Identification of genetic signatures predictive of progression risks in oral pre-malignant lesions

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.

Epigenetically silenced tumour suppressor genes in lung cancer

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.

Characterization of a new checkpoint in hematopoietic stem cell development

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.

The role of Notch in Endothelial Cell Survival and Apoptosis

Cardiovascular disease is a leading cause of death worldwide. Some people are born with a heart defect, while others develop atherosclerosis — a build up of waxy plaque in the blood vessels which results in the narrowing of the arteries, increasing the risk of heart attack and stroke. The thin layer of cells that line the blood vessels and heart chamber are called endothelial cells. These cells are vulnerable to injury and/or death due to the constant exposure to injurious agents in the blood such as bacterial and viral particles, homocysteine — an amino acid associated with heart disease, and high blood glucose resulting from diabetes. It is when these endothelial cells become injured or die, that cardiovascular disease occurs or worsens. Continuing the work she began with her MSFHR-funded Master’s research, Linda Ya-ting Chang is studying the function of a particular family of proteins called Notch, in the survival of endothelial cells. Two proteins known to protect against death in other cells show increased activity when Notch is present. Chang is investigating whether the same protection is seen with endothelial cells, and how Notch proteins increase the rate of cell survival. The long-term goal is to identify molecules that protect endothelial cells from injury, lessening the progression of atherosclerosis and congenital heart disease, and potentially reducing the risk of heart attack and stroke.

Identification of Predictive Drug Response Signatures and Novel Resistance Genes by Whole Genome Profiling of Lung Tumors

Lung cancer causes more than a quarter of cancer deaths in Canada, with five-year survival rates among the lowest for commonly diagnosed cancers. Non-small cell lung cancer accounts for about 80 per cent of all lung tumours. Unfortunately, many cases are inoperable by the time they’re diagnosed, leaving chemotherapy as the main option for treatment. However, response to chemotherapy varies, and the presence of even a small number of unresponsive tumour cells can cause the disease to recur. With his second MSFHR award, Timon Buys is continuing his research on identifying genetic alterations in lung cancer tumours. He is working to identify genomic “signatures” that might predict how effective a drug will be in treating a given tumour. Using “array comparative genomic hybridization” — a technology that allows researchers to assess cancer-associated gene alterations throughout the whole human genome — Buys will characterize the genetic changes in lung tumour tissue that has been isolated from patients before and after treatment. He will use this data to determine whether mis-regulation of specific genes is associated with a patient’s response to different types of chemotherapy treatments, essentially identifying those genes that play a role in resisting drug activity. As resistance genes are identified, treatment strategies can be tailored so that they will be most effective for a specific tumor. This approach to “personalized medicine” – matching treatments to the genetic make-up of individual tumors – may greatly improve patient survival rates.

Molecular Epidemiology of Gastric and Esophageal Cancer Survival

Cancers of stomach and esophagus (the tube from the mouth to the stomach) are a major cause of illness and death. Worldwide, the incidence of tumours at the stomach-esophagus border is increasing more rapidly than any other type of cancer. Historically, gastric and esophageal cancers have been studied separately; however, recent evidence suggests these cancers have a lot in common. As a result, studying these cancers together may result in information about the origin or effective treatment of one cancer having similar implications for the other. Morteza Bashash is investigating whether certain genes are associated with the disease progression of these cancers. Specifically, he is testing whether these patients have alteration of two groups of genes that are associated with cancer progression, Matrix Metalloproteinase (MMP) and Tissue Inhibitors of Metalloproteinase (TIMP). He is monitoring newly-diagnosed patients to determine whether the progression of the disease depends on these genes or other possible determinants such as family history, and/or the patients’ ethnicity. He is also assessing whether the effects are different in geographic areas where the cancers are becoming more common (BC), and areas where the cancers are already common. The results from this research could help identify high risk patients and provide them with more effective treatment.

Mechanisms for selectivity of vascular-disrupting anti-cancer therapies

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.

Measurement error issues in studying the effect of gene-environment interactions on disease risks

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.

Epigenomic variation in normal and cancer cells

Tumour suppressor genes (TSGs) are DNA blueprints for proteins that stop cells from dividing and increasing in numbers. Each TSG comes in pairs called alleles: one from the mother and one from the father. Cancer is caused by the uncontrolled division of cells; in order for cancers to grow, both tumour suppressor alleles need to be turned off. It was previously thought that the only way to turn off genes like TSGs was through permanent changes to the normal DNA sequence, called mutations. However, another way to turn off genes is to add small chemical “tags” – called methyl groups – to a gene. This causes the DNA blueprints to fold up and become unreadable. Another complexity is that some regions of DNA that are normally folded up because of methylation become de-methylated as cancer progresses. This turns on cancer-promoting genes and increases DNA instability. Therefore, it is important to determine the DNA methylation patterns of all DNA in cancer cells in order to know what and how genes are turned on and off. Jonathan Davies previously received a Junior Graduate Studentship from MSFHR. Now funded with at Senior Graduate Studentship, he is researching techniques to identify genes and regions in normal and cancer genomes that may be turned on or off by DNA methylation. These techniques could be used to tailor treatments to individual patients, leading to improved recovery rates, and avoiding costly and ineffectual treatments.

The molecular characterization of murine hematopoietic stem cell self-renewal divisions

Every day, billions of new blood cells are produced in the human body. The origin of these cells, which are produced in the bone marrow, can be traced back to a tiny population of self-maintaining cells known as blood stem cells. Drugs used in current cancer treatments cause considerable damage to these stem cells and this can prevent more effective doses from being used for treating a number of cancers. Better ways to protect blood stem cells or to increase their numbers in a controlled fashion are needed. Additionally, many types of leukemia are known to be sustained by mutated blood stem cells. More detailed understanding of the mechanisms that regulate normal blood stem cells and how they become mutated is needed to determine how leukemia arises and how the many types of the disease can be treated more effectively. David Kent and his colleagues have recently developed a technique that allows them to isolate nearly pure populations of normal blood stem cells from the many different cell types (blood stem cells are at a frequency of between 1 in 10,000 and 1 in 15,000 cells) present in the bone marrow of adult mice. They are now able to stimulate these cells to behave differently (i.e.: to give rise to a daughter stem cell or not) in short term cell culture using different growth factors. Kent is comparing the sets of genes in these purified and differentially manipulated blood stem cell populations to identify genes that are involved in the regulation of normal blood stem cell expansion. He hopes his work will facilitate further research into the controlled expansion of stem cells and other blood cell types, and offer insight into the mechanisms by which stem cells mutate and replicate as cancer cells. He also hopes to expand fundamental knowledge of stem cells as a potential source of treatments for multiple cancers.