The role of the Ahi-1 oncogene in the regulation of hematopoietic stem cell development, function, and leukemogenesis

Chronic myelogenous leukemia (CML) is a cancer of the white blood cells. The disease starts when genetic changes in blood stem cells (hematopoietic stem cells, or HSCs) cause them to become malignant (leukemic stem cells) and grow uncontrollably. Normally, HSCs make all the white and red blood cells that function to protect our bodies from infections and to carry oxygen and nutrients to other cells in the body. In CML, leukemic stem cells crowd out all other cells in the bone marrow, leading to illness and eventually, if uncontrolled, death in the patient.

Dr. Kevin Lin's research group recently discovered that the Ahi-1 gene plays an important role in CML. The gene contributes to leukemic stem cell activity and can influence how these cells become resistant to current drug therapy. The goal of Dr. Lin’s research is to understand exactly how Ahi-1 contributes to CML disease development in HSCs and leukemic stem cells. Using a new mouse model that is deficient in this gene, he will examine what happens to the development and function of HSCs when Ahi-1 is absent. The findings from this project will contribute to our understanding of the biology of normal hematopoietic stem cells and malignant leukemia stem cells. This new knowledge will then be applied to develop better diagnostics and eventually better treatments for patients suffering from CML.

Promotion of metastasis by hypoxic tumour cells

Nine out of ten Canadians who are killed by cancer die because their tumour has metastasized, or spread, to other parts of their body. Metastasis occurs when tumour cells escape from the original, or primary, tumour and then grow into life-threatening metastatic tumours in other organs. Despite the fact that thousands of tumour cells can escape from a primary tumour every day, most cells do not live long enough to grow into metastatic tumours. As well, metastatic tumour cells can only grow in specific organs. Most primary tumours contain cells at lower oxygen levels than normal tissues, and these low-oxygen tumour cells make tumours more aggressive and metastatic.

Based on these facts, Dr. Bennewith's team is developing new approaches to help identify tumours that contain low-oxygen tumour cells in patients. In addition, Dr. Bennewith and his colleagues have recently discovered that proteins made by low-oxygen tumour cells cause the body's normal bone marrow cells to enter the bloodstream and build up in specific organs. These cells create an environment where metastasizing tumour cells can survive and grow into metastatic tumours. Dr. Bennewith’s team intends to identify the specific proteins that control bone marrow cell behavior in order to develop targeted therapies that will prevent the build-up of bone marrow cells in organs and thus inhibit metastatic tumour growth. Metastatic tumours are very difficult to treat, but by studying how tumour cells spread and grow into tumour metastases, more effective cancer treatments can be designed. Dr. Bennewith's expertise in metastasis research combined with his unique research program will improve our understanding of how low-oxygen tumour cells promote metastasis. Importantly, his work will help to create more effective methods to both detect and to treat metastatic cancer in the clinic.

Generation of a humanized mouse xenotransplant model of myelodysplastic syndrome

Myelodysplastic syndromes (MDS) are diseases of the blood and bone marrow. MDS originate when a stem cell, from which all other blood cells originate, becomes mutated and then overgrows and crowds out other cells. This results in reduced numbers of red cells (anemia), white cells (leukopenia) and platelets (thrombocytopenia) circulating in the blood. As the disease progresses, bone marrow may completely fail to produce normal cells, and the myelodysplastic stem cell may develop into cancer, Acute myeloid leukemia (AML). The exact molecular causes for MDS are unknown; however, a common feature of MDS is chromosomal abnormality, the loss of the long arm (q) of the chromosome 5 being one of the most common in a subtype of MDS called 5q- syndrome. This lost region of 5q likely harbors several important genes, which may prevent MDS.

Dr. Joanna Wegrzyn Woltosz's research project will decipher the molecular mechanism of the disease and identify targets of a new drug (lenalidomide) currently used in MDS treatment. She is studying two important factors that are located on the 5q arm and are involved in the development of MDS (1) the RPS14 gene, which is thought to be responsible for the anemia seen in MDS patients, and (2) microRNAs, whose loss allows the abnormal MDS stem cells to survive and grow more than the other bone marrow cells. Since lenalidomide reverses symptoms resulting from loss of the microRNAs, she will also study whether lenalidomide increases the expression of these microRNAs. Currently, the only treatment for MDS is high-dose chemotherapy with stem cell transplantation, which is risky and challenging for patients to endure.

