Dr. Jim Davie is a Professor in the Department of Biochemistry and Medical Genetics at the University of Manitoba, a Senior Scientist at the CancerCare Manitoba Research Institute, and Scientist at the Children’s Hospital Research Institute of Manitoba. He is the Secretary of the Canadian Society for Molecular Biosciences, a Fellow of the Canadian Academy of Health Sciences and the Royal Society of Canada, and a Tier 1 Canada Research Chair in Chromatin Dynamics.
Epigenetic is a term used to describe changes in gene expression that are stable between cell divisions. Chromatin modifying enzymes including lysine acetytransferases (KATs), histone deacetylases (HDACs), histone kinases, histone phosphatases, lysine/arginine methyltransferases, lysine/arginine demethylases, ATP-dependent chromatin remodeling complexes and DNA methyltransferases mediate chromatin remodeling and are components of a complex epigenetic network regulating gene expression during development, differentiation and disease. Multistep tumourigenesis is a progression of events resulting from alterations in the processing of the genetic information. These alterations result from stable genetic changes (mutations) in tumour suppressor genes and oncogenes (e.g. RAS) and potentially reversible epigenetic changes. DNA methylation and histone post-translational modifications (PTMs) are two epigenetic mechanisms that are altered in cancer cells.
Dr. Davie's research program has three research themes designed to understand the roles of epigenetic programming and nuclear structure in gene expression in normal and cancer cells:
Children’s Hospital Research Institute of MB
600A-715 McDermot Avenue, JBRC
Winnipeg, MB R3E 3P4 Canada
In maintaining integrity and homeostasis of multicellular organisms, the balance between cell death and survival is fundamentally important. When this balance is altered, diseases such as cancer occur. One protein important in the regulation of cell death is BNIP3 which is induced under low oxygen (hypoxia) conditions and is over expressed in solid tumours. This paradox of BNIP3 killing cancer cells while being over expressed in live cells within tumours is a focus of our research. Three explanations could account for these differences and act as a mechanism for cancer progression.
Cell survival is as important as cell death. The epidermal growth factor receptor (EGFR) is expressed at high levels in several cancers including breast cancer. We discovered that pretreatment of breast cancer cell lines with epidermal growth factor (EGF) effectively blocked drug and death receptor induced apoptosis. This protection from apoptosis is mediated by a serine threonine kinase (AKT) through up-regulation of the Bcl-2 anti-apoptotic family member Mcl-1. Besides breast cancer, we have found that a lipid, lysophosphatic acid (LPA) blocks apoptosis in chronic lymphocytic leukemia (CLL) cells using a similar mechanism. We are currently investigating the regulatory elements controlling Mcl-1 expression.
The goal of my research is to define the signal transduction pathways leading to cell death or survival. This will elucidate targets that could tip balance in favour of cell death and will be the foundation to establish clinical trials using molecular targeted therapies to increase effectiveness of chemotherapy in cancer.
5008b-675 McDermot Ave
Email: Dr Spencer Gibson PhD
Designing therapies slowing down or inhibiting estrogen signaling in breast cells has already saved thousands of women. Unfortunately, resistance to a specific drug can occur in some patients and alternative treatments remain needed. It appears that a combination of drugs, targeting different critical points of estrogen signaling at different times, will provide a more efficient protection and overcome the potential resistance to a single drug.
My current research aims at defining the mechanisms of action of the protein SRAP (Steroid Receptor RNA Activator Protein), product of the SRA1 gene. Several groups have explored the function of the non-coding SRA transcripts produced by this gene and demonstrated its role in activating estrogen signaling. In contrast, little is known about the function of the protein encoded by the coding SRA messengers we identified 17 years ago. We have however found that SRAP expression could be used as a prognostic and predictive factors in specific patient subgroups. We have also recently shown that SRAP controls cancer cell motility, suggesting a potential role in the mechanisms underlying invasion and metastases formation.
We hypothesize that further characterizing SRA RNA/SRAP mechanism of action will provide new windows of opportunity to design innovative therapeutic or preventive strategies to fight breast cancer.
5029 - 675 McDermot Ave
Winnipeg, MB R3E 0V9
Lab: (204) 787-2844
Fax: (204) 787-2190
Email: Dr Etienne Leygue PhD
Dr. Jassal’s research focuses on the complementary use of multimodality cardiovascular imaging in the non-invasive assessment of heart failure syndromes at St. Boniface Albrechtsen Research Centre.
