Close to 5,000 Canadians are diagnosed with pancreatic cancer every year and it is the fourth most common cause of cancer-related deaths in Canada. Unfortunately, a majority of these patients die within a year of their diagnosis, due in part to late diagnosis and tumour resistance to chemotherapy. In addition, most patients who are successfully treated eventually recur and succumb to the disease.
There is a need for reliable blood tests for more routine diagnosis, monitoring treatment response, and detecting tumour recurrence in pancreatic cancer patients. We seek to develop such tests using cell-free DNA in the blood. Mutant forms of cell-free DNA that originate from tumours can be detected in the blood of patients with pancreatic cancer, and this project will explore how we can use it to:
- Diagnose pancreatic cancer earlier
- Detect cancer recurrence earlier
- Identify patients whose tumours do not respond to chemotherapy in order to help guide treatment decisions
We will collect blood from patients who have undergone surgical removal of pancreatic cancers and follow their progress over two years to examine whether we can detect cancer recurrence by monitoring the presence of mutant cell-free DNA after surgery. We will also collect blood from patients with advanced stage pancreatic cancer who are undergoing treatment to explore whether changes in mutant cell-free DNA levels predict whether their tumours respond to chemotherapy.
In these ways, a non-invasive blood test will help to improve quality of life and optimize treatment for thousands of Canadians diagnosed with pancreatic cancer.
Michael Smith Foundation for Health Research/BC Cancer Foundation Post-Doctoral Fellowship Award
High-grade serous ovarian cancers (HGS) have a low five year survival rates at less than 40 percent. This is partly because of high relapse rates due to resistance to platinum-based therapies, which is the current standard of treatment. Although these therapies are effective at treating the primary tumour, cancers develop resistance to platinum drugs in almost all instances and the tumours recur.
How genomic instabilities evolve in HGS tumours and lead to platinum-resistance is poorly understood, and there are currently no biomarkers that give a reliable prognosis. We seek to identify effective genomic biomarkers for determining which HGS patients will respond more effectively to platinum-based chemotherapy.
This project will build on our research group's recent observations of differences in global genomic patterns between platinum-sensitive and platinum-resistant groups. We will analyze an HGS cohort of seventy cases composed of short- and long-term survivors with five year clinical follow-up data by:
- Comparing and contrasting the entire DNA sequence of tumours to the patient's normal DNA to identify global patterns of genomic instability
- Comparing and contrasting genomic profiles from the whole genome of the short-term and long-term survivors
- Studying diversity via deep-sequencing data of the tumours.
Ultimately, the results of this project and future work could allow for a long-term prognosis and optimized treatments for patients with HGS ovarian cancer.
Human cells experience DNA damage every day, but DNA repair systems ensure that resulting mutation rates are extremely low. Two main pathways repair severe DNA damage in cells. The 'copying' pathway connects broken DNA ends by copying the missing sequence from the second DNA copy that is present before cells divide. The 're-joining' pathway simply re-joins the broken DNA ends irrespective of the missing sequence. Mutations in these pathways are frequently found in cancer cells, which can accumulate thousands of mutations.
Recent studies show that tumours with mutations that inactivate the copying pathway can be effectively treated with drugs that inhibit the re-joining pathway. After drug treatment, both repair pathways are impaired in tumour cells, whereas normal cells still retain one functional pathway. As a result, doses can be adjusted so that side effects of chemotherapy are milder.
A protein named CDK12 appears to be a regulator of the copying pathway, and cells with abnormal CDK12 are sensitive to drugs that inhibit the re-joining pathway. Mutations in CDK12 have been found in many tumour types. Our preliminary results show that CDK12 regulates an essential cellular process termed 'alternative splicing,' where gene segments are assembled in different orders to create different versions of the same gene.
We will examine how CDK12 changes the alternative splicing of genes after DNA damage, and how this regulation is impaired by mutations in CDK12 that have been found in tumours. Ultimately, this work could lead to new research tools and help to define the population of cancers that can be treated with CDK12-based therapy.
Lymphomas are a group of cancers derived from white blood cells. This project focuses on how some lymphomas carry mutations that render the immune system unable to recognize and destroy them.
We have recently described a gene named CIITA that is mutated in certain lymphomas. CIITA plays a major role in regulating the production of proteins on the surface of cells that allow cells of the immune system to recognize them. Mutations in CIITA can lead to a reduction in these proteins so the cancerous cells are not controlled by the immune system.
We will use DNA sequencing to explore genetic changes within CIITA in a large number of tumour samples from lymphoma patients. We will compare these genetic findings with the clinical data from the patients and look for survival trends. We will also use cell lines and mouse models to investigate the impact of CIITA mutations on tumour biology.
Ultimately, we hope to unveil novel mechanisms that will help build the foundation for the development of new diagnostic tests and/or therapeutic strategies.
