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.
Year: 2011
Mitigation of hippocampal dysfunction and cognitive deficits in early-symptomatic YAC128 transgenic mice for Huntington’s disease
Huntington's disease is a devastating neurodegenerative disorder affecting between three and 10 individuals per 100,000 in the Western world. It is caused by a mutation in the huntingtin gene, which results in the accumulation of mutated huntingtin protein in the brain and the eventual degeneration of certain types of brain cells. The disease is primarily characterized by the onset of motor deficits; this develops when the striatum region deep within the brain begins to degenerate. However, Huntington’s disease patients commonly show cognitive impairments decades before the onset of the motor symptoms. The hippocampus is a brain region known to be involved both in cognitive (i.e. learning and memory) and emotional (i.e. depression) processes.
Dr. Joana Gil-Mohapel is investigating whether the hippocampus is involved in the early cognitive impairments in Huntington’s disease. She is working with a mouse model of Huntington’s disease, which closely mimics the human condition. These mice demonstrate profound structural and functional deficits in this region; significantly, as seen in Huntington’s disease patients, these deficits can be detected when the animals are still in an early-symptomatic stage, before the onset of motor symptoms. Therefore, the goal of the present research is to gain a better understanding of how this structure is affected in this mouse model.
Dr. Gil-Mohapel will investigate whether relevant cellular pathways are altered in this brain region and whether therapies aimed at promoting hippocampal function can reverse these deficits and be of therapeutic value for Huntington’s disease. She hopes her research will help elucidate novel targets for the mitigation of the cognitive deficits characteristic of early-stage Huntington’s disease patients.
Investigating biochemical signatures of radiation resistance in human breast and prostate cancers via single cell Raman spectroscopy
Radiation therapy is the recommended treatment for about one-third of all cancer patients, including those with breast and prostate cancer. One factor limiting the use of radiation therapy is the considerable difference in radiation response between patients. There are currently no proven biochemical or imaging methods to assess a cancer patient's radiation response during an extended radiation therapy treatment. There is a need to develop customized radiation treatments to accommodate the variations in radiation response from individual patients; however, implementing such personalized treatments requires a better understanding of the fundamental biochemical responses of human tumour cells to ionizing radiation. Dr. Quinn Matthews is investigating the use of Raman spectroscopy as a way to monitor radiation responses in cancer patients undergoing radiotherapy. Raman spectroscopy is a non-invasive technique that shows great promise for the biochemical analysis of cellular radiation responses, as it can provide sensitive molecular information from biological samples, such as human cells or tissues. Recent laboratory studies have shown that single-cell Raman spectroscopy techniques applied to irradiated cells can detect radiation-induced changes in certain proteins, lipids and nucleic acids within human prostate, breast and lung tumour cells. These results suggest that certain types of radiation-induced biochemical changes measured with Raman spectroscopy are correlated with tumour-cell resistance to radiation treatment. The goal of Dr. Matthews' research project is to apply the proven capabilities of Raman spectroscopy to investigate the biochemical radiation response of a variety of human breast and prostate cancers, irradiated both in vitro (in the lab) and in vivo (in the organism). The results of this research will lead to increased effectiveness of radiation therapy by facilitating the development of personalized adaptive treatments designed to account for individual radiation response.
Resiliency and mental health: Strengths and protective factors in individuals with severe mental illness adjudicated under the forensic mental health system
Proteolytic signatures and networks in breast cancer metastases
Breast cancer is the second most common form of cancer. A crucial event in the development of the disease is when cells start to leave the breast tumour, enter the bloodstream and start to form a new tumour in other organs, such as the lung and bone. This process, called metastasis, dramatically reduces the patient's chances of disease recovery. Hence, in depth understanding of this process is key to successful development of novel anti-cancer drugs to provide effective treatment for cancer patients. Although the genetic changes that cause cancer to develop and metastasize are being studied, there are other molecular events that contribute to cancer. The post-translational modification of proteins — which refers to the changes that occur after the proteins are built — can dramatically alter the protein function, putting it in a different place or switching the activity on or off. One way to modify a protein is to cleave a part of it off, exposing a new protein """"tail.” Identification of the actual modification patterns in different disease situations will presumably allow for a much more precise disease diagnosis. Knowing the protein differences between metastases, which are surprisingly different from the tumours they originate from, will help to identify the fundamental causes and provide great insight into the cellular processes affected during cancer. Dr. Philipp Lange's research involves the identification of protein """"tails"""" in different cancer tumours and metastases in order to identify differences between the two. He will also introduce a new protein into the tumours that can mediate the cleavage reactions in a controlled manner, which will enable him to deduce how the individual protein components of tumours were originally connected. As a final step in his research, he will investigate the key protein modification patterns (or """"signatures"""") found in the mouse model and see if this signature exists in patient tumour samples taken from the Tumour Tissue Repository at the BC Cancer Agency. The impact of Dr. Lange's work will be twofold. First, the protein modification signatures he identifies will be used to develop a powerful new method to support earlier breast cancer diagnosis and determination of patient prognosis. Second, the identified key network modulators serve as potential drug targets for the development and testing of new breast cancer therapeutics.