Although the multifaceted treatment approach including radiotherapy, surgical resection, and chemotherapy can lead to remission in breast cancer patients, these methods can lead to harmful cardiotoxic side effects. The introduction of two chemotherapeutic agents, Doxorubicin and Trastuzumab, has led to an increase in overall survival in breast cancer; however, despite their beneficial effects in reducing tumour proliferation, these two anti-cancer drugs are associated with an increased risk of cardiotoxicity in nearly 1 in 4 women receiving this anti-cancer treatmetnt. Therefore, there is a need to further characterize this damage and mitigate its effects on cardiac health. Approximately 30% of breast cancer patients consume flaxseed in the management of their underlying disease. In addition to its ability to reduce the risk of tumour progression, this nutraceutical agent has potent cardiovascular properties. The FANTAM study is currently evaluating the cardioprotective effects of flaxseed and/or is bioactive components against Doxorubicin and Trastuzumab induced cardiotoxicity.
An increased understanding of the pathophysiology of colorectal and renal cancers has led to the development of targeted therapies, including Bevacizumab (BVZ) and Sunitinib (SNT). Despite the effectiveness of these anti-cancer agents, their use is associated with an increased risk of developing cardiotoxicity. Although heart failure medications including renin-angiotensin system (RAS) antagonists are commonly used after cardiac dysfunction is detected in the cancer setting, little is known on their prophylactic role in the prevention of BVZ and SNT mediated cardiac dysfunction. Our study is evaluating the cardioprotective effects of RAS inhibitors in the prevention of BVZ and SNT mediated cardiotoxicity.
Dr. Davinder S. Jassal
Rm. 4010, St. Boniface Hospital Research, 351 Tache, R2H 2A6
Lab Phone. (204) 237-2599
Lab Office. (204) 235-3056
Hospital Office. (204) 237-2023
I am interested in understanding mechanisms tumor cells utilize to bypass anticancer treatment in patients and use this information to develop more effective anticancer therapies. This includes testing the efficacy of novel small molecules, evaluating synthetic lethal combinations, and the use of nanotherapeutic strategies. Although I utilize mice for this research, such animal models have limitations for some human cancers, in particular brain cancer. We are employing methods to isolate brain tumor cells directly from patients and have generated an extensive brain tumor cell resource. This invaluable resource allows my translational team to test therapeutic strategies and address important questions related to gliomagenesis, stem/ progenitor cell plasticity, cellular heterogeneity within human brain tumors, survival strategies, and mechanisms of tissue invasion and metastasis of adult brain tumors. In addition, we employ brain tumor cells and patient blood samples to identify potential protein biomarker signatures and monitor immunological responses in glioblastoma patients.
Two molecular systems of great interest to me are the membrane-anchored G protein coupled relaxin receptor system and the nuclear stem cell factor High Mobility Group A2 (HMGA2) in brain and breast cancer cells. My team established a role for the relaxin receptor RXFP1 in human glioblastoma and identified a novel ligand of RXFP1 in human brain tumors. Using our established resource of isolated human glioma cells from human patients, my team was able to show a novel mechanism by which this RXFP1 receptor system mediates chemoresistance to temozolomide in patient brain tumor cells. My research on the chromatin-binding protein HMGA2 has revealed important roles of this stem cell factor in human patient glioblastoma cells. We showed that HMGA2 is a base excision repair (BER) enzyme and protects replication forks and telomeres. We also demonstrated that HMGA2 alters the activation state of the ATR-CHK1 DNA repair signaling which protects GB cells from apoptosis upon exposure to DNA alkylating agents like temozolomide. Currently, we study the interaction of HMGA2 with key proteins involved in cell survival and investigate proteins and pathways we identified as synthetic lethal with HMGA2. Collectively, our results suggest that the RXFP1 receptor system and HMGA2 exert novel protective mechanisms at different cellular levels which collectively result in enhanced chemoresistance in cancer cells. Our ongoing research addresses two main goals: (i) identify protein signatures from patient blood samples that can indicate the presence of glioblastoma and (ii) use sophisticated basic science strategies to inform the development of more efficacious treatment options for cancer patients.
