Evaluation of the tumour microenvironment in HER-2 positive breast cancer with non-invasive imaging and molecular techniques: Implications for rational combination therapies

Despite major advances in diagnosis and treatment, one in 25 Canadian women will die of breast cancer. Breast cancer patients whose tumours express (produce) high levels of the protein HER-2, in particular, have poor prognosis. This type of tumour is especially aggressive, metastatic, resistant to treatment, and has individual cells capable of withstanding adverse conditions in the tumour. Herceptin®, a drug that specifically targets HER-2, has shown remarkable results in some women with HER-2 overexpression; however, a significant number of women with this type of tumour do not respond to the drug. In order to identify aspects of HER-2 tumours that may have an impact on therapy, Dr. Mihaela Ginj is using a combination of non-invasive imaging methods to evaluate physiological functions in the tumour microenvironment, such as oxygen status, blood flow, and metabolism. This innovative study of tumour biology may enable physicians to monitor tumour response to therapy more rapidly and with greater specificity. This “personalized” approach for tumour treatment would maximize therapeutic effects and spare patients from side effects of treatments that may be ineffective. Findings from this study could have an impact on the clinical management of breast cancer in the near future.

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.

Discovery of novel biomarkers in lung cancer using an integrative genomics approach

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.

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 Genetic Alterations Involved in the Progression of Epithelial Cancers

Cancer causes six million deaths worldwide each year, and is the second leading cause of death in developed countries. Of 227,000 new cases diagnosed in Canada this year, about 80 per cent will be some type of carcinoma, a malignant tumor that begins in the epithelial cells lining the inner and outer surfaces of our organs. Carcinomas comprise a vast array of cancers, including lung, breast, prostate, colorectal, oral, esophageal and cervical. Although current treatments can be effective, survival rates vary for these different types of cancer. Mutations in genes are responsible for the development of all cancers. But the nature of epithelial cancer cells makes it difficult to distinguish which mutations initiate the process. William Lockwood is using new technology to define patterns of DNA change in people with early stage epithelial cancer and to identify the genes responsible for the progression of the disease. Ultimately, these genes may be used to predict which pre-cancerous lesions are prone to develop into tumours to improve early detection and treatment.

Mining the genome and transcriptome of lung cancer for clinically relevant molecular signatures

Lung cancer is responsible for the greatest number of cancer deaths in Canada. Current chemotherapy treatments are largely palliative, and only a small percentage of patients show a favourable response. Like other cancers, the progression of lung tumours is driven by a series of genetic alterations that can vary significantly between patients. The specific set of changes that occur in any individual tumour influences not only its aggressiveness and outcome, but also the effectiveness of cancer treatment. Scott Zuyderduyn will determine the genetic changes in several hundred lung tumour samples for which treatment and outcome is known. He will then employ computational and statistical approaches to determine which changes can accurately predict how a tumour will respond to different treatments. This research has important implications for determining, at diagnosis, the best choice of cancer-fighting treatment.

T Cell Therapy of Breast Cancer: Defining and Circumventing Barriers to T Cell Infiltration of the Tumour Microenvironment

T cells are white blood cells involved in a variety of our immune system responses, including detection and destruction of cancer cells. With T cell therapy, “tumour-reactive” T cells are isolated from a patient’s blood, and large numbers are grown outside the body. These T cells are then infused back into the patient to help the body recognize and destroy cancer cells, a method called adoptive immunotherapy. Michele Martin is studying the potential for using T cell therapy to treat breast cancer. Early results show about 19 per cent of tumours will regress or shrink with this treatment – unprecedented with other types of treatment – while the rest have partial or no regression. Michele is investigating how some of the tumours manage to exclude the T cells and also whether combining T cell therapy with low doses of chemotherapy can facilitate T cell infiltration into these tumours. If successful, this approach could improve breast cancer cure rates and reduce the side effects associated with current treatments.