Population-Based Genetic Studies of Cancer and Healthy Aging

The number of elderly Canadians is increasing as the baby boomers age. Insight into how to promote healthy aging, coupled with advice that can be provided to our population as it ages, will influence Canada’s healthcare costs, as well as the quality of life of a large segment of our population. Cancer and aging are intimately connected. Cancer incidence rises with age, and this increase accelerates dramatically over 60 years of age. Cancer and other aging-associated diseases like cardiovascular disease are thought to result from the interaction of numerous genetic and environmental or lifestyle factors. Population-based studies that use large groups of affected and unaffected individuals are now the preferred method to study the genetics of complex diseases. This program has clinical relevance and involves close collaboration with clinical experts to study healthy aging and two specific cancers, non-Hodgkin lymphoma and cervical cancer. The overall objective is to discover genetic factors that contribute to susceptibility to cancer or confer long-term good health. The program will use state-of-the-art genetic analysis methods, and over the next 5 years will expand these projects and add additional types of cancer. This coordinated study of cancer and healthy aging is a unique and innovative approach by which we will increase our understanding of the connection between cancer and aging and benefit from new knowledge regarding the basis of common aging-associated diseases like cancer. This research will lead to development of clinically useful markers that will help individuals avoid developing diseases as they age.

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.

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.

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.

Targeting Lung Cancer Genomics: A Whole Genome Approach to Predicting Drug Response

Lung cancer is the leading cause of cancer death worldwide, with five-year survival rates among the lowest for commonly diagnosed cancers. The high mortality rate is partially due to the lack of effective treatment options since surgery and chemotherapy are common options, yet non-curative. The epidermal growth factor receptor (EGFR) gene is overexpressed in a majority of lung cancers. Researchers recently discovered a new drug designed to target the product of this gene. Although the drug didn’t benefit the majority of patients, a positive response was often seen in non-smoking women of Asian descent. At the BC Cancer Research Centre, Trevor Pugh is researching why this drug works for this subgroup and not for other patients. Using tumour samples and patient outcomes data, he is searching across the entire genome to pinpoint specific genetic features shared by drug-responsive tumours in patients with lung cancer. Ultimately, his work could result in improved diagnostic tests for predicting who will benefit from specific therapies, and new candidates for gene-targeted cancer drugs.

The endothelium: Function and dysfunction

The interior lining of blood vessels is known as the endothelium. Endothelial cells, which make up this inside layer of all blood vessels, are remarkably responsive to changes that occur in the blood and tissues, both under normal conditions and in disease states, sending signals back to the blood and tissues to organize a response. Endothelial cells initiate and direct the growth of new blood vessels within a tissue that is not receiving a sufficient supply of oxygen and nutrients. This growth of new blood vessels can be either beneficial or detrimental to a person’s health. When blocked blood vessels are contributing to the lack of sufficient blood supply (e.g. hardening of the arteries or diabetes), the body’s creation of new blood vessels can prevent tissue damage and promote healing. However, new blood vessels also required for cancer growth by providing the tumour with the oxygen and nutrients it needs. Dr. Aly Karsan is studying several molecules on the surface of endothelial cells to determine how they regulate the growth of new blood vessels. With greater knowledge about the molecular processes underpinning blood vessel growth, he hopes to identify new ways to either promote or restrict these processes to combat a variety of diseases.

Priority setting methods for cancer control and care

Priority setting is the focus of health economics—a branch of economics concerned with issues related to the scarcity of health care resources. With cancer expected to be Canada’s primary cause of death by 2010, priority setting in cancer control and care is imperative. An aging population, rising health care costs and increasing demand have resulted in the need for identifying effective and cost-effective ways to improve cancer patient outcomes. Basing his work on an internationally-recognized economic framework for priority setting (called Program Budgeting and Marginal Analysis), Dr. Stuart Peacock is developing new evidence-based methods to help health care decision-makers determine the most effective cancer interventions to fund. His research will develop three significant innovations within this framework: methods to address improvements in life expectancy and quality of life from health programs; methods to address community preferences and equity concerns; and measures to evaluate priority setting and evidence-based decision-making. Dr. Peacock’s goal is to develop an evidence-based framework for decision-making in cancer services that is transparent, explicit and accountable.