Dr. Thomas Klonisch
Professor & Head
Dept. of Human Anatomy and Cell Science
Director of the Histomorphology and Ultrastructural Imaging Platform
Director of the Glioma Cell Resource
Depts. of Surgery, Medical Microbiology & Infectious Diseases
Adjunct Scientist, CancerCare Manitoba
Honorary Professor of Shantou University Medical College, Shantou, China
Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba
133-745 Bannatyne Avenue, Winnipeg, Manitoba, Canada, R3E 0J9
Phone: +1 204 789 3893
Fax: +1 204 789 3920
Julian Kim is a radiation oncologist at CancerCare Manitoba, and an Assistant Professor of Radiology in the Rady Faculty of Health Sciences at the University of Manitoba.
Dr. Kim is leading a study assessing a technique to diagnose non-small cell lung cancer using blood samples in order to speed up the diagnosis and treatment of non-small cell lung cancer. The diagnostic tests currently used to identify specific types of lung cancer from tumour biopsies can often take a month or longer. Since lung cancer often presents at a late stage and can grow quickly, timely diagnosis is imperative in order to initiate treatment prior to the disease spreading in the body. Dr. Kim is using an artificial intelligence technique called machine learning to analyze blood samples from Manitoba lung cancer patients to search for metabolomic signatures or patterns that identify lung cancer, which would speed up diagnosis and allow treatment to begin sooner. This study is funded by the Canadian Institutes for Health Research and the CancerCare Manitoba Foundation.
Dr. Kim is also leading a Phase II randomized clinical trial (The PREMIUM Trial) testing a common diabetes medication (Metformin) that has the potential to reduce unwanted side effects experienced by men with prostate cancer who are treated with androgen deprivation therapy (ADT) and radiotherapy. ADT causes many prostate cancer patients to gain weight, which can lead to elevated blood pressure, blood sugar, and cholesterol. Metabolic syndrome occurs when all of these conditions occur together. Metabolic syndrome increases the risk of heart disease, stroke, and diabetes, so this study has the potential to reduce these other health risks for men with prostate cancer. This study is funded by the CancerCare Manitoba Foundation and the Alberta Cancer Foundation.
Dr. Kim is also a co-principal investigator of a joint clinical study with the Mayo Clinic (The GENRE Study) which is examining the impact of a new genetic test that predicts a women’s risk of developing breast cancer. The study’s goal is to determine if women who learn they are at high risk of breast cancer are subsequently more inclined to take Tamoxifen and other drugs that reduce their risk of getting breast cancer.
1) Julian Kim, Charles Butts, Wilson Roa et al. Dose-escalated Hypofractionated Intensity-Modulated Radiation Therapy With Concurrent Chemotherapy For Inoperable or Unresectable Non-Small Cell Lung Cancer. American Journal of Clinical Oncology. Vol 40(3), June 2017.
2) Julian Kim, Faith Davis, Charles Butts, Marcy Winget. Waiting Time Intervals for Non-Small Cell Lung Cancer Diagnosis and Treatment in Alberta: Quantification of Intervals and Identification of Risk Factors Associated with Delays. Clinical Oncology. Vol 28 (16), Dec 2016.
3) Rene Razzak, Eric Bedard, Julian Kim, et al. MicroRNA expression profiling of sputum for the detection of early and locally advanced non-small cell lung cancer: a prospective case-control study. Current Oncology, Vol 23, No 2, April 2016.
4) Julian Kim, Sayf Gazala, Eric Bedard et al. Non-Small Cell Lung Cancer Detection Using MicroRNA Expression Profiling of Bronchoalveolar Lavage Fluids and Sputum. Anticancer Research. Vol 35, No 4, April 2015
5) Julian Kim, Roy Ma, et al. Long-Term Outcomes of Fractionated Stereotactic Radiotherapy (FSRT) For Pituitary Adenomas at the BC Cancer Agency (BCCA). International Journal of Radiation, Biology, Physics, Vol 87, No 3, Nov 2013.
One area of research in my laboratory is the study of programmed cell death or apoptosis, a form of cell suicide. As a result of genetic changes, cancer cells have a reduced or slowed ability to undergo apoptosis, which can also make tumour cells more resistant to anti-cancer drug treatment. To better understand programmed cell death, we have taken a genetic approach. Several mutant cell lines have been isolated that are defective in apoptosis. This was done by using a specially constructed virus that, after it infects a cell, integrates into genes and interferes with their function. After selection for drug resistant cells, the underlying genes disrupted by the virus are studied for their role in programmed cell death and drug resistance. By understanding the genetic basis of resistance to cell death, completely new treatments can be devised.
