Even though it is the most preventable of all cancers, lung cancer is the leading cause of cancer death for both men and women. The incidence continues to climb among women while decreasing among men. About 23,300 Canadians will be diagnosed with lung cancer in 2007, and 19,900 will die of the disease. Although studies have identified genetic differences in lung cancer, genetic targets for cancer diagnosis and treatment have not yet proven effective. Rajagopal (Raj) Chari is conducting a study to examine the full range of genetic and non-genetic mechanisms that affect the DNA and give rise to huge diversity among individual lung tumours. Chari wants to identify common functional disruptions based on these differing mechanisms, with the goal of determining which changes in key genes cause tumour growth. These genes should provide effective biomarkers for diagnosing and treating lung cancer, leading to more personalized medicine targeting the individual differences in tumours.
Research Location: BC Cancer Agency - Vancouver
Characterizing novel transcripts enriched in human embryonic stem cell lines
Human embryonic stem cells were successfully cultured in a lab for the first time in 1998. Scientists believe that transplanting these cells holds great promise for treating injury and disease because they have the unique ability to replicate themselves indefinitely and develop into a wide variety of other types of cells. But a number of challenges have to be tackled before stem cells can be safely used in the treatment of patients. These include understanding and being able to control how stem cells are transformed into other types of cells, overcoming immune rejection in patients receiving transplanted cells, and understanding any links between stem cells and the origin of cancer. Jaswinder Khattra is tackling a related challenge: defining the activity of novel genes and proteins in stem cells. Although thousands of human genes are known, many remain uncharacterized. Khattra is investigating the properties of novel genes discovered in stem cells to define how they act within the cells, and whether they play a role in controlling how stem cells differentiate into other cells. This research also examines the proteins produced by these genes and how they interact in regulating cell growth and function. Improved understanding of the molecular structure and function of these genes and proteins could contribute to improvements in cell-based therapies and drug screening for a range of diseases.
Predicting the outcomes of cancer care services
With an aging population, rising costs and an increasing number of cancer cases, predicting the outcome of cancer care services is important for health care planning. Predictions can be based on computer models that take information from simple processes into larger systems. A model’s accuracy can be determined by comparing its predictions with real-world data and activity. As an MSFHR scholar, Dr. Chris Bajdik created a model to predict demand for hereditary cancer services in BC. He is now working to further develop prediction models for cancer care services. These new models will predict outcomes associated with cancer screening, treatment, supportive and palliative care. The predictions described through modeling will be compared with observed outcomes from provincial, national and international cancer care services. Dr. Bajdik’s approach provides a cost-effective way to predict outcomes – using the experience reflected in previously-collected data. Most importantly, these models will provide healthcare planners with a tool to predict the outcomes associated with new cancer care services and health policies. If the predictions are considered accurate, health care agencies can better plan and evaluate their services to care for those with cancer. The methods can be generalized to develop models for other forms of health care and other diseases.
Patterning and Organogenesis of the Mammalian Embryo
The development of a single cell to a multi-cellular organism, with each tissue and organ having a distinct architecture and function, is truly remarkable. Cells must co-operate and communicate with one another so they divide, migrate, form connections, change their identity, and die in co-ordinated patterns. These processes are complex, thus little is known about developing embryos and the genes that regulate their development. As an MSFHR-funded scholar, Dr. Pamela Hoodless examined how cells communicate with one another during embryonic development. This work continues, with a focus on two areas: the gut and heart. Congenital heart defects occur in about one per cent of births, making it a most common form of birth defect. With genomic technology, Dr. Hoodless can look closely at the genes involved in forming the valves and septa in the heart. She has identified two genes that control the activity of other genes, known as transcription factors, and is studying the functions of these genes in valve formation. Dr. Hoodless is also working to understand how the first stem cells of the gut are formed, and how these cells change to become other organs (liver, pancreas, stomach, etc). Identified for further study are three genes that are expressed (turned on) in these tissues, but not in the development of other body tissues. Understanding how gene regulation controls the development of the heart and gut in the embryo has far reaching implications for medical therapies, ranging from refining the repair of congenital defects to promising technologies such as stem cell therapies and tissue engineering.
Germline and Somatic Cancer Genetics: Tools for population based individualized cancer care
Today’s cancer treatment is dictated by the anatomic location of the cancer, its histology, and how far it has spread. The Human Genome Project and the development of new drugs targeted against specific features of cancer cells have led to the possibility of individualized cancer care. This is a fundamental shift in cancer management and will involve integration of each patient’s inherited genetic characteristics and the molecular signature of their tumour. My laboratory uses genetic tools to predict inherited cancer susceptibility and genomic based tumour characteristics to determine therapeutic options. In British Columbia, the central referral system for cancer patients provides the opportunity to deliver equitable individualized cancer care across a whole population. I am fully committed to this challenge and dedicate my research, clinical practice, teaching, and administrative skills to this task. My clinical work occupies <25% of my time and involves the genetic based care of familial cancers. The remainder of my time is divided evenly between (1) research infrastructure development and furthering the translational research of my colleagues and collaborators and (2) the pursuit of my own research interests. My major research projects focus on the genetics and molecular pathology of hereditary cancers, with the goal of streamlining cancer susceptibility testing and identifying therapeutic opportunities for hereditary cancers and their sporadic counterparts. Current projects include the study of gastric, breast, and ovarian cancer susceptibility. My research in hereditary gastric cancer is already shaping the worldwide management of this cancer susceptibility syndrome. To develop useful laboratory tests based upon tumour characteristics, I developed and now co-direct the Genetic Pathology Evaluation Centre (GPEC) which is Canada's leading tissue based biomarker validation laboratory and a key element in the BC research landscape. My time spent directing GPEC and other such research entities is mutually beneficial as I am user of the research infrastructure I have helped to create. All of my projects are completely congruent with my stated vision of genetic based individualized cancer care for whole populations. Although this is an aggressive agenda, I believe my record in translational research during the first 4 years of my MSFHR scholarship indicates a great likelihood of future success.