Ovarian cancer is the most lethal cancer of the female reproductive system and the fifth leading cause of cancer-related death in Canadian women. Ovarian cancer is not one disease, but rather comprises several tumour types that likely develop through unique mechanisms from different cell types. Previous research suggests two types of ovarian cancer — clear cell carcinoma (CCC) and endometrioid carcinoma (EC) — may develop from ovarian endometriosis, a condition associated with increased inflammation. Dr. Alicia Tone is investigating how endometriosis-associated inflammation can influence the development of CCC and EC by looking at the specific role that the ARID1A gene plays in inflammation. ARID1A has been shown to increase the activity of the glucocorticoid receptor, which plays a crucial role in reducing the duration and intensity of an inflammatory response. In addition, the ARID1A gene was recently found to be mutated in both CCC/EC, and the mutated gene is associated with endometriosis lesions. Dr. Tone intends to 1) identify which specific inflammatory genes are altered in CCC/EC cells and associated endometriosis; 2) compare the response of cells obtained from endometriosis and CCC specimens with and without mutations in the ARID1A gene; and 3) determine the mechanism by which ARID1A regulates the response to inflammatory mediators. This study will help our understanding of how endometriosis may develop into ovarian cancer (CCC and EC); more importantly, pointing to the development of new preventive strategies. Research aimed at understanding what is involved in the early stages of development of these different cancers may reduce the number of deaths associated with ovarian cancer.
Circulating T-cells are the key players in our adaptive immune system and are particularly important for recognizing and killing cells that are infected with viruses or carry cancer-causing mutations. T-cells have the ability to potentially recognize vast numbers of different infectious agents and cancer- or tumour-associated mutations. The T-cell receptor, on the surface of the T-cell, is responsible for this task, and the variation required for recognition is generated mainly by shuffling the large number of short DNA segments that comprise T-cell receptor genes. Although the central importance of the T-cell receptor in adaptive immunity is well established, the actual number and diversity of T-cells that exist in an individual (i.e. the T-cell repertoire), how this changes in response to immune challenge, and how it varies from one individual to the next, remains a mystery. Dr. Rob Holt’s lab is using the latest DNA sequencing technologies to directly sequence T-cell receptor genes in order to examine the T-cell repertoire in a given blood sample. Using this approach, the lab has identified populations of unique T-cell repertoires in bone marrow stem cell transplant patients and in colorectal cancer patients. Dr. Kristoffer Palma’s research project is to take this approach one step further by developing a novel, high-throughput screen for the molecular patterns (antigens) recognized by donor T-cells and to find out how these are related to transplant success in bone marrow transplants. The second application of his research is to determine if there are T-cell receptor commonalities in patients with colorectal cancer tumours, how T-cell receptor commonalities relate to disease prognosis, and what tumour-associated antigens may be recognized by T-cells in patients with high survival rates. In the case of bone marrow transplants, Palma anticipates that his research will lead towards the earlier diagnosis and intervention in graft versus host disease, which is the most immediate and life-threatening complication of bone marrow transplant, affecting 30 to 80 per cent of patients. With regard to colorectal cancer, Palma hopes his research will contribute to the creation of a high-resolution diagnostic screening test to identify early stage cancer that would be undetectable with current assays and aid in the eventual development of cancer-specific vaccines.
Myelodysplastic syndrome (MDS) is one of the most frequent bone marrow malignancies, affecting around 1,500 Canadians every year. It is characterized by anemia and a high risk of transformation to acute myeloid leukemia (AML). The only curative option is bone marrow transplantation, which carries high mortality and morbidity. Other standard treatment modalities such as lenalidomide and 5-azacytidine are characterized by a short response and a high degree of relapse. The molecular causes of treatment resistance and disease transformation in this situation are not fully understood. Dr. Martin Jadersten aims to investigate the genetic changes associated with initiation of MDS and understand how these changes contribute to subsequent therapy failure or disease progression. He will investigate serial samples from 10 MDS patients before and after leukemic transformation. RNA and DNA will be extracted from bone marrow cells and marrow fibroblasts (non-malignant control cells), and global genetic investigations such as exome (DNA), transcriptome (RNA) and micro RNA (regulatory RNA) sequencing will be conducted. Powerful bioinformatics methods will be used to analyze the data and identify genomic alterations, including gene fusions, DNA insertions/deletions, and alternative expressions of genes (isoforms). These identified genetic alterations will be validated for recurrence in a large group of MDS patients, and candidate genes will be tested functionally with cell line experiments and mouse models. Dr. Jadersten’s work is already well underway. He has processed three samples from one MDS patient with all of the methods above and has shown that there are significant changes in micro-RNA expression between these time points. As the disease has progressed in this patient, a number of alternatively expressed genes appear, which potentially indicates alterations in the RNA-splicing machinery. By the time the patient develops AML, there is almost a complete loss of two clusters of important regulatory genes involved in embryogenesis and cancer. As this patient sequentially received the only two registered drugs for MDS (lenalidomide and 5-azacytidine), Dr. Jadersten will attempt to determine potential resistance mechanisms using the data already obtained. Identification of key mediators of disease development, leukemic transformation and drug resistance may sharpen our prognostic tools, improve clinical management and provide a basis for development of targeted therapy.
