Title: c-Myc-dependent targeting of lymphoma in vitro and in vivo Lymphomas often involve the c-myc oncogene. It was found that inhibiting an enzyme called calpain causes c-myc-transformed cells, but not normal cells to die. The goals are to evaluate how c-myc sensitizes human lymphoma cells to calpain inhibition and to optimize its use in a lymphoma model. This project will provide information on the function and potential of calpain as a lymphoma target
Title: Understanding and exploiting chromosome instability associated with NHL for the discovery of broad spectrum therapeutics.
Understanding and exploiting chromosome instability associated with NHL for the discovery of broad spectrum therapeutics. ...this research is significant both in the context of understanding the basic biology of chromosome instability underlying the onset of NHL, and the potential to identify novel therapeutic targets and drugs that could dramatically improve the quality of life and treatment of NHL.
Title: c-Myc-dependent targeting of lymphoma in vitro and in vivo
Lymphomas often involve the c-myc oncogene. It was found that
inhibiting an enzyme called calpain causes c-myc-transformed cells, but
not normal cells to die. The goals are to evaluate how c-myc
sensitizes human lymphoma cells to calpain inhibition and to optimize
its use in a lymphoma model. This project will provide information on
the function and potential of calpain as a lymphoma target.
Dr. Xiaoyan Jiang, Terry Fox Laboratory, BC Cancer Agency, "Molecular and Functional Characterization of a Novel Oncogene (AHI-1) in Human Cutaneous T-Cell Lymphomas." Because many forms of human lymphoma originate in blood stem cells, uncovering the changes that occur in these cells is crucial to understanding how these diseases develop and progress. This study is focused on investigating a newly discovered oncogene (cancer causing gene), AHI-1 that was recently identified. AHI-1 is involved in murine lymphoma development (lymphoma in mice) and shows abnormal expression in human blood cancer cells, including Sezary cancer cells from patients with cutaneous T-cell lymphoma and leukemic stem cells from patients with chronic myeloid leukemia. These findings are highly intriguing indicators that AHI-1 is likely to be an important new cancer causing gene involved in development of lymphomas and leukemia in humans. The investigations should help to identify critical target genes that interact with AHI-1 and play crucial roles in altering T-cell signaling pathways involved in processes of human T-cell lymphoma development. This investigation is expected to translate into new diagnostic and treatment strategies leading to the development of targeted cancer treatment that will be more effective and have fewer side effects than currently used chemotherapy. Dr. Martin Alberto, University of Toronto, "Characterizing the Biochemical Mechanism of Somatic Hypermutation" The immune system plays a major role in protecting humans from bacteria, viruses and toxins. One of the ways that the immune system accomplishes this is by producing antibodies that bind to and neutralize these pathogens. B cells produce antibodies and can increase the binding strength of the antibody to the specific pathogen by making changes (i.e. mutations) in the antibody genes. This process is termed somatic hypermutation and is initiated by an enzyme called activation-induced cytidine deaminase (AID). Although AID mutates antibody genes, this enzyme sometimes makes mistakes and mutates other genes. Unfortunately, some of these other genes can cause cancer if mutated. Three types of lymphomas might be caused by mistake made by the AID enzyme, namely Diffuse Large B Cell Lymphoma, Chronic Lymphocytic Leukemia and Burkitt’s lymphomas. The overall goal of this research is to determine how the AID enzyme produces mutations in antibody genes as well as in other genes with the goal to gain further insight into AID’s oncogenic potential.
"A common theme in cancer is the dysregulation of a normal development process that either directly causes cells to grow in an uncontrolled manner, or renders them susceptible to other deleterious changes that, in turn, lead to uncontrolled growth. One example of this situation occurs with a gene called Notch, which is important for guiding the development of normal lymphoid cells that help the body to fight infection. We recently discovered that the Notch gene is mutated in over 50% of cases of a pediatric and adult lymphoproliferative disorder, T-cell lymphoblastic lymphoma/acute lymphoblastic leukemia. The Notch mutations we identified lead to inappropriate activation of several other genes, and thus, these “downstream” genes are actually responsible for enacting the cancer program and causing uncontrolled tumour growth. We intend to study these downstream genes to determine the molecular mechanism by which they promote malignant transformation of normal lymphoid cells and drive the growth of established lymphoid tumour cells. Furthermore, since the Notch signaling pathway is so highly conserved in the immune system, we anticipate these downstream genes will also be relevant in the pathogenesis of other types of lymphoma. By identifying the molecular pathways most critical to lymphoid tumour development/growth, we will be able to design more effective and less toxic therapies for lymphoproliferative disorders."
“Mantle Cell lymphoma is an aggressive lymphoma for which conventional therapy is ineffective in most cases. Based on the previous data, they believe that a cancer-causing gene, STAT3, may contribute to the formation of a subset of MCL by promoting cell growth and survival advantage. To determine the importance of STAT3 in MCL, they will investigate a large number of MCL patient tumour samples, to establish if STAT3 in MCL is associated with other biological or clinical markers. Second, the will employ several cell culture experimental models in which the biological activity of STAT3 can be experimentally modulated, to determine if STAT3 inhibition is a feasible treatment approach for MCL patients.”
Dr. Tony Reiman, Cross Cancer Institute for his study of The Centrosome as a Therapeutic Target in Multiple Myeloma
Multiple Myeloma is an incurable lymphoproliferative cancer for which new treatment approaches are needed. The centrosome is an important structure in human cells that controls cell division, and other processes. We have discovered that the centrosome and some proteins in the centrosome are altered in multiple myeloma cancer cells, in a way that correlates