Identification of microRNAs, their targets and roles in human embryonic stem cells
Stem cells are a special variety of cells that can self-renew indefinitely and can become a multitude of cell types. Embryonic stem cells are the most versatile variety of stem cells and can potentially develop into any adult cell type. Many cancer researchers believe that in most (if not all) types of cancers, there is a population of cancer stem cells that actively sustain the production of cancer cells. A better understanding of stem cells is crucial in advancing knowledge of all cell types, including cancer cells. Before manipulation of embryonic stem cells can be explored as a method of treating disease, and before anti-cancer drugs that target cancer stem cells can be designed, there is a need to understand the genetic structure and the signaling pathways that maintain these cells. Ryan Morin’s research is directed at understanding how the regulation of gene expression differs between embryonic stem cells during their differentiation into other cell types. His particular focus applies new sequencing technologies to unravel the cellular complexity of the regulatory molecules known as microRNAs and their involvement in embryonic stem cell gene regulation.
Adjusting for missing information in multilevel models with a non-binary response: identifying socioeconomic, cultural, demographic and clinical predictors of end-of-life health care service …
Many Canadians believe that equal access to health care is a fundamental right; however, evidence suggests that people experience unequal access to end-of-life care. For example, approximately 70 per cent of cancer patients die in hospital. Although little is known about Canadian preferences, international studies suggest people prefer to die at their home. Socioeconomic status is known to play a role in explaining health inequities. Michael Regier is examining whether the impact of the Canadian cultural mosaic (ethnic groups, languages and cultures that interact within Canadian society) on the use of health services is more complex than socioeconomic status alone. Each culture has its own expectations for health services, so the health system must be flexible enough to integrate various cultural understandings of health, but uniform enough to reach everyone. Regier is studying how additional “ecosocial” factors like ethnicity, language, family structure, religious beliefs and acculturation contribute to the way individuals and communities understand and use health care. He is investigating the place of death for cancer patients in BC from this perspective to determine differences in health determinants for end-of-life care. Health planners can use this information to improve access to end-of-life care across cultures, geographic areas and socioeconomic differences.
Characterization of the function of the nuclear matrix protein Lamin A in the organization of telomeres and chromosomes to determine the role in the pathology of Hutchinson-Gilford Progeria Syndrome
Hutchison-Gilford progeria syndrome (HGPS) is a rare, fatal disease that affects children and causes accelerated aging. Symptoms include dwarfism, loss of body fat and hair, aged-looking skin, stiff joints and hip dislocation. Children with this disease usually die of a heart attack or stroke at an average age of 13. HGPS is caused by a mutation in the LMNA gene which encodes a protein called Lamin A. The mutation causes instability in the cell nucleus, which is believed to lead to the premature aging in HGPS. Michelle Decker is looking for differences in the way normal and mutant versions of the Lamin A protein interact with chromosomes in the cell nucleus. Research has shown that cells from patients with HGPS have shorter than usual chromosome ends (called telomeres) than are usually found in cells of other children. Telomeres normally protect chromosomes from degradation and instability. By improving the understanding of the role that Lamin A and telomeres have in Hutchison-Gilford progeria syndrome, Michelle’s research may contribute to new understandings and therapies for the disease.
SHIP Down-Modulation as a Potential Approach to Protect Hematopoietic Cells During Chemotherapy or Radiotherapy
Chemotherapy and radiotherapy are currently used to treat many types of cancer. However, these treatments are not ideal because they target all dividing cells, including both cancerous and healthy cells. Blood cells, for example, have a finite lifespan and new cells are continuously being generated in the bone marrow. Unfortunately, the high doses of chemotherapy or radiation necessary to destroy malignant cells also kill these bone marrow cells. This reduces the body’s ability to replenish healthy blood cells, leading to life-threatening side effects such as anemia, infections, and uncontrolled bleeding. In such cases, the chemotherapy or radiation dose must be reduced, which, in turn, reduces the likelihood that cancerous cells will be eradicated. Melisa Hamilton is studying ways to protect blood cells during cancer treatment, with a particular interest in understanding how the SHIP protein inhibits blood cell survival. Melisa wants to determine whether reducing the level of this protein can increase cell survival during treatment. This would enable patients to withstand higher doses of chemotherapy or radiation with fewer side effects and increase the likelihood of killing the cancer cells.
Notch signalling in mammary tumorigenesis
Breast cancer is the most common cancer among Canadian women. One in nine women is expected to develop breast cancer in her lifetime, and one in 27 will die of the disease. Metastasis, or the spread of the tumour to another site, is the major cause of death. Notch receptors are cellular proteins required for normal growth and development. However an overproduction of an active component of Notch can cause abnormal cell growth, leading to tumour formation and the spread of cancer to distant sites. Iva Kulic is examining how another protein, called Slug, functions with Notch to promote breast cancer. Both Notch and Slug are found at high levels in some human breast cancers and are a sign of poor outcome. Slug prevents tumour cells from dying and allows them to detach from neighbouring cells and travel to other sites within the body – two key features in tumour development and metastasis. This research will explore whether reducing or eliminating the Slug protein will inhibit breast tumour growth and block the spread of cancer cells. Resolving whether Slug is essential in Notch-induced breast cancer could lead to new ways of preventing and treating the disease.