Interdisciplinary
Oncology Program
Leukemias and Lymphomas
Dr. Angie Brooks-Wilson
Dr. Brooks-Wilson leads a cancer genetics research laboratory at the Genome Sciences Centre of the British Columbia Cancer Agency here in Vancouver, BC. Her current work focuses on the genetics of healthy aging and the genetics of susceptibility to cancer, particularly lymphoid cancers, in families and populations. She leads the Healthy Aging Study in which exceptionally healthy elderly individuals (‘Super-Seniors’) are helping to determine the genetic influences that contribute to healthy aging and protect against age-related diseases.
Admin Email: vzhu@bcgsc.ca
Dr. Connie Eaves
Experiments in this laboratory and elsewhere have established the existence in adults (both mouse and man) of primitive hematopoietic stem cells capable of permanently reconstituting the production of mature blood cells in marrow-ablated or suppressed recipients. A major part of our work continues to focus on the development, validation and use of quantitative assays that are specific for biologically distinct subsets of these stem cells using syngeneic (mouse-mouse) and xenogeneic (human-mouse) hosts. We have also identified a developmental “switch” that alters stem cell proliferation and self-renewal control in the post-natal period. We are now trying to elucidate the molecular mechanisms underlying each of these causes of variable stem cell behavior using defined culture systems, gene transfer strategies, and genome-wide gene expression analyses. We have pioneered the development of quantitative assays for normal mouse and human breast epithelial stem cells and these are being used to identify their distinguishing features and growth regulation. Studies to adapt these methods for application to human breast cancer are underway. The objective is to provide a basis for analyzing molecular and genetic determinants of breast cancer at the level of the breast cancer stem cell and thereby develop more rational, patient-targeted therapies.
Admin Email: atoner@bccrc.ca
Dr. Alina Gerrie
Dr. Alina Gerrie is a hematologist and Assistant Professor in the Divisions of Hematology and Medical Oncology at the University of British Columbia (UBC) and a Clinician Investigator at the Centre for Lymphoid Cancer at BC Cancer. Dr. Gerrie is involved in translational, clinical trial and outcomes-based research related to leukemia and lymphoma. Other academic interests include the investigation of novel therapeutics and stem cell transplant for chronic lymphocytic leukemia (CLL) and lymphoma and improving long-term outcomes for lymphoma and stem cell transplant survivors. Dr. Gerrie currently holds a Michael Smith Health Research Investigator Award and grant funding through the Mitacs Accelerate Program and Cancer Research Society to investigate the impact of genetic abnormalities on population-level outcomes in chronic lymphocytic leukemia (CLL) patients. She is a co-investigator on a Genome Canada Large-Scale Applied Research Project (LSARP) to advance personalized treatments of lymphoid cancer patients in collaboration with Drs. Christian Steidl and David Scott, and is a collaborator on a number of CIHR grants and industry-sponsored clinical trials.
Dr. Kevin Hay
My research focuses on preclinical development, bench-to-bedside translation, and clinical evaluation of novel cellular immunotherapeutic approaches, with an expertise in chimeric antigen receptor (CAR-)T cell therapy. A CAR is comprised of an extracellular antigen recognition domain linked to intracellular T cell signaling domains, which after introduction into the T cell enables T cell activation upon encounter with the target antigen. Clinical trials of CAR-T cells targeting CD19 have demonstrated impressive results in the treatment of patients with relapsed/refractory B-cell malignancies such acute lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma, and chronic lymphocytic leukemia (CLL), with response rate >80% for some cancers, highlighting the promise and feasibility of this cellular therapeutic approach.
My laboratory aims to: (a) develop CAR-T cells targeting other malignancies, such as myeloma, and (b) modify CAR-T cells so as to improve efficacy and decrease toxicity. We are exploring multi-antigen targeting approaches, modifications to the CAR construct, and different approaches to T cell manufacturing. My clinical research with the Leukemia/BMT Program of BC focuses on the development of a CAR-T program in BC and involvement in clinical trials of CAR-T cell therapy.
