Squamous cell carcinoma (SCC), a cancer of the epithelium, is the most common human cancer throughout the body. When SCC occurs in the oral cavity, the five-year survival rate is less than 50 per cent. Before SCC develops, pre-malignant changes often become visible to patients or clinicians. While this offers the opportunity for early intervention to prevent the progression to cancer, only 15-20 per cent of oral pre-malignant lesions (OPLs) will progress to invasive carcinomas. Currently, it is not possible to determine which lesions will develop into cancer. It may be possible to predict cancer risk by studying the molecular features of OPLs. The progression to cancer is caused by genetic alterations to cells; some changes are the “driver” genetic alterations that lead to cancer, while others are random genetic changes. Determining the specific genetic events that are associated with progression to cancer would help identify those at greatest risk for cancer. Ivy Tsui is studying the initiating genetic events at the pre-malignant stage to identify genetic markers that can predict whether an OPL will become malignant. To do this, she is studying the molecular mechanisms of oral cancer progression. Using DNA from banked samples, she is assessing DNA alterations across the whole genome of late stage OPLs and tumours. Once she has identified recurring alterations, she will compare them with the genomes of early stage OPLs – both those that are known to have progressed to cancer, and those that did not. Once validated, these genetic markers will used to develop a clinical diagnostic tool. If DNA from a patient’s OPL can be assessed, patients at risk could be treated early and immediately to prevent progression to cancer. The identified genes critical for oral cancer development could also be used to develop therapeutic targets to treat oral cancer patients.
Lung cancer continues to kill more British Columbians each year than any other cancer. Diagnosis typically occurs late, leaving only toxic chemotherapy and radiotherapy as the treatment options. Medicine needs better ways to screen for lung cancer in high risk individuals, and better ways to treat them if lung cancer is found. Cancer cells have their cellular “brakes” cut, bypassing the checkpoints in normal cells that stop them from dividing too fast. Human DNA has two copies of each of these checkpoint genes, to ensure a backup in case one copy is damaged. In cancer cells, however, both copies are often damaged by two different mechanisms. One copy may be totally removed, and the other may be silenced by a mechanism called DNA methylation. Because cancer cells go to such great lengths to disrupt both copies of the gene, these genes are likely very important to the continued survival of the cancer. Identifying these genes in early cancers could lead to new screening and therapeutic targets. Ian Wilson is jointly funded by MSFHR and the BC Cancer Foundation. He is working to identify these gene targets, using approaches that enable the entire genome of the cancer cell, as well as every gene product of the cancer cell, to be analyzed simultaneously. He is searching for checkpoint genes in the lung cancer genome that are aggressively shut down in the cancer cell, determining the role of these genes in transforming normal cells into malignant ones. The identification of key checkpoint genes will be very useful as screening markers. This could lead to earlier diagnosis of lung cancer and new targets for therapeutic intervention.
While the fundamental unit of life is the cell, it is the cell’s DNA which instructs how a cell is to function. These microscopic blueprints can be read. Reading DNA sequences has enabled genes to be identified and revealed insights about the causes of many human diseases such as Huntington’s and numerous cancers. Reading and understanding how DNA functions, however, is only half the challenge in genetics research. To correct genetic errors accumulated in diseased genes, it is necessary to also write in DNA. But while DNA is essential in all genetics research, it is difficult to produce. Methods to rewrite or create new DNA sequences from scratch are limited. Regions of DNA can be copied, but there are relatively few methods of generating new fragments. Nucleotides are the characters of the DNA language. A 1,000 nucleotide gene costs approximately $1,000 to construct. Given that the average human gene is more than 3,000 nucleotides long, and that regulatory regions of DNA can be tens of thousands of nucleotides long, the cost of producing DNA becomes daunting. Daniel Horspool is researching a new laboratory technique for DNA construction. While the primary method involves adding one nucleotide at a time chemically to the growing sequence, the new technique relies on stitching multi-nucleotide fragments together in parallel. This process could be much faster and less error prone than the conventional method, and by using microfluidic devices, DNA could be produced at a much lower cost. The research could lead to an approach for constructing complete genes, which would be an important new tool for basic and applied biomedical research. The research could ultimately contribute to efforts to realize the promise of genomic and personalized medicine.
