In 2006, it was estimated that 153,100 new cancer cases were diagnosed in Canada, and 70,400 patients died of cancer. Improving our understanding of the molecular changes in cancer development is essential for designing more effective strategies for cancer prevention and treatment. In the past few years, studies on the biological functions of the tumour suppressor ING1b have attracted much attention in the scientific community. Dr. Aijaz Wani and his colleagues have found that ING1b can enhance DNA repair and promote programmed cell death – key biological functions that prevent cancer cells from developing and growing. However, information on the regulation of ING1b expression and its activity is lacking. Wani’s recent studies have uncovered that that the amino acid serine 126 attaches a phosphate group to ING1b, a process known as phosphorylation. He also confirmed that serine 126 phosphorylation is essential for ING1b protein stability. Now, he is investigating in detail how serine 126 phosphorylation of ING1b regulates the biological functions of this tumour suppressor. Wani’s research will provide new insights into the mechanisms on the regulation of ING1b activity and its biological functions. Ultimately, this work may lead to novel strategies for cancer prevention and treatment.
Year: 2008
Conditional genetic screens to define gene-gene and gene-drug interactions in normal and malignant human cells
Approximately eight per cent of breast cancers are caused by inherited mutations in genes called BRCA1 and BRCA2 (BReast CAncer 1 and 2). Since the BRCA genes were first identified in patients with inherited breast cancer, it has become obvious that they are also mutated in many non-inherited cancers. Understanding their function in normal and tumour cells is therefore an important problem in breast cancer research. Genes usually carry out their functions through interactions with other genes, organizing the different steps into pathways. Cells often use two or more different pathways to respond to the same stimulus. For example, there are multiple pathways that repair damaged DNA; one involves BRCA2, while a gene called PARP1 is involved in other pathways. Even when radiation and chemotherapy disable the BRCA-2 pathway, the intact PARP1 repair pathways may compensate and enable the cancer cells to survive. PARP1 inhibitors are currently undergoing clinical trials at various centres, including the BC Cancer Agency. Dr. Hong Xu is identifying interactions between the BRCA2 and PARP1 DNA repair pathways. She is also screening for gene mutations that make normal and BRCA2-mutated breast cells more sensitive to PARP1 inhibitors, which could help physicians determine appropriate doses based on a tumour’s genetic profile. Xu’s work will enhance our understanding of the roles of BRCA2 and PARP1, and accelerate the development of new individually tailored therapeutic treatments for breast cancer.
Cognitive contributions to checking compulsions
Obsessive-compulsive disorder (OCD) is an anxiety disorder that afflicts three percent of all Canadians. The disorder is characterized by intrusive and unwanted thoughts, images or impulses that cause anxiety, and that are temporarily relieved by the execution of specific compulsions. Obsessions and compulsions can occupy a large proportion of individuals’ time and energy and can interfere with daily routines, functioning at work, social activities and relationships with others. Checking compulsions are among the most common manifestations of OCD. Individuals with checking compulsions have intrusive concerns that they have failed to perform some task (such as locking the door or turning off the stove) and feel compelled to repeatedly check to ensure that the task was indeed completed. Preliminary evidence suggests that impaired prospective memory may play an important role in checking compulsions. Prospective memory is the ability to remember plans and intentions at a later moment. Everyday life and clinical observations show that checkers’ compulsions are related to this future-oriented aspect of memory and that the types of activities that tend to trigger checking compulsions are prospective memory tasks. Dr. Carrie Cuttler was previously supported by MSFHR with two research training awards. Her current work continues her exploration of whether individuals with checking compulsions have a cognitive deficit related to prospective memory. She hypothesizes that checking compulsions may develop to compensate for an impairment in prospective memory. In other words, individuals who frequently forget to perform tasks may develop a strategy of repeatedly checking to ensure that important tasks are not forgotten. Cuttler’s research focuses on improving our understanding of the mechanisms underlying OCD. The results will improve the quality of OCD patients’ lives by setting the stage for more effective treatments for reducing the frequency of checking compulsions.