Dr. Rob Holt
The Holt Lab uses cutting edge tools and methodologies to investigate the biology of cancer from several different angles. Focusing on the immune system, the group has used deep sequencing to survey T cell repertoire diversity at the resolution of individual clonotypes and are now using these methodologies to explore the role of T cells in cancer. They are also working to develop cancer immunotherapies using engineered T cells to selectively deliver cytotoxic payloads to bolster the anti-cancer immune response and to enhance tumour cell killing. The group employs their expertise in DNA sequencing and computational analyses to investigate the role of infectious agents in cancer development and were the first to demonstrate a strong link between the pathogen Fusobacterium nucleatum and colorectal cancer. Finally, they apply deep sequencing technologies to identify the spectrum of mutations in various cancer types, with a particular focus on tumour evolution and the identification of antigens for cancer vaccines.
Dr. Xiaoyan Jiang
The overall goal of Dr. Jiang's research program is to understand the molecular mechanisms and cellular functions of specific oncogenes, tumor suppressor genes, miRNAs/target genes, and their associated pathways/networks, in the regulation of the properties of cancer/leukemic stem cells, signal transduction events, metabolism/mitochondria vulnerabilities, immune responses and initiation and progression of human leukemia and drug resistance. The ultimate objective is to identify and characterize key druggable molecules and pathways, using our well-established in vitro and patient-derived xenotransplantation (PDX) models, which will lead to new, rationally designed, more effective, and less toxic, personalized anti-cancer therapies. In particular, Dr. Jiang and her lab are extremely interested in developing mechanism-based combination therapeutic strategies that can directly target drug-insensitive leukemic stem cells and mutated drug-resistant cells, to improve outcomes in leukemia patients, especially those destined to develop drug resistance.
Dr. Aly Karsan
My lab focuses on two major areas in normal and malignant blood cell formation: (1) Understanding the molecular basis of myeloid malignancies, such as the preleukemic bone marrow failure condition called myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML); and (2) Determining the role of the endothelium in the development of the hematopoietic system.
With respect to the myeloid malignancies, we have a major focus on understanding the relationship of non-coding RNAs and the regulation of the epigenome. We have taken genomic approaches to study patient material followed by functional analyses of specific microRNAs. One example of translation of genomic studies to understanding biologic function is our discovery that microRNAs residing on the long arm of chromosome 5 act to independently regulate innate immune signaling and DNA methylation. Deletion of chromosome arm 5q is the commonest structural anomaly seen in MDS, and current studies centre around establishing the function of these microRNAs, deregulated innate immune signaling and remodeling of the epigenome in the manifestations of MDS.
We have also identified specific defects in the ubiquitin pathway in AML that are potentially tied to regulation of the epigenome, and we are using proteomic, genomic and in vivo methods to define the role of this pathway in leukemogenesis and hematopoietic stem cell function. We are using a variety of in vivo transplantation assays, in vitro cell biology and cell signaling studies as well as additional genomic approaches to answer these questions.
Dr. William Lockwood
Lung cancer is the leading cause of cancer mortality worldwide, suffering from a late stage of disease at the time of diagnosis and a paucity of effective therapeutic strategies to treat advanced tumours. However, with our increasing understanding of lung cancer biology has come the advent of targeted therapies to combat this devastating disease. These therapies target mutated components of key cellular pathways on which tumours have become dependent on for survival, yielding drastic initial response rates without the major side effects of traditional chemotherapies. Despite these successes two major problems remain: first, the majority of lung cancer patients have tumours without mutations in targetable genes and; second, all patients eventually develop resistance to treatment with these targeted agents. In addition, since lung tumours commonly have hundreds of mutated genes, it is difficult to pinpoint those that are responsible for tumour growth and resistance to therapy, creating a clear bottleneck in the translation of laboratory findings to a clinical setting.
My lab utilizes an integrative strategy to address these issues. Through analysis of the genomic profiles of human lung tumours, we aim to identify novel genes and pathways that are altered during lung cancer development. Furthermore, by combining this information with the characterization of mice genetically engineered to develop lung tumours, we attempt to elucidate the key genes driving lung cancer initiation, progression and response to therapy. Lastly, by screening libraries of chemical compounds across lung cancer cells, we aim to characterize novel inhibitors of these identified genes and their corresponding pathways that show promise for use as targeted therapies. Together, this work will further our understanding of lung cancer biology and create insight toward the development of new approaches to diagnose and treat patients suffering from this disease.