Investigation of breast cancer genome heterogeneity in predictive models of drug action
A common method of testing new cancer drugs is to use human breast tumour cells that have been transplanted into mice. How this transplantation process and drug treatments affect the grafted cells is not known. In particular, we need to know if certain types of mutation within the tumour may survive the process of engraftment better than others, resulting in a transplanted tumour that has a different composition and different properties from the original human tumour. Dr. Peter Eirew's aim is to study in detail how the “landscape” of different gene mutations in the tumor evolves when tumour cells undergo transplantation and subsequent treatment with anti-cancer drugs. Dr. Eirew will sequence the entire DNA and RNA (a measure of the active genes in a cell) of breast cancer patients' tumours before and after transplantation into mice to see how the frequency of each mutation changes over time. Dr. Samuel Aparicio's group has already read the entire DNA sequence of human breast cancer — both the original tumour and a recurrence in a different part of the patient's body nine years later — and showed that the type and frequency of the mutations changed over time. In the second part of the study, he will sequence these human tumour cells before and after the drug treatment to determine the types of mutations that survive. This will set the stage for a follow-on clinical study to determine how closely the drug response of these human cells predict how tumours in patients respond to the same drugs. This study will be the first attempt to define how grafted breast cancer cells behave in mice and how this behaviour is affected by the choice of grafting methods and treatment with existing drugs. This information will be used to improve the methods that are currently used to test potential new cancer drugs, with the ultimate aim of bringing new breast cancer treatments into routine use more quickly than in the past. Knowing the types and combination of mutations that are present in a tumour and how this combination changes during treatment will be the key to developing new and more effective drugs. The study may also identify new mutations in breast tumours, which have the potential to answer more specific questions about how these cancers arise, progress and become resistant to treatment.
Synthetic lethal interactions with cancer CIN genes: investigating potential therapeutic targets
Genetic instability is a hallmark of cancer cells. One type of genomic instability seen in >80 percent of solid tumours is called Chromosome Instability (CIN). Cancer cells can contain mutations in CIN genes, and these genes make the cells more genetically susceptible to mutation than normal cells. Cells with CIN have large aberrations in chromosome structure and/or number, including the gain or loss of chromosomes and chromosomal breaks and fusions. This creates a vulnerability that can potentially be exploited therapeutically to selectively kill these cells. However, because of their nature, mutated CIN genes are difficult to identify directly.
Dr. Melanie Bailey is using RNA interference (RNAi) technology to specifically identify CIN genes of interest. She will be collaborating with Dr. Jason Moffat's laboratory at the University of Toronto to search for genes that pair with known CIN genes and are mutated in spontaneous and rare hereditary cancers. She will also be collaborating with Dr. Phil Hieter's lab at the University of British Columbia (UBC) to test a network of gene pairs previously identified by computer analysis of a public genetic database (BIOGRID) in a human cell line using RNAi.
By combining these approaches, Dr. Bailey expects to identify novel gene pairs that will be further studied using various cell biology and biochemical methods. She hopes that her research will help to better understand how CIN works and that it will provide insight into finding novel ways of killing CIN-mutated cells. Finally, Dr. Bailey will identify inhibitors of the CIN genes through collaboration with Dr. Michel Roberge, whose lab at UBC regularly screens chemical compounds for their inhibitory potential. These inhibitors may represent a viable cancer therapy for the future, as they would be specific for killing CIN-mutated cells.
Effects of Adult Aging on Neural Control and Muscle Fatigue
Individuals 65 years of age and older constitute the fastest growing age group in Canada. With natural adult aging, the neuromuscular system (the muscles of the body and the nerves that supply them) undergo degenerative changes that are characterized by reductions in strength and power due to decreased muscle size. This age-related muscle weakness and overall decline in muscle function is referred to as sarcopenia. Sarcopenia not only interferes with tasks as lifting and carrying groceries, navigating stairs, and performing smooth complex movements, it is highly linked to physical disabilities and risk of falls. Sarcopenia is caused by a decrease in the number and function of motor units (MU), which consists of a single nerve branch and all of the muscle fibres it supplies. During the aging process, some of the MUs die off, while other MUs change structurally to compensate. As a result, there are fewer MUs present, but each one supports more muscle fibers. This MU remodeling process is a compensatory mechanism that acts to maintain muscle strength until a critical threshold is reached and strength decreases at an accelerated rate, usually by the eighth decade of life.
To understand the underlying biological mechanisms of MU remodeling, Dr. Brian Dalton is using a technique called single-unit microneurography. This research tool uses tiny electrodes inserted through the skin and into a peripheral nerve to stimulate and record signals from individual MUs. Using this technique, he will measure the integrity of functioning MUs in aged adult volunteers to determine if MU remodeling impairs neuromuscular function and muscle performance in the older adult. This work will help build a more comprehensive understanding of the neuromuscular system, specifically the process of sarcopenia and how it impacts natural adult human aging. The information gained from this study will aid in the design of functional training programs to improve and maintain muscle function — and quality of life — in older adults.
Immunobiosensor-Based Analysis of Antigen-Specific B-Cell and Plasmablast Responses during HIV-1 Infection
The study of the cellular basis of antibody-mediated immunity in infection is an exciting, emerging field of research that has profound implications for our understanding of host-virus interactions, protective immunity and HIV vaccine design. Antibodies are proteins that are produced by plasma cells and bind to molecules on the surface of invading pathogens, flagging them for destruction. Research in the field of HIV/AIDS has shown that antibodies, which neutralize a broad range of HIV isolates in test tubes, also protect animals from HIV-like pathogens, such as simian immunodeficiency virus (SIV). Thus, there has been a concerted effort to design vaccines that elicit broadly neutralizing antibodies targeting HIV. HIV-infected people rarely produce protective antibodies against a broad range of viral variants; this is of great concern to those attempting to produce a vaccine. Currently, there is no way of isolating the blood plasma cells that produce and secrete antibodies against a particular molecule or pathogen (antigen).
Dr. Naveed Gulzar's research involves an innovative approach to identify single, live HIV-specific plasma cells whose secreted antibodies bind proteins associated with HIV. He is working with a multidisciplinary team to develop an immunobiosensor that will allow him to locate single cells that secrete HIV-specific antibodies from thousands of antibody-secreting cells from the blood of HIV-infected people, and to isolate them for subsequent analyses. His goal will be to characterize the antibody response against HIV envelope proteins, and see how these change during the course of infection. The genes encoding these antibodies will be analyzed and their features compared. The results may provide new insights into our understanding of the immune response against HIV infection.
Dr. Gulzar's team includes Dr. Jamie Scott and several different analytical chemistry, physics and engineering research groups at Simon Fraser University and the University of Victoria, along with Cangene, a Canadian industrial partner. They anticipate that by understanding the genetic and cellular features associated with antibodies that neutralize a broad range of viral variants, they will be able to better inform the design of an HIV vaccine that elicits broadly neutralizing antibodies.
Signalling pathways that control the development and function of T regulatory cells
Autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and psoriasis, arise from an overactive immune response against one’s own substances and tissues. If this overreaction against the body persists for an extended period of time, it results in chronic inflammation. Currently, there are no cures for autoimmune diseases; at best there are only treatments that mildly alleviate the symptoms. A patient with an autoimmune disease is typically treated with drugs to suppress the immune system, which diminishes immune responses in general. This type of treatment means that the individual becomes susceptible to infection and cancer as their immune system is effectively turned off. Dr. Scott Patterson’s research project focuses on an immune cell called a T regulatory cell (Treg). These cells have the ability to suppress immune responses and normally prevent autoimmune diseases. Since the method by which Tregs turn immune responses off is not clearly understood, Dr. Patterson’s goal is to characterize the molecular mechanisms that allow Tregs to work. In parallel, he will study how Tregs interact with other types of immune cells. Using animal models of inflammatory bowel disease and multiple sclerosis, this work will investigate the interactions Tregs have with immune cells in the body during autoimmune diseases. Gaining a greater understanding of how the actions of Tregs are controlled will be a big step in developing new therapies for autoimmune diseases and reducing the dependency on non-specific immunosuppressive drugs. Inflammatory bowel disease and diabetes each affect more than 200,000 people in Canada alone; thus, this research aims to improve the quality of life for this segment of the Canadian population.