Hodgkin lymphoma is the most common type of malignant lymphoma in young people in the Western world. Despite modern treatments, about 20 per cent of patients die. Present studies have tried to identify ways to predict which patients are likely to be cured, using characteristics such as age, stage (degree of spread of the lymphoma), blood tests and x-rays or scans. However, these predictions are often inaccurate. Other genetic approaches to testing have proved difficult because malignant cells are present in very low numbers. Dr. Christian Steidl’s research focuses on developing tests to identify patients who will not be cured with current standard therapy, so that they may enrol in clinical trials testing innovative, new treatments. He is using a laser beam to capture individual malignant cells within lymph nodes so they can be studied separately from the surrounding non-malignant cells. This enables him to investigate how the genetic material in the malignant and non-malignant cells is altered and how this affects the behaviour of these cells – leading to the identification of markers that can predict treatment response. With a better understanding of the markers that can predict treatment response, physicians will be able to choose the right therapies for patients with Hodgkin lymphoma. This will help prevent both insufficient treatment and excessive treatment, which can lead to toxic side-effects. Identification of genes that are important for the malignant cells to survive will also help to develop new drugs that specifically target these cells.
Research Pillar: Biomedical
Pharmacogenomics of anthracycline-induced cardiotoxicity in childhood
Serious adverse drug reactions (ADRs) are the fourth leading cause of death and illness in the developed world, claiming many lives and costing billions of dollars each year. Children are especially at risk for ADRs: an estimated 15 per cent of all children admitted to hospitals get ADRs. Although many factors influence the effect of drugs, such as age, weight and organ function, genetic factors account for a great proportion. Small genetic differences between patients can cause serious ADRs. One group of drugs, called anthracyclines, are an effective treatment for many children and adults with cancer. However, they can sometimes be very harmful or damaging to the heart (cardiotoxicity), resulting in life-long drug treatment, the need for heart transplantation, or death. Dr. Henk Visscher is working to find the genetic factors behind this phenomenon. He is comparing gene variants between children who have experienced severe cardiotoxicity after receiving anthracyclines with children who did not. Using high-tech machines, he can screen for thousands of gene variants at the same time, making it more likely to find the gene(s) involved. Once identified, he will conduct a number of studies to confirm that the identified gene variants are the “culprits.” Visscher plans to create a diagnostic test based on the variants that can predict cardiotoxicity in patients taking anthracyclines. This would enable physicians to identify at-risk patients before they take the drugs, allowing them to adjust the dose, choose a different drug or monitor a high-risk patient more closely. Ultimately, this may help prevent potentially fatal heart disease among cancer survivors.
Functional analysis of the tumour suppressor ING1b Ser126 phosphorylation
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.
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.
Microglia homeostasis and function in CNS disease
Microglia play a critical role as immune cells in the central nervous system (CNS), helping protect the nervous system in response to neural damage or inflammation. Microglia are also thought to play a role in neurodegenerative disorders such as Alzheimer’s disease, dementia, multiple sclerosis and amyotrophic lateral sclerosis (ALS). Microgliosis – the accumulation of microglia – is a common response to multiple types of damage within the CNS. However, the origin of microglia involved in this phenomenon remains elusive. It has been shown that, as a result of radiation therapy or bone marrow transplant, this increase may be due to recruitment of bone marrow-derived progenitor cells that are capable of forming microglia. In the absence of therapies that manipulate the body’s blood production system, however, this is not the case. Bahareh Ajami has observed in her previous studies that recruitment does not account for the massive increase in microglial cells that occur in two different CNS disease models: neurodegeneration and traumatic injury. Instead, microgliosis is solely the result of the expansion (division and growth) of microglia already residing in the CNS. She is now working to determine whether bone marrow-derived progenitor cells have a role in microglia accumulation in multiple sclerosis, which is an autoimmune disease of CNS. In parallel, she will also explore the effect of microglial cells on nerve cell survival in the CNS. Ajami’s results will not only contribute to the field of neuroscience, but could also provide new targets for developing gene and drug delivery systems that treat CNS disease.
Yeast oxysterol binding proteins and the cholesterol dependent regulation of Rho-GTPase mediated polarized cell growth
Heart disease is the leading cause of death for Canadians. More than one million Canadians currently live with this chronic disease and every year, more than 81,000 die. A major contributor to heart disease is cholesterol. Ironically, even though too much cholesterol is bad for our health, it cannot be completely removed from our bodies because it is essential for human life. Controlling dietary cholesterol is not always enough to reduce cholesterol levels in the body since our cells can also produce their own cholesterol. Loss of cholesterol regulation in our bodies not only leads to heart disease, it is also causes problems inside cells that can lead to other disease states. In fact, recent studies showed that the use of cholesterol-reducing drugs not only lowered cholesterol, they also decreased the incidence of breast cancer in Canadian women by 74 per cent. Recently, a group of cholesterol-binding proteins were identified and have been shown to mediate many of the functions linked to cholesterol. Gabriel Alfaro is using microscopy, biochemistry, and genetics to determine the mechanisms underlying how these proteins affect cholesterol regulation and mediate cellular functions. His research uses baker’s yeast as a model system, since the regulation of cholesterol in yeast is similar to its regulation in humans. Gabriel Alfaro’s research will enhance our understanding of the role cholesterol plays in the cell, and potentially point to new drug targets that could have fewer side effects relative to the current broad spectrum cholesterol inhibitors. Furthermore, his research will help elucidate the mechanism underlying cholesterol-related diseases
YB-1 induction of PIK3CA mediates herceptin resistance in Breast Cancer patients
Breast cancer accounts for more than 30 per cent of all new cancer cases in Canada. One in nine women will be diagnosed with breast cancer in their lifetime, while one in 27 will die of the disease. This translates to 23,000 new diagnoses and 5,300 deaths in Canada every year. An aggressive form of breast cancer is called the Her-2 subtype. These tumours produce a protein called Her-2, which helps the cells grow uncontrollably. The drug Herceptin acts against the Her-2 protein. While this drug is effective, there are limitations to Herceptin’s usefulness since many patients develop resistance to the drug. Recent research has uncovered a protein called Y-box binding protein-1 (YB-1), which is expressed (produced) at high levels in the Her-2 subtype of breast cancer. While the YB-1 protein is not found in normal cells, it is found in 66.4 per cent of Her-2 subtype breast cancers. This makes YB-1 an attractive target for treatment, as inhibiting it will not affect normal cells. The protein promotes tumour growth by altering the levels of other tumour-enhancing proteins, such as PI3K. Arezoo Astanehe is investigating whether the increase in PI3K by YB-1 is one reason that cells become resistant to the effects of Herceptin. She hypothesizes that by inhibiting YB-1 and PI3K expression, Her-2 cancer cells would remain sensitive to Herceptin. Astanehe’s findings could identify new drug targets to help prevent Herceptin resistance and increase long-term survival of women with this aggressive and deadly form of breast cancer.