Flow cytometry (FCM) is a method of sorting and measuring types of cells by fluorescent labelling of markers on the surface of the cells. It plays a critical role in basic research and clinical therapy in the areas of cancer, HIV and stem cell manipulation. For example, it can be used to diagnose some types of cancer, based on which labelled antibodies bind to a particular cell’s surface. It is widely recognized that one of the main stumbling blocks for FCM analysis is in data processing and interpretation, which heavily relies on manual processes to identify particular cell populations and to find correlations between these cell populations and their clinical diagnosis and outcome (e.g. survival). Manual analysis of FCM data is a process that is highly tedious, time-consuming (to the level of impracticality for some datasets), subjective and based on intuition rather than standardized statistical inference. Dr. Ali Bashashati has developed a “pipeline” for automatic analysis of FCM data – a computational platform that can identify cell populations, find biomarkers that correlate with clinical outcomes, and label the samples as normal or diseased. Preliminary evaluations of this pipeline have shown accuracy levels of more than 90 per cent in identifying some sub-types of lymphoma. Moreover, a biomarker that contributes to a more aggressive behaviour of a specific sub-type of lymphoma has been discovered. Bashashati is now testing and refining the platform to improve its analytical power and applicability to a range of FCM data, testing its performance across a number of ongoing FCM studies in BC. Ultimately, he hopes to provide an accurate, powerful computational platform to increase the efficiency of using FCM for research and clinical purposes.
Non-Hodgkin lymphoma (NHL) is a specific type of cancer where an abnormal growth of immune cells produces what is known as a lymphoid tumour. Since the 1970s, NHL has become increasingly common, indicating that lifestyle and environment are likely causative factors. However, certain individuals may also have a genetic make-up that makes them more susceptible. NHL tumours often show a type of DNA damage called a translocation, where two chromosomes are incorrectly joined together. In NHL tumours, translocations are generally found near genes that are important for the development of immune cells. They cause changes in how these genes are regulated (turned on or off), that result in abnormal cell growth. Certain genes are responsible for repairing damaged DNA. If these genes are not functioning properly, DNA breaks will not be repaired and harmful translocations may occur. Previous studies have found that a common DNA sequence change at one of these DNA repair genes, called H2AX, was much more frequent among the NHL patients than unaffected individuals. Individuals who carry this gene variant have twice the risk of NHL as those who do not carry it. Dr. Karla Bretherick is interested in how common genetic variants influence risk for complex diseases. MSFHR has previously funded her graduate training, which involved studying the genetic factors that contribute to premature menopause. Now, she is looking at why individuals with the H2AX gene variant have increased risk of NHL. She will look at how this DNA sequence change affects H2AX gene regulation, modifies protein binding, and affects the ability of the cell to repair DNA damage. Ways to understand, prevent, and avoid NHL and other cancers are of increasing importance for the Canadian healthcare system. Understanding how and why this specific gene variant increases risk for NHL will lead to a better knowledge of how this cancer develops. This information will eventually be useful for identifying new drug targets and therapies for NHL, and may also provide insight into the development of cancers in general.
A stem cell can both self-renew and divide to form differentiated daughter cells. In adult tissues, stem cells have the ability to generate mature cells of a particular tissue through differentiation, and to do so multiple times. Such cells were recently identified in a mammary gland, and demonstrated their capacity to regenerate their structures in other breast tissues. This was an important discovery, as it is speculated that these stem cells are central to the development of breast cancer. Because stem cells are relatively long-lived compared to other cells, they have a greater opportunity to accumulate mutations leading to cancer. Also, these cells have a pre-existing capacity for self-renewal and unlimited replication. The idea that stem cells are inherent to malignant transformation has wide-stretching implications for therapeutics, particularly with regards to drug resistance. Angela Beckett is studying the growth and differentiation of normal breast stem cells, which will provide knowledge about what drives malignant transformation and how to prevent cancer initiation. By obtaining basic information on stem cell regulation, this research is taking an important step in designing novel therapeutic approaches to their malignant counterparts, cancer stem cells.
