Research Location: BC Cancer Agency - Vancouver

Lung cancer remains the leading cause of cancer death for both men and women in Canada and Small Cell Lung Cancer (SCLC) accounts for about 25% of all cases annually. Patients diagnosed with SCLC have a very poor prognosis, with statistics indicating that only 10% of patients will survive past 5 years. This survival rate has seen little improvement over the past several decades and new targets for therapy and diagnosis of SCLC are desperately needed. SCLC is particularly challenging for researchers because samples are relatively difficult to obtain. Because the type of cell from which SCLC develops is not known, it is also difficult to define normal gene expression (RNA) levels for comparison. Bradley Coe is investigating SCLC gene expression levels by focussing on changes found in the DNA rather than in the RNA. Analysis of DNA has a significant advantage in that the source cell is not needed for establishing a baseline. Bradley is comparing the DNA profiles of SCLC cells with profiles generated from similar types of lung cancer which are less aggressive – an approach that has been made possible because of new genome comparison technology. The results of his research will include a list of genes which may contribute to the aggressiveness of SCLC. His research will also contribute to increased knowledge of the biology of SCLC, which will assist in the classification and diagnosis of this disease and in the identification of potential new targets for drug therapy.

Pancreatic cancer is the fourth leading cause of all cancer deaths and one of the most drug-resistant cancers known. New drugs and therapeutic approaches for this disease are urgently needed. Sulfasalazine (SASP) is an anti-inflammatory drug used in clinical treatment of inflammatory bowel disease and rheumatoid arthritis. Studies have indicated that SASP is also potentially useful for treatment of a variety of cancers, including pancreatic cancer. In addition it has been reported that SASP can overcome resistance of pancreatic cancer cells to treatment with drugs. Maisie Lo is investigating the molecular basis of the anticancer activity of SASP and its effects on a recently developed, new model for human pancreatic cancer in immuno-deficient mice, i.e. alone and in combination with conventional drugs. If successful, the studies will indicate a new potential therapy for pancreatic cancer and form the basis of a future clinical trial.

During heart development a subset of cells that line the inside of the heart, called endocardial cells, undergo a transformation termed endothelial-to-mesenchymal transformation (EMT). This transformation is critical for normal development as it generates the cells that form the walls which divide the adult heart into chambers and the heart valves which regulate blood flow. It has been shown that Notch proteins (signaling molecules highly localized within the endocardial cells of the developing heart) play an important role in EMT as the activation of Notch signaling induces the EMT process. In about 1% of newborns, anomalies in this process are associated with congenital heart defects. Kyle Niessen is investigating a key transcription protein, called Slug, shown to be involved in the initiation of EMT. The Slug protein binds to DNA and affects the cellular composition of a cell. Kyle is examining the importance and the role of Slug during EMT and from this hopes to define the key regulatory steps required for heart development. Kyle’s research will contribute to a better understanding of the molecular mechanisms of normal heart development, and provide insights into correcting and preventing congenital heart defects.

Gene expression is the process by which a gene’s information is interpreted via RNA messengers to regulate all aspects of cell growth and function. Errors in this complex process can cause birth defects and diseases such as cancer. Although the mapping of the human genome was a major breakthrough in gene research, much remains to be learned about the molecular mechanisms which determine when a gene will be turned on and off (i.e. signaled to start or stop the production of messengers to co-ordinate specific types of cellular activity). Monica Sleumer is studying how genes are controlled at the molecular level. She is using the nematode (roundworm) C. elegans as a model organism because its genome has been fully sequenced (its genes are known) and it has been shown to share basic regulatory elements with humans. Using sophisticated bioinformatic methods for sorting and analyzing genetic data, Monica is investigating what turns genes on and off under different conditions and in different tissues. Ultimately, results from Monica’s research on the C. elegans will lead to new understanding of the much more complex human genome and the consequences for health when regulation errors occur.

All multi-cellular organisms begin as a single cell that multiplies and develops into a fully formed adult. While millions of cells are produced during development, the process of programmed cell death (apoptosis) removes obsolete cells. Errors in this process can cause neurodegenerative disorders and cancers. Suganthi Chittaranjan aims to identify the genes that control cell death. Using powerful tools available at Canada’s Michael Smith Genome Sciences Centre, Suganthi has identified 500 genes that are activated before cells die. One gene in particular may play a role in both programmed cell death and the immune system’s defensive response. If the research succeeds in identifying a common gene that controls both processes, the gene could be used as a target in developing therapy for controlling cancer and improving the immune system of cancer patients.

Embryonic stem (ES) cells have the ability to differentiate into any cell type, such as skin, muscle or nerve cells. Differentiated ES cells potentially could be used to replace damaged tissues. However, undifferentiated EC cells form benign tumours following transplantation, thus ES cells must first properly differentiate into the desired cell type. Frann Antignano is investigating what causes ES cells to either self-renew or differentiate. The long version of a protein called SHIP plays a role in differentiation, while a shorter version called sSHIP is found in undifferentiated cells. Frann is examining the role of sSHIP in ES cell renewal by reducing the protein’s levels to see if that leads to increased self-renewal. Results from the research could lead to therapies for controlling ES cell differentiation to treat a variety of conditions, including Parkinson’s disease.

Mantle cell lymphoma (MCL) is an aggressive cancer of the lymphatic system that is incurable with chemotherapy or radiation. MCL has a survival rate of approximately three years, with no long-term survivors. Ronald deLeeuw is studying the biology of this disease to learn more about how it progresses. He is focusing on secondary genetic alterations concurrent to a characteristic feature of MCL: the switching of a genetic segment from one chromosome to another (translocation), which results in uncontrolled growth of lymphatic cells and an unregulated growth signal. Using new technology that reveals previously undetectable genetic changes, Ronald is compiling a comprehensive list of secondary genetic alterations that could contribute to progression of MCL. The research could provide insights about potential targets in treatment of MCL.