The information Dr. Wegrzyn Woltosz expects to obtain from this study will not only help to better understand the molecular mechanism underlying MDS, but will suggest novel steps towards the development of better therapies that will improve treatment and quality of life and increase survival for MDS patients.

Evidence Values and Priority Setting Methods in Cancer Control

The overarching goal of this study is to develop a framework to combine evidence and public values to set priorities for cancer control programs (including prevention, screening, treatment and palliative/supportive care). Its objectives are to: (a) develop better methods for identifying, interpreting and applying evidence in different cancer control decision-making contexts; and (b) better understand if, when, and how public engagement and public values should play a part in priority setting processes for cancer control.

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Improving Access to Quality Cancer Care using Operations Research Methods

Radiotherapy is used for curative and palliative (symptom relief) purposes for patients with cancer, with 30 to 40% of patients receiving radiotherapy during some point in their illness. Wait times for radiotherapy have been shown to lead to poorer outcomes for those treated as part of curative treatment, and to increased suffering for those treated for palliative reasons. Wait times occur either because of equipment and/or staff shortages, or due to resources not being used in the most optimal manner. Demand for radiotherapy fluctuates over time, leading to unpredictable surges in demand that are difficult to meet in a timely fashion.

Dr. Scott Tyldesley is working to improve understand of the root causes of the fluctuation in demand for radiotherapy, and to develop approaches to predict and address demands. He, and his colleagues, are creating a detailed model of the radiotherapy system, which will allow him to simulate current cancer patient flow, and to test proposed improvements to the system. Development of the model will also allow the group to explore how the radiotherapy system can improve how it forecasts demand for services, and how it deploys its resources. These results will be tested in system-wide models and then considered for implementation at the BC Cancer Agency (BCCA). The research team is a unique collaboration between specialists in operations research from the Sauder School of Business at UBC and clinical decision-makers and administrators from BCCA. The results of Tyldesley’s research will directly affect clinical practice for patients with cancer and be transferable to other health care environments.

Development and application of data standards for flow cytometry

Flow cytometry is a method of identifying and sorting cells and their components by staining with a fluorescent dye and detecting the resulting fluorescence (usually by laser beam illumination). Flow cytometry is widely used in health research (e.g. for stem cell identification and vaccine development), and in the diagnosis, monitoring and treatment of a variety of diseases, including cancers and HIV/AIDS.

Recent advances in high-throughput flow cytometry allows for the analysis of thousands of samples per day, creating detailed descriptions about millions of individual cells. Managing and analyzing this volume of data is a challenge that Dr. Ryan Brinkman is addressing through the development of data standards, algorithms, and bioinformatics tools. Dr. Brinkman is also applying these methodologies to the analysis of several large clinical flow cytometry datasets in an effort to identify biomarkers for lymphoma, neonatal auto-immunity, and graft versus host disease.

Priority Setting Methods in Cancer: Evidence-Based Marginal Analysis

The challenge of priority setting in cancer has never been so great. Over the past 20 years, over 2.3 million Canadians developed cancer, of which 1.1 million died prematurely. Over the next 20 years, these levels will rise by approximately 56% and 48% respectively. Cancer control and care in BC faces many other challenges: the rising costs of innovation and technology, allocating resources across the spectrum of interventions, a lack of incremental funding growth despite growth in incidence and prevalence, growth in all cancer control programs, need for new programs required with no defined funding, and rising community expectations and demand. A systematic organization of the limited resources in cancer control and care is urgently needed to respond to the potential impacts of cancer.

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Oncology Nutrition

This award supports the creation of a team focused on advancing research in a new and emerging field: oncology nutrition. Through conferences, educational sessions and workshops, the team aims to achieve key goals that include: identifying research priorities and resources; identifying partners for individual and multi-centre projects; and gaining consensus on research design and methodology. Other goals include mentoring cancer care staff and developing a database within cancer treatment centres for future research.