Antiangiogenesis-induced changes in the tumour microenvironment: a window for therapeutic exploitation in pancreatic cancer
Pancreatic cancer is the deadliest form of cancer, with an average life expectancy of three to six months after diagnosis. Surgical removal of the tumour is the only curative treatment, but the majority of patients have inoperable tumours. A promising treatment strategy for many cancers types is to kill blood vessels in tumours. When blood vessels are disrupted, the tumour becomes starved of nutrients and oxygen. Some success in has already been seen with two different types of drug treatment: drugs that act specifically on blood vessels, and standard anti-cancer drugs delivered at low but continuous doses. While these treatments are promising in the context of pancreatic cancer therapy, their specific effects on pancreatic tumours are unknown. Dr. Jennifer Flexman is studying the effects of both types of drug on tumour growth and blood vessels. Using a variety of imaging techniques and biological methods, she will investigate how the tumour microenvironment (e.g. blood flow, oxygen levels) is changed by antiangiogenic drug therapies. Experimental results could lead to a rational basis for selecting treatments that takes advantage of physiological changes in the tumour. Dr. Flexman hopes her research will ultimately lead to the development of novel and more effective treatments for a deadly and largely untreatable disease, with the end goal of improving the quality of life and prognosis for patients
Peripheral neurophysiological basis of sensorimotor deficits in individuals with essential tremor
Essential tremor (ET) is a neurological disorder characterized by shaking of the hands (and sometimes other parts of the body) that occurs with voluntary movement. Often mistaken for Parkinson’s disease, it is the most common tremor disorder. Approximately 75 per cent of people living with ET experience some limitation in their activities, and these limitations typically get worse with increasing age. Therapies for essential tremor focus on tremor reducing medications, but effective treatments remain limited. Consequently, new insights into disease mechanisms are needed to guide the development of more effective therapies. The origins of essential tremor are believed to involve abnormal rhythmic activity in the brain, which then travels down to the peripheral nervous system. However, the specific neural pathways that the tremor travels, as well as how ET influences the recruitment of muscles for movement, remains unclear. Also unknown is the impact of tremor on sensory receptors found within skeletal muscles, which provide the sense of position and movement of the limbs. Dr. Martin Héroux is conducting studies on British Columbians with ET to determine how their muscles and sensory receptors are affected by abnormal rhythmic activities of essential tremor. He hopes these studies will increase our knowledge of the neural mechanisms involved in the generation of essential tremor and provide a better understanding of the motor-sensory deficits associated with tremor disorders. Ultimately, this knowledge could contribute to the development of more effective anti-tremor therapies.
Modulation of ocular motor decisions by reward: an investigation of neural processes using converging methods
The prospect of reward or punishment is known to affect how people make decisions. However, it is not clear which neural systems are involved in this process. This is an important topic in healthcare, because impaired processing of reward information is known to affect the decision-making abilities of many people, including those with damage to the frontal lobe of their brains, Parkinson’s disease, depression/anxiety, obsessive compulsive disorder, and even normal aging. A striking example of this situation occurs among some people with Parkinson’s disease, who can develop pathological gambling behaviours as a result of taking dopaminergic drugs. An effective way to study these neural systems is to track eye movement decisions – in other words where people focus their visual attention. Typically, people are faster to make an eye movement and are more accurate in their eye positions when the movement is rewarded by monetary gain. However, these effects are degraded in certain psychiatric conditions, such as anxiety and depression. Dr. Linda Lanyon is investigating the brain circuits that mediate these reward-related decisions in healthy humans. Her findings will enable her to develop a computer model of the brain circuitry and function that is able to simulate the behaviours observed in humans. In addition to demonstrating how these systems operate in healthy humans, the computer model can also be selectively damaged in order to simulate pathological behaviours observed in patients. By using healthy subjects to create a computer model for decision-making, Linda hopes to improve the understanding of the pathology of neurologically-impaired circuits.
Examining the interplay between adherence and antiretroviral treatment on disease outcomes over time in HIV/AIDS-infected patients
HIV therapy has evolved tremendously due to the development of new drugs, new technologies to measure viral response and drug resistance, and an improved understanding of how the virus progresses in the body. Modern highly active antiretroviral therapies (HAART) suppress the amount of virus circulating in the blood to nearly undetectable levels for long periods, enabling the immune system to rebound, reducing HIV drug resistance and preventing this otherwise fatal disease from progressing. Clinicians have identified that many people on HAART therapies do not fully adhere to the prescribed therapy, and that their level of adherence typically changes over time. This lack of adherence is known to increase the risk of illness and death, but the specifics remain unclear. More information is needed to determine how adherence dynamically affects disease progression and outcomes, so those at higher risk of treatment failure can be identified in advance and helped with their treatment. Dr. Viviane Lima is exploring the relationship between regimen-specific adherence for key HAART therapies and the disease outcomes for patients. She will determine the levels of adherence required at each stage to reduce or prevent a number of disease outcomes: viral rebound, immune cell loss, HIV drug resistance, the emergence of AIDS-related conditions, and death. She hypothesizes that for each disease outcome, there is a distinct, clinically-significant interaction between adherence and type of HAART therapy. Long-term management of HIV/AIDS requires a long-term commitment from patients to adhere to therapy, a high level of expertise among practitioners to deal with complex and rapidly evolving treatments, and the development of clinically meaningful tools to enhance adherence over time and across varied treatments. Lima’s study will provide an evidence base to identify best treatment practices.