A gene that came out of these screens was the Dlc-2 (Deleted in liver cancer two) tumour suppressor gene. We are now studying the role this gene plays, along with the closely related Dlc-1 gene, in tumour cell progression and drug response. The Dlc-1 gene is found deleted in over 50 percent of breast, lung, liver and colon cancers. Also, the other normal copy of the gene is frequently silenced by promoter methylation. To study the role these genes play in the body, we have developed conditional knockout mouse models. With these mouse models, we can study the role the Dlc genes play in lung, and breast cancer spread through the body and anti-cancer drug response.
5022-675 McDermot Ave
Winnipeg, Mb R3E 0V9
Email: Dr Michael Mowat PhD
Since estrogen is a major driver of human breast cancer, and the action of estrogen changes during breast tumourigenesis and breast cancer progression, the overall aim of my research program is to elucidate the mechanisms by which estrogen action changes during the development of breast cancer and how breast cancers develop resistance to endocrine therapies and progress from hormone dependence to independence. To do this my group is identifying the molecular players involved in the estrogen receptor signaling pathways in human breast tissues, how they are altered during tumourigenesis, and breast cancer progression to hormone independence.
We are specifically determining the types and putative function of estrogen receptor isoforms, i.e. estrogen receptor alpha and beta and its phosphorylated forms, that are expressed in human breast tissues in vivo, using tissues obtained from the Manitoba Breast Tumour Bank/Clinical Database. We have identified a phosphorylation profile of estrogen receptor alpha with prognostic significance. The kinases that are involved in regulating the estrogen receptor alpha phosphorylation score in vivo are now being studied as potential therapy targets. Estrogen and androgen signaling may have a role in some lung cancers so in collaboration with Drs Marshall Pitz, Shantanu Banerji, Sri Navaratnam and Gefei Qing, we are developing human lung cancer tissue microarrays and associated clinical information to explore the molecular players involved in the estrogen and androgen signaling pathways in lung tissue and relationship to clinical outcome.
In collaboration with Dr Peter Watson and the Manitoba Tumour Bank, we are also investigating tissue collection issues that may affect detection of various gene products in banked tissues. Through the Manitoba Tumour Bank, we are contributing to genomic, proteomic and metabolomic cancer studies locally, nationally and internationally.
Research Institute in Oncology and Hematology
6020-675 McDermot Ave
Winnipeg, Mb R3E 0V9
Email: Dr Leigh Murphy PhD
My long term research program is based on identifying breast/breast cancer specific biomarkers and understanding the biological role of these markers in the progression of breast cancer from a localized disease to metastases. Our research efforts over the last few years have been focused on two molecules, claudin 1, and the human prolactin inducible protein/gross cystic disease fluid protein, PIP/GCDFP-15.
PIP/GCDFP-15 is an established biomarker for abnormal breast function. PIP/GCDFP-15 is abundantly found in the fluid of benign cysts of the breast and its gene expression has been detected in more than 90% of breast cancers. Currently, its role in breast cancer as well as in normal breast development is presently not known. Our laboratory generated the first transgenic and knockout mouse models to address the function of this protein. Recent studies from our laboratory show that the role of the PIP/GCDFP-15 protein is multifunctional and may have an immunomodulatory role.
We are studying the role of the tight junction protein, claudin 1, in breast cancer progression and metastasis. Tight junction proteins are localized in the membrane of epithelial cells, including mammary epithelial cells, the milk secreting cells of the breast. Most breast cancers develop from this cell type. Tight junction proteins are important for cell-cell interactions, regulating the transport of ions and nutrients between these cells. The breakdown of cell-cell interaction and a loss of tight junction proteins have long been associated with the progression of several cancers. However, such an involvement of claudin 1 in breast cancer has not been delineated. We are focusing on in vitro and in vivo approaches to address this question, as well as examining relationships between claudin 1 expression and tumour aggressiveness and patient survival in human invasive breast cancer cohorts.
