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.

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.

Molecular Imaging of Cancer with Positron Emission Tomography

Recent developments in imaging devices provide researchers with powerful tools to detect cancers and explore the impact of therapy on tumour cells. This research program plans to leverage the strengths of positron emission tomography combined to computed tomography (PET/CT) to characterize and rapidly assess response to therapy in 3 common cancers (breast, prostate, and lymphoma) and combine this information with other predictors of aggressiveness and treatment failure. PET/CT imaging is a powerful technique that combines the strenghts of a PET scanner (which can measure tumor receptors and metabolic activity) with those of a CT scanner (which provides detailed images of a patient’s anatomy). The combination of both approaches could rapidly identify patients that are likely to fail conventional therapy and offer them alternatives that are better suited to the nature of their cancer. The research program is designed around 3 core themes. The first research them focuses on the development of methods to predict the outcome of patients with breast cancer who are treated with chemotherapy or hormone therapy. We will pursue ongoing work to develop animal models of breast cancer and imaging methods to monitor response of these tumors to chemotherapy and hormone therapy. We will also conduct clincial studies to correlate the results of imaging studies performed with PET/CT with outcome and response to therapy. The second theme focuses on the development of new probes that target specific proteins that are overexpressed at the surface of breast and prostate tumors. These probes might eventually be translated into clinical studies as breast and prostate cancer diagnostic agents for use with PET/CT, or even for therapy by tagging them with radioisotopes that can destroy tumor cells by proximity. The last theme proposes practical research studies of immediate clinical interest. We will assess the accuracy of PET/CT imaging in staging prostate cancer (with 2 radiopharmaceuticals designed to assess tumor lipid synthesis and bone turnover). We will also extend to the Vancouver site an ongoing study that assesses PET/CT imaging to predict the early response to chemotherapy in large cell lymphoma.

Genome-scale variation in health and disease

The sophisticated approaches of genomics are increasingly being used to analyze the majority of the genetic material contained within cells. The tools of genomics have catalyzed remarkable developments in health and disease research. These tools continue to evolve at a rapid pace, making possible additional health research opportunities that are increasingly comprehensive. Dr. Marco Marra is Director of the British Columbia Cancer Agency Genome Sciences Centre. Dr. Marra was funded as an MSFHR Scholar in 2001, with a specific focus of using genomics to comprehensively search for genes that play roles in cancer. In 2003, Dr. Marra also distinguished himself as leading the team that cracked the genetic code for SARS. In addition to his continuing work in cancer genomics, Dr. Marra is also working to identify and analyze DNA mutations correlated with, or causing, mental retardation. A consistent theme in Dr. Marra’s research is the identification and analysis of new genes and new gene products to determine their potential for use as new therapies or vaccines to combat cancer, infectious diseases, and other disorders.

Priority setting methods for cancer control and care

Priority setting is the focus of health economics—a branch of economics concerned with issues related to the scarcity of health care resources. With cancer expected to be Canada’s primary cause of death by 2010, priority setting in cancer control and care is imperative. An aging population, rising health care costs and increasing demand have resulted in the need for identifying effective and cost-effective ways to improve cancer patient outcomes. Basing his work on an internationally-recognized economic framework for priority setting (called Program Budgeting and Marginal Analysis), Dr. Stuart Peacock is developing new evidence-based methods to help health care decision-makers determine the most effective cancer interventions to fund. His research will develop three significant innovations within this framework: methods to address improvements in life expectancy and quality of life from health programs; methods to address community preferences and equity concerns; and measures to evaluate priority setting and evidence-based decision-making. Dr. Peacock’s goal is to develop an evidence-based framework for decision-making in cancer services that is transparent, explicit and accountable.