Admin Email: cclugston@bccancer.bc.ca
Dr. Gregg Morin
The general theme of our research program is to understand the functional mechanisms of somatically mutated or differentially expressed proteins in cancer pathology. The research integrates proteomic, genomic, chemical biology and bioinformatic technologies with more traditional biochemical and molecular biology methodologies. Our goal is to develop large scale integrative programs to understand the causes, and identify therapeutic targets, for multi-factorial diseases such as cancer. To learn more about Dr. Morin's research, read The Protein Link to Cancer, published in the BC Cancer Foundation Spring 2015 Partners in Discovery magazine.
The functions of most proteins are defined by or mediated through interactions with other proteins. These interactions are organized into complex networks regulated, in part, through modulation of protein phosphorylation by an elaborate interconnected system of kinases and phosphatases. We use quantitative proteomic techniques to study how protein networks, protein-protein interactions and post-translational modifications are aberrantly regulated in cancer.
Admin Email: alroth@bcgsc.ca
Dr. Arefeh Rouhi
Drug resistance is one of the main treatment barriers in cancer therapy. Understanding how resistance emerges and how to overcome it are crucial to the development of new therapeutics. I am interested in understanding the molecular mechanisms of drug resistance as well as relapse in acute myeloid leukemia (AML) and multiple myeloma (MM). Factors such as tumor heterogeneity as well as cell intrinsic and microenvironmental changes lead to drug refraction. Understanding these mechanisms and creating novel drug combinations targeting multiple tumorigenic pathways, will result in a more specific, efficient and sustained therapy with potentially less side-effects.
Dr. Kirk Schultz
My work has evaluated clinically driven issues related to hematopoietic cell transplantation. Clinical investigations have focused on age-related factors affecting graph-versus-host disease (GVHD), graft-failure and graft-versus-leukemia (GVL). Laboratory investigations have used pre-clinical models and the performance of correlative studies in humans to investigate the mechanisms of GVHD and GVL and to develop experimental approaches to modulate these phenomena.
Our laboratory has evaluated the hypothesis that manipulation of MHC class II antigen presentation can alter T cell responses to endogenous antigens. We have investigated the importance of two MHC class II antigen presenting cells in vivo, B cells and dendritic cells, for T cell priming responses to leukemia, and minor histocompatibility antigens (MiHC). We have also investigated whether inhibition of MHC class II antigen presentation by lysosomotropic agents such as chloroquine can inhibit T cell responses to MiHC and development of GVHD. We have translated these pre-clinical observations into clinical studies. We have been one of the first groups to identify chronic GVHD biomarkers in children.
Dr. David Scott
The focus of the research in the Scott laboratory is aimed at improving outcomes of patients with lymphoid cancers through precision medicine. This involves unravelling the molecular determinants of treatment failure, applying cutting edge technology to patient biopsies, and then translating that knowledge into assays that can be used to guide treatment management. These approaches have led to the development of prognostic and predictive biomarkers for classical Hodgkin lymphoma, diffuse large B-cell lymphoma and mantle cell lymphoma that are applicable to routinely produced formalin-fixed paraffin-embedded biopsies – allowing these assays to be used in clinical practice.
The poor outcomes seen when patients experience treatment failure have led to an emphasis on the biology of these cancers at the time point of relapse, exploring high-risk genetic features and evolution of tumors as they are exposed to immuno-chemotherapy. The Scott laboratory is now leading and co-ordinating correlative studies in clinical trials of treatment of relapsed and refractory aggressive B-cell lymphoma. Finally, the Scott laboratory has broadened the biobank at BC Cancer to enable the expansion of this research into chronic lymphocytic leukemia (CLL).
Admin Email: aleli.capuno@bccancer.bc.ca
Dr. Christian Steidl
Dr Steidl is an Associate Professor in the Department of Pathology (University of British Columbia) and Lymphoid Cancer Research (BC Cancer Agency). He is holding an MD degree from the University of Muenster, Germany, and a PhD equivalent degree from University of Witten-Herdecke, Germany. Dr Steidl has expertise in clinical malignant hematology, cytogenetics, molecular genetics, next-generation sequencing and functional genomics. Dr. Steidl joined the Centre for Lymphoid Cancer at the British Columbia Cancer Agency in 2006. He is currently supervising a translational research laboratory focusing on the pathogenesis of B cell lymphomas. Dr Steidl is most known for his work on biomarkers in Hodgkin lymphoma and discovery of novel gene fusions in B cell lymphomas. He has authored 74 refereed articles in the field of hematological malignanices and has been an invited speaker at many conferences. He also serves as a member of the Lymphoma Research Foundation’s Panel of Scientific Advisors and the Medical Expert Committee of the Cancer Research Society. Dr Steidl holds research funding as the principle investigator by the Canadian Institutes of Health Research (CIHR), the Leukemia and Lymphoma Society of Canada (LLSC), the Canadian Hematology Society (CHS), and is co-investigator on a Genome Canada grant to advance personalized treatments of lymphoid cancer patients. Dr. Steidl also holds a career investigator award by the Michael-Smith Foundation for Health Research and a New Investigator Award by the CIHR.