Blood cells are critically important to human health and a significant perturbation of blood production is life-threatening. In addition, the transformation of blood cell precursors leads to fatal leukemias, lymphomas and myeloma that remain difficult to treat and are often fatal within a few years of diagnosis. All blood cells must be produced from a common pool of self-maintaining cells called blood stem cells. Understanding the regulation of these cells and their immediate derivatives is critical because they are thought to be the origin of most blood cancers and it is the transplantation of these cells that is required to rescue the blood-forming system in patients who can benefit from treatment with an otherwise lethal dose of chemotherapy or require replacement of a defective blood-forming system. Although the use of blood stem cell transplants can be life-saving, its application is still limited. A major barrier to more widespread use is the extremely limited number of blood stem cells in the tissues where they are produced, and our inability to grow or expand these cells in tissue culture. Previous research has demonstrated that as they develop from fetal to adult cells, blood stem cells undergo an abrupt change that reduces their capacity to expand. Michael Copley’s research at the Terry Fox Lab focuses on improving our understanding in molecular terms of the mechanism that switches the ability of blood stem cells to expand that occurs shortly after birth. This could lead to the development of ways to block or reverse the switch, so that adult stem cells can be made more effective. It could also lead to an increased understanding of why different types of leukemias and other early onset blood disorders develop in children and adults.
Complex diseases, such as different types of cancers, are influenced by genetic and environmental factors and their interactions. There is overwhelming evidence that the effects of environmental factors on most cancers are modified by individual genetic characteristics. The accuracy of assessing the effects of gene-environment interactions on disease risks depends on how accurately the exposure to environmental factors can be measured or how accurately genetic makeup can be classified or both. Measurement error or misclassification can seriously distort the true effects of gene-environment interaction and produce biased estimates of the effects. Dr. Shahadut Hossain is developing a flexible modeling approach to adjust for biases when some of the quantitative environmental exposures are measured inaccurately. Hossain is also working to extend this methodology so that it can incorporate both exposure measurement errors and gene misclassification. His research involves studies of non-Hodgkin lymphoma, ovarian cancer and prostate cancer conducted with the Cancer Control Research Program at the BC Cancer Agency. Hossain hopes his work will enable the assessment of gene-environment interactions to be done more precisely, contributing to a better understanding of the effects of these interactions and more effective intervention strategies to prevent these diseases.
Solid cancers rely on blood vessels for delivering the oxygen and nutrients that allow them to grow and metastasize (spread to other parts of the body). Chemotherapy treatment also relies on the vessels for effectively delivering anti-cancer drugs to the tumour cells. When blood vessels have abnormal features, such as in cancerous tumours, the tumours appear to be more resistant to conventional chemotherapies as the result of this abnormal vasculature. A new focus in cancer research attempts to exploit vessel abnormalities that are specific to cancer by using them as cancer therapy targets. A new class of anti-cancer drugs currently under development and in clinical trials targets the blood vessels that supply tumours in two ways: vascular targeting agents (VTAs) damage the existing blood vessels that supply tumours, while anti-angiogenic agents (AAAs) inhibit the growth of new vessels. Although VTAs cause catastrophic damage to blood vessels in the centre of tumours, they leave a rim of viable cells and vessels at the periphery that survive to regrow the tumour; AAAs are also only effective on select populations of vessels within a tumour. Jennifer Baker is studying whether vascular targeting and angiogenic agents will work more effectively in combination with eachother or with other conventional chemotherapies to stifle this subsequent tumour growth. Baker is examining which blood vessels are sensitive or resistant to the drugs, what damage the drugs cause, and how this damage affects tumour growth. The findings could result in more effective combined treatments that are capable of cutting off the blood supply to cancerous tumours, thereby preventing the tumour from growing and metastasizing.
Male sex hormones (androgens) regulate tumour growth in prostate cancer. The only effective treatment for advanced prostate cancer is the removal of androgens using medication, or the surgical removal of the testes — treatments that cause impotence and a decreased sex drive. The results are usually temporary since some tumour cells survive, become independent of androgens, and continue to grow. Prostate cancer cells depend primarily on the androgen receptor, which encodes genetic information, for growth and survival. Gang Wang is studying how the androgen receptor decreases the expression of the SESN1 gene — a gene that may inhibit the growth of prostate tumour cells. Wang believes the SESN1 gene is no longer repressed when patients receive hormone therapy. This would explain the initial suppression of prostate cancer cells seen in these patients and the subsequent reappearance of cancer cells which later follows. Wang will confirm if the androgen receptor begins lowering the gene following therapy, allowing the cancer cells to grow. If so, the SESN1 gene could be a promising therapeutic target for treating prostate cancer.