Notch signaling in Lymphoid Neoplasia

A common theme in cancer is the dysregulation of a normal developmental process that either directly causes cells to grow in an uncontrolled manner, or renders them susceptible to cellular damage that, in turn, leads to uncontrolled growth. One example of this process occurs with a normal cellular gene called Notch, which is inappropriately activated in a large fraction of cases of a certain type of blood cancer called T cell acute lymphoblastic leukemia (T-ALL). During normal development of the immune system, regulated Notch activity is required for formation of mature lymphocytes that protect the body from infection. When activated, Notch promotes the formation of normal T lymphocytes, but if this signal is not turned off in time, these T cells can undergo malignant change and become cancerous. Dr. Andrew Weng is studying the signals that are generated by Notch activation and the context in which these signals are received by the cell. By understanding the role of Notch in cancer development, he hopes to develop methods for manipulating Notch activity to shut down the growth of established cancer cells, and perhaps also to prevent it from occurring in the first place.

Molecular characterization of Ahi-1, a novel signaling molecule with an SH3 and multiple WD40-repeat domains, in normal and leukemic hematopoiesis

Because many forms of leukemia originate in blood stem cells, uncovering the changes that occur in these cells is crucial to understanding how these diseases develop and progress. Dr. Xiaoyan Jiang is studying Ahi-1, a newly-discovered oncogene (cancer causing gene) that is involved in murine leukemia development (leukemia in mice) and shows abnormal expression in human leukemic cells, including leukemic stem cells from patients with chronic myeloid leukemia and Sezary cancer cells from patients with cutaneous T-cell lymphoma. Her research team recently found that over-expression of Ahi-1 gene alone can cause leukemia in mouse models and suppression of Ahi-1 gene can normalize its transforming activity in human leukemia cells, a strong indicator that Ahi-1 is likely to be an important new oncogene involved in the development of leukemia in humans. Dr. Jiang’s research will explore the normal function(s) of Ahi-1 in the development of blood cells, and how this is altered when cells become leukemic. This research will also begin to identify new intracellular molecules that interact with Ahi-1 and the cellular and molecular pathways through which these interactions occur. Understanding how and by which pathways Ahi-1 contributes to the development of leukemia may provide important new molecular targets for the development of targeted cancer treatment that will be more effective and have fewer side effects than currently used chemotherapy.

A novel approach to studying DNA copy number variation in schizophrenia and bipolar disorder

Schizophrenia and bipolar disease are severe mental illnesses that affect thinking, mood and behaviour, and cause lifelong disability. Schizophrenia alone costs the Canadian economy about $2.5 billion per year. While the exact causes remain unknown, both disorders are thought to arise from the interaction of genetic defects with environmental factors. Research into these psychotic disorders lags behind advances in other health fields, so new and innovative research strategies are needed. Studies have shown that certain DNA changes can strongly predispose people to psychotic disorders, but the full scope of DNA changes in schizophrenia and bipolar disease has not been explored. Dr. Robert Holt is using new technology called microarray comparative genome hybridization to scan the entire genome of patients with schizophrenia and bipolar disease to detect losses or gains of DNA. The research could contribute to better understanding of the genetic factors that predispose people to schizophrenia and bipolar disorder, lead to diagnostic tests to identify those at risk, and strategies for early intervention to achieve better outcomes.

Cancer Control Research Unit

This unit combines the skills and talents of researchers in the BC Cancer Agency’s Cancer Control Research Program and Canada’s Michael Smith Genome Sciences Centre to create a critical mass of expertise in cancer epidemiology, environmental exposure assessment, genetics and biostatistics. The unit will explore the interaction between environmental toxins and genetic susceptibility in determining cancer risk, focusing on environmental, genetic and gene-environment studies in non-Hodgkin’s lymphoma, skin cancer, ovarian cancer and cancers of the mouth.

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Terry Fox Laboratory

The overall goal of this unit is to make breakthroughs in the prevention, early diagnosis and treatment of cancer by focusing on the role and therapeutic promise of stem cells. Studies will focus on defining molecular pathways that govern stem cell renewal, viability, their development into specific types of cells (such as bone and blood) and their ability to multiply in a variety of body tissue. Researchers are particularly interested in understanding how inherited and acquired gene mutations may influence these processes and contribute to the development of cancer.

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