Dr. Leandro Venturutti
Dr Leandro Venturutti began his scientific career at the Faculty of Pharmacy and Biochemistry (University of Buenos Aires, Argentina), where he studied the structure and function of a protein lost in the hereditary neurodegenerative disease Friedreich Ataxia. Pursuing his profound interest in biomedical sciences and mechanisms of disease, he moved on to the cancer research field for his PhD studies. He devoted a significant part of his thesis work to exploring pathways of metastatic dissemination, identifying clinically useful predictive biomarkers, and developing novel therapeutic tools for breast and gastric tumors. Dr Venturutti completed his training working as a postdoctoral researcher at the Division of Hematology and Oncology (Weill Cornell Medicine, USA), where he investigated how recurrent mutations in aggressive B-cell lymphomas alter the epigenome and contribute to the early stages of malignant transformation. Dr Venturutti was recruited to the BC Cancer Research Institute in 2021 to start his own research group. His goals are to identify and understand the mechanisms driving the progression and dissemination of B-cell lymphomas, as a means to develop minimally invasive diagnostic tools, and novel prophylactic and curative treatments. His group exploits modern high-parameter technologies to study clinical specimens, and develops sophisticated models of disease to tackle profound biological questions with translational potential.
Dr. Ly Vu
The overarching goal of our laboratory is to understand the control of stem cells in development and diseases. Our research group is focused on uncovering novel mechanisms of post-transcriptional and translational regulation during normal and malignant hematopoiesis. We aim to develop innovative therapeutic approaches targeting these regulatory pathways in cancer.
While disruption of genetic and epigenetic mechanisms and altered signaling networks are commonly studied, the role post-transcriptional and translational regulation in tumorigenesis has only recently recognized. We are particularly interested in defining the regulation of mRNA decay and translation mediated by poly(A) tail length and RNA deadenylation complexes in the context of normal and leukemia stem cells. Despite the central role of mRNA decay and poly(A) tails in regulating and coupling RNA metabolism and translation, it is virtually unknown how these processes contribute to drive and maintain the self-renewal and oncogenic gene expression programs in stem cells and cancer. Our work will provide insights into this largely unexplored area and enable development of new therapies. The laboratory employs human and mouse models; a broad range of molecular biology methods and a global approach using next generation sequencing techniques to decipher regulation of gene expression at multiple layers from transcription to mRNA biogenesis and translation.
Admin Email: Akotzer@bccrc.ca
Dr. Andrew Weng
My research program focuses on the pathogenesis of lymphoid malignancy and entails two major arms. First, we have explored the role of NOTCH1 and other oncogenes/tumor suppressors in the genesis and propagation of T-cell acute lymphoblastic leukemia (T-ALL) including studies on downstream target genes/pathways and identifying mechanisms operative in leukemia stem cells. We have addressed these questions in cells from different developmental stages and tissue contexts on the hypothesis that preset epigenetic programs may restrict the oncogenic trajectories available to the cells as they undergo the initial stages of transformation and clonal establishment. Many of our findings have direct clinical relevance in that they serve as basis for the development of rational therapies that target disease-specific phenotypes.
As a second and more recent focus, my lab has explored the use of state-of-the-art mass cytometry (CyTOF) to obtain highly resolved phenotypic maps of heterogeneous cell populations in present in patient lymphoma biopsy samples including both malignant and reactive immune cell compartments. We have used this methodology to characterize intratumoral heterogeneity/subclonal diversity among malignant cell populations and stereotyped or patient-specific immune responses. This work is also of direct clinical relevance in providing detailed phenotypic characterizations that are required in order to define biomarkers for lymphoma classification and prognosis, and monitoring of patient-specific responses to therapy.