Genetics of healthy cardiovascular aging
Statistics Canada projects that there will be more than 1.6 million seniors over 85 by the year 2041. Only a minority who reach this age maintain a good quality of life and are free of major age-related diseases such as cardiovascular disease (CVD), cancer, lung disease, diabetes, and Alzheimer’s disease. Advancing age is the biggest risk factor for cardiovascular disease. However, a minority of people older than 85 — called “”super seniors”” — seem resistant to the most common age-related diseases, including CVD. These people may represent a group that either lacks genetic susceptibility factors that contribute to disease in the majority of people or may possess genetic resistance factors that enhance their ability to resist disease and prolong lifespan. Dr. Maziar Rahmani seeks to answer whether people whose hearts remain healthy well into their 80s and 90s have “good genes.” He is studying more than one thousand residents in the Metro Vancouver area, using cutting-edge technologies to scan the entire genome of each study participant. He will look across more than a million potential variances to find genetic commonalities among super seniors in Vancouver, and compare these findings to other studies using European and other North American populations. Identifying and understanding genetic factors that influence resistance or susceptibility to heart problems could open the way for personalized, optimized disease prevention and treatment strategies.
Statistical models for clinical genomics of cancer
Ovarian cancer is the most fatal gynecological cancer in North American women and the fifth most common cause of cancer death. Breast cancer is the most common cancer in women worldwide. Recent approaches to improving clinical outcomes for these two diseases have focused on defining distinct subtypes within ovarian and breast tumours that differ in their clinical outcomes and responses to therapy. Preliminary evidence suggests that subtypes can be detected from biopsies by performing state-of-the-art molecular tests to determine specific molecules (called markers) that distinguish the subtypes. It is also expected that an even smaller subset of markers could be used as indicators for determining prognosis and for directing therapy tailored to the subtype. A number of BC research programs are currently working collaboratively to identify and characterize the subtypes of ovarian and breast cancers, using more than 2,000 breast cancer and 400 ovarian cancer tumours for which clinical outcomes are known. This work generates massive amounts of molecular data (more than 100,000 data points per tumour). Previously supported by MSFHR funding for his PhD training, Dr. Sohrab Shah focuses his post doctoral work on developing bioinformatics (the application of computer science tools and research to biology) and statistical modeling approaches that can help pinpoint potential markers among the reams of data. Shah’s research is key to developing tools that help uncover the molecular characteristics of the subtypes of breast and ovarian cancers, and provide state-of-the-art classifiers for improved outcomes for patients with these devastating diseases.
Modulating mood with transcranial direct current stimulation: basic research and clinical applications for treating depression
Approximately 8 per cent of all Canadian adults will experience at least one major episode of depression during their lifetimes, and up to 6.5 per cent of Canadian children currently meet the criteria for clinical depression. Efforts to understand the neural mechanisms underlying depression and to develop new treatment methods for the mood disorder have the potential to facilitate improvements in quality of life for people throughout Canada and around the world. Neuroimaging studies show that negative mood and depression are associated with increased activity in the right prefrontal cortex and decreased neural activity in the left prefrontal cortex. Dr. Bradley Vines is examining how changes in neural activity in the prefrontal cortex influence mood. He is also exploring the therapeutic potential of transcranial direct current stimulation (TDCS) as a treatment for clinical depression. TDCS is a safe, painless, and non-invasive brain stimulation technique that modulates neural activity in targeted brain areas. It has been shown to significantly influence behavioural and cognitive performance. The technique involves running a low-level direct current between two electrodes placed on a person’s scalp. The neurons underneath the positively-charged anode fire more rapidly, whereas the neurons underneath the negatively-charged cathode become less active. Using tDCS, it would be possible to simultaneously increase neural activity in the left prefrontal cortex and decrease activity in the right prefrontal cortex – potentially correcting the neural imbalance that is characteristic of depression. Vines’ research promises to advance our understanding of how the prefrontal cortex contributes to emotional states and mood disorders, and to determine the viability of using tDCS as a therapy for depression.