The traditional view of cancer is that tumours are composed of identical cells, and thus the goal of treatment is to kill every one of those cancer cells in the body. In a tumour, it is estimated that a very small fraction of cells (perhaps 1 in 10,000) are ""cancer stem cells"", which are the cells that have the capacity to self-renew or to create progeny that carry the same properties as the parent cell. A new cancer treatment theory hypothesizes that to treat cancer, the only cells that need to be killed off are these cancer stem cells, and once they are gone the rest of the tumour should regress on its own. The challenge becomes to first identify the cancer stem cells and then design a drug that would specifically kill those cancer stem cells only. Dr. Vincenzo Giambra's lab has recently shown that cancer stem cells exist in a particular type of blood cancer called T-cell acute lymphoblastic leukemia (T-ALL). Although T-ALL is not a common form of cancer, it is unique in that more than 50 per cent of cases carry mutations that inappropriately activate a gene called Notch1, which plays an important role in normal stem cell maintenance. Dr. Giambra's research objectives are to identify how cancer stem cells are able to evade the immune system and thrive in T-ALL, and to design a drug that specifically kills those cancer stem cells. He will be isolating cancer stem cells from a unique mouse model that has Notch1-induced T-ALL, using specific molecules on the surface of cancer stem cells. He will also compare leukemias generated from mice of different ages to see if they express different genes, with the goal of using this information to design new drugs that may help to cure more patients with leukemia. These studies will allow Dr. Giambra to define the genetic programs and pathways that are responsible for conferring self-renewal upon the leukemia stem cells; they will also provide rationale for the design of new therapies that specifically target the stem cells. In focusing his efforts toward killing only the cancer stem cells, Dr. Giambra expects these therapies will be more effective for achieving a cure and less toxic to the patient. Finally, he anticipates that some of the genetic programs and pathways he will identify will be critical for self-renewal of Notch T-ALL stem cells and may be important for self-renewal of all cancer stem cells in general. Thus, these results may prove useful to investigators studying other cancers as well.
The billions of cells in your body share the same DNA sequence and yet display a vast array of morphologies and functions. Understanding how this same genetic material is interpreted in diverse cell types remains a challenge. Epigenetic modifications are those that change how DNA is expressed without altering the genome sequence. For example, chemical modification of histones, the proteins that bind DNA into the large chromosome structures, can influence how genes are expressed.
In a related process, DNA itself can become methylated, which is typically thought to be a gene-silencing signal. Understanding how epigenetic modification influences gene expression has significant therapeutic potential and may provide us with insights into how we can disrupt abnormal cell divisions in cancer or promote self-renewal in stem cells for clinical use in repairing damaged or diseased tissue.
Dr. Cydney Nielsen aims to characterize epigenetic changes of stem cells, from which all other cells in the body arise. Stem cells can either self-renew to form identical daughter cells or can divide and differentiate into specialized cell types. Dr. Nielsen will use next-generation sequencing technologies and develop new data analysis techniques to examine the epigenetic changes and determine gene expression patterns in stem cells before and after differentiation.
Using these data sets, she will determine if characteristic epigenetic modification patterns exist for self-renewing cells. She will also use this information to determine if certain therapeutics are able to induce self-renewal in stem cells, to determine what the epigenetic changes are in this case, and if this ''reprogramming'' of cellular state opens up promising therapeutic applications. Such an approach will be valuable in evaluating the extent to which chemically induced cells have been reprogrammed and are appropriate for therapeutic use for regenerative medicine.
The genome of each cell within an organism contains hereditary information. Among other features, the genome contains genes – DNA sequences that specify the genetic code (encode) for functional products such as proteins. The product of a gene is produced when the gene is turned on (expressed). The process of turning certain genes on or off is governed by regulatory proteins called transcription factors (TFs). While cells of different tissues within an organism contain the same genome, their function may be different due to the fact that they express different genes. While in simpler organisms gene expression is regulated by individual TFs, in more complex organisms such as mammals, several TFs may work together to control the expression of a gene. Many complex diseases such as cancer are at least partially due to improper expression of certain genes. Understanding how gene expression is regulated in an organism, including identifying what TFs work together to regulate particular genes, is instrumental to understanding the biology of numerous health conditions. Olena Morozova is working as part of a large research project aimed at identifying genetic networks governing development. Using the mouse as a model system to study the regulation of gene expression, she is focusing on how different TFs interact to regulate the development of mouse pancreas, heart, and liver, and how these interactions can be used to identify master regulators and the main control nodes in the development of these organs. Overall, this project will provide invaluable insights into mammalian gene regulation and will ultimately help to understand the biology of diseases resulting from errors in the regulation of gene expression. The identified TFs that work together with many other TFs are potentially useful targets for effective disease therapy.