University of Manitoba Department of Pathology
P228E Pathology Building
770 Bannatyne Ave Winnipeg, Mb R3E 0W3
Email: Dr Yvonne Myal PhD
Dr. Stephen Pistorius is a Senior Scientist at the Research Institute for Oncology and Hematology (RIOH). He serves as the Director of the Medical Physics Graduate Program and the Vice Director of the Biomedical Engineering Program at the University of Manitoba where he is a Professor of Physics and Astronomy and Associate Professor of Radiology. He served as the President (2006-2008) of the Canadian Organization of Medical Physics (COMP) and is currently the President of the Canadian Association of Physicists (CAP). He is a certified Medical Physicist, a licensed Professional Physicist (P.Phys.), a senior member of the IEEE, and a Fellow of the Canadian Organization of Medical Physics (FCOMP).
Prof. Pistorius is interested in improving, optimizing and quantifying various diagnostic and therapeutic techniques and in understanding the radiation transport of clinically useful imaging and treatment modalities. He supervises numerous graduate and undergraduate students carrying out research in cancer imaging, specifically, in developing improved systems for cancer diagnosis which use scatter enhanced x- and g-ray techniques and microwaves; as well as on-line megavoltage portal imaging, aimed at real time in-vivo tracking of motion and optimization of complex radiotherapy treatments and in the use of artificial intelligence to help analyze images and to detect and classify tumors. The author of over 200 publications and presentations, he has received over $4.5M in grant funding in the last 5 years, is a Fellow of COMP, and he and his students have received numerous national and international awards for their research. Students interested in research in any of the above areas are welcome to contact him.
Dr. Marshall Pitz is the Section Head of Clinical Research at the Research Institute at CancerCare Manitoba (CCMB). He conducts clinical research on brain, breast, and lung cancers, as well as health services research on the use of information technology in the delivery of cancer care. Dr. Pitz is also a medical oncologist at CCMB where he treats patients with brain and breast cancers; an Associate Professor of Medicine in the University of Manitoba’s Rady Faculty of Health Sciences; and CCMB’s Chief Medical Information Officer responsible for the clinical use of the electronic medical record.
Dr. Pitz leads a research team testing an advanced type of magnetic resonance imaging (MRI) to improve the treatment of patients with glioblastoma, the most aggressive type of brain cancer. Conventional MRIs cannot reliably distinguish brain tumour progression from a phenomenon called pseudo-progression, which may be brain tissue inflammation that is a positive response to treatment. If the advanced MRI technique is more effective at distinguishing true tumour progression from pseudo-progression, it will allow Dr. Pitz and other oncologists to identify patients who require additional treatments, and spare other patients from aggressive (and potentially harmful) surgeries and/or chemotherapy they are unlikely to benefit from.
Dr. Pitz is a member of a multi-disciplinary research team evaluating physical therapy and acupuncture as treatments for a disabling side effect of chemotherapy (peripheral neuropathy) in breast cancer patients.
Using tissue specimens from the Manitoba Tumour Bank, Dr. Pitz led a research team that examined how androgens (steroid hormones) may affect the treatment outcomes of patients with non-small cell lung cancer, the most common type of lung cancer.
Dr. Pitz has published over 25 peer-reviewed papers since 2002, including one of the most frequently cited 2014-2018 papers with a Research Institute scientist as its lead author.
Phone: (204) 787-2197
It is becoming clear that progress in treating breast cancer effectively requires a better understanding of the cells that generate and maintain breast tumours (cancer stem cells) and how they are abnormal patients. Accumulating evidence suggests that breast cancer tumours are maintained by a rare subset of cells that have stem cell properties, indicating that new therapies are needed to eliminate them to achieve more effective treatments with decreased chance of tumour recurrence. This concept reinforces the hypothesis that normal stem and progenitor cells are important cellular targets in the initiation and recurrence of human breast cancer. Indeed, mutations arising in stem cells could represent an efficient process for hijacking the regulated proliferation and differentiation of primitive normal mammary cells.
My research program has 3 objectives:
Toward accomplishing this objective we have developed techniques to isolate highly purified populations of stem cells and distinct progenitors from breast tissue to examine the specific roles of breast oncogenes such as the NOTCH receptors and non-coding RNA such as H19 and Insulin-like growth factor binding protein 7 (IGFBP7) in regulating the biology and function of these rare cells in health and in disease (i.e. breast cancer).
Basic Medical Science Building
613-745 Bannatyne Avenue
Winnipeg, MB, Canada
Office number 204-975-7704
Lab number 204-975-7703
Email: Dr Afshin Raouf PhD