Research Location: BC Cancer Research Centre

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.

Sarcomas are an aggressive type of childhood cancer arising from bone or soft tissue. Despite advances in cancer treatment, sarcomas remain a deadly disease because of their tendency to spread throughout the body (metastasis). Following cancer surgery to remove a malignancy, remnant sarcoma cells are often able to remain dormant in the body for months or years, in spite of efforts to eradicate them with chemotherapy. When such therapies are ineffective, these hibernating cells may revive and regrow as deadly metastases. Under laboratory conditions, cultured cancer cells are able to survive for long periods in the form of multi-cellular clusters called “”spheroids””. Interestingly, these spheroids also appear to enter a hibernation state, with cancer cells trading away their ability to grow rapidly in favour of the ability to survive for long periods. The cells use their “oncogenes” to suppress the expression of their growth-promoting genes, despite the fact that oncogenes are normally known for their cancer-promoting properties. It is believed that cancer cells and their oncogenes target a new set of genes to drive this hibernation. Tony Ng is screening all human genes for ones important in maintaining this hibernation. Using a technique called gene expression profiling, he will determine which genes become more active when cancer cells hibernate. He is also studying two genes, TXNIP and YB-1, which appear to be important for spheroid survival and dormancy. Laboratory results will be validated using clinical samples of dormant tumour cells from childhood cancers. Ng hopes that the genes identified in these studies will become the basis of chemotherapies to specifically kill these hibernating cells, resulting in therapies that are more effective and less toxic to patients.

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.

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.

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.

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.

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.