancer on our society is enormous. According to the Canadian Cancer Society, an estimated 9,300 people will die of cancer in British Columbia in 2011, with 22,100 new cases being diagnosed. Despite the many different treatment options that have been developed in the past several decades, the high death rate demonstrates that new and better therapeutic approaches are necessary. Cancer is often caused by the disruption of cellular control and regulatory mechanisms. One such regulatory mechanism known as “”autoinhibition”” allows proteins in the cell to switch their own function on or off. Genetic mutations or viral infections can result in the disruption of this autoinhibitory function, which can lead to a continuous activation of these autoinhibitory proteins. This can result in cell changes and can ultimately lead to cancer. Dr. Joerg Gsponer is taking a new approach to understanding how cancer develops and, ultimately, how it may be controlled. His research group is is aiming to improve our understanding of the mechanisms of autoinhibition with the help of computational methods. His team will develop new computational algorithms that will help identifying proteins in the cell that are regulated by autoinhibition and reveal how the autoinhibition works and how it is disrupted in the disease case. Ultimately, this will further our understanding of how cancer develops and will hopefully help to identify new drug targets for cancer therapy.
ATP-sensitive potassium channels: electrical signaling of cellular metabolism
Many types of rare inherited genetic disorders profoundly affect children and their families. While disorders like Anderson syndrome, Bartter's syndrome, and DEND (Diabetes with Epilepsy and Neuromuscular Defects) affect different organ systems and manifest with different symptoms, these diseases are all caused by genetic mutations in the KIR family of proteins. Mutations in KIR proteins can also be involved in less severe symptoms, including cardiac arrhythmias and vascular defects. The KIR proteins are a family of ion channels known as inwardly rectifying potassium channels. These ion channel proteins form pores in cell membranes, which can be switched on or off, by opening or closing “gates” in the ion-conducting pore. When the gates are open, charged ions can pass across the membrane, generating electrical currents and influencing the membrane voltage. These KIR proteins regulate a diverse set of processes, from beating of the heart to hormone release from the pancreas, and can be influenced by a number of cellular processes and molecules.
Dr. Harley Kurata’s work is focused on the KATP channel, which is a member of the KIR family and is regulated by the “fuel” (ATP) that drives all cells. The KATP channel can sense the metabolic state of cells and serves as a critical trigger for insulin release from pancreatic beta-cells. KATP channel mutations are now recognized as an important cause of genetically inherited insulin disorders, ranging from diabetes (too little insulin released) to hyperinsulinism (too much insulin). Dr. Kurata's team hopes that by identifying the specific mutations involved in KATP, therapeutic approaches to both diseases can be developed. KATP channels are also present in the heart, and although their role in cardiovascular function remains enigmatic and controversial, further investigation of this unique set of proteins has the potential to impact other diseases.
Melanoma and neurofibromatosis: genetic diseases linked by dark skinned mouse mutants
Melanoma is the most dangerous type of skin cancer. The incidence and rate of death from melanoma is rising in Canada. Since 1988, the death rate from melanoma increased 41% in men and 23% in women, which is the highest rate of increase for any type of cancer. Melanoma is primarily caused by repeated sun damage, which leads to the accumulation of mutations in the genes that regulate the survival and growth of pigment cells in the skin. The disease has a molecular basis, so it only makes sense that a molecular approach is being taken to find new therapies to treat this deadly disease. Dr. Catherine Van Raamsdonk is taking a unique molecular approach to identify genes that may be involved in melanoma. By studying three mouse strains that have a darker dermis (the lower-most layer of the skin), Dr. Van Raamsdonk and her colleagues have discovered three genes named GNAQ, GNA11 and NF1 that are important for pigment cell growth and survival. By studying how these genes interact with each other and how they are regulated at different stages of development, she hopes to understand how they may contribute to melanoma. This work will help to reveal the molecular basis of melanoma as well as other cancers. For example, the NF1 gene is also mutated in human neurofibromatosis, a genetic disease in which patients develop disfiguring tumors and hyper-pigmentation of the skin. Dr. Van Raamsdonk and her colleagues have also discovered that GNAQ and GNA11 are mutated in 78% of human uveal melanomas, the most common type of eye cancer. This breakthrough is significant because the mutations associated with uveal melanoma were previously unknown. Dr. Van Raamsdonk is the only professor in the world examining the role of GNAQ and GNA11 in mouse pigment cells, making this work unique and essential. The information she gains may be used to prevent, diagnose, and treat different types of cancers, including melanomas.