Regulation of intestinal homeostasis by colonic goblet cells in response to commensal and pathogenic bacteria
The gut lumen (interior space of the intestine) has developed to live in harmony with trillions of bacteria, many of which are beneficial to human health by helping in digestion and making vitamins. However, this harmony can be broken if the bacteria start to enter body tissues instead of staying in the lumenal space. Preventing this is the lining of the gut surface, which is made up of a single layer of different cells, including goblet cells. Goblet cells are single-celled mucus factories, specialized to make molecules that form a layer of mucus over the intestinal wall. While the mucus layer is believed to have a protective role, its function is not well studied in people. However, animal models that that lack mucus in the gut develop unwanted inflammatory responses and even cancer, suggesting an important function for this layer. Furthermore, defective mucus production is seen in patients with inflammatory bowel disease (IBD), which is characterized by excessive immune responses to our normally friendly bacteria. Previously funded by an MSFHR Junior Graduate Studentship award, Kirk Bergstrom is continuing his studies on how mucus-producing goblet cells promote healthy interactions with beneficial bacteria in the gut, and how they defend against harmful bacteria. He is using animal models of bacterial-driven gut inflammation, including an infection model that copies human disease. Bergstrom’s studies will shed light on how goblet cells help maintain this delicate balance within the gut. Also, since mucus production by goblet cells can be controlled by certain foods, these studies could lead the way toward new, noninvasive therapies based on nutrition to treat patients suffering from bacterial infections of the gut, or IBD.
Organizational effects of the neonatal testosterone surge on the hypothalamic-pituitary-adrenal axis
Mood disorders affect nearly 10 per cent of the population globally and have an enormous impact on society as a whole. Stress, and how the body deals with it, is known to be a contributing factor in mood disorders. One of the main neural systems involved in stress is the hypothalamic-pituitary-adrenal (HPA) axis, a complex system that connects input from the brain to the synthesis and release of glucocorticoid hormones from the adrenal gland. Although glucocorticoids (e.g. cortisol) play an important short-term role in helping us respond to stress, prolonged activation of the HPA axis can detrimentally affect brain function and behaviour. Research indicates that sex steroids such as testosterone help shape stress-related pathways in the brain, and contribute to why some individuals are predisposed to stress-related mood disorders. Prior to birth, males normally experience a surge in testosterone that has been shown to have a profound and permanent influence on brain structure, behaviour, and HPA function during adulthood. However, where and how this occurs in the brain has not been determined. Brenda Bingham is determining the HPA-regulating regions in the brain that are altered by this early surge in testosterone. She will explore how early testosterone exposure determines the capacity of these brain regions to respond to changes in circulating testosterone levels during adulthood. She is focusing on the function of androgen receptors, which allow the brain to respond to testosterone, and on the neuropeptide vasopressin. Bingham’s research will provide insight into the HPA-regulating brain regions and circuits that are altered by testosterone exposure early in life. Ultimately, she hopes this work will lead to the development of novel therapeutic strategies aimed at tackling depressive disorders.
Extraction and evaluation of transcription factor gene-disease association
Genes are the basic blueprints used by the cells in our body. When a gene is modified, the cells in our body can be affected; in the worst case, this can cause a disease. A researcher can often be faced with several candidate genes to study in relation to a particular disease, and choosing the genes with the best potential for discovery is important for making the best use of research resources. Around the world, researchers are studying thousands of different genes to understand their roles in health and disease states. Their findings – in the form of abstracts and annotations – are captured in a variety of databases. However, this vast source of biomedical literature is an under-utilized resource. Powerful computational biology methods are required to allow researchers to mine this information. Warren Cheung is developing an automated system that can examine the available biomedical literature and quantitatively determine which genes are most likely involved in a particular disease. Not only will the system identify previous relevant findings, its integration of data and annotations from many studies is expected to identify previously unknown associations between genes and diseases. Cheung’s research will initially focus on the involvement of transcription factor genes in brain diseases and cancer. However, the techniques developed and tested will be easily adaptable to all types of genes and diseases. Cheung’s award is jointly funded by MSFHR and the Down Syndrome Research Foundation. With the ability to automatically look at all the papers that have been published on genes and their functions, this system will make unbiased predictions and previously unknown linkages. This promises to be a powerful tool for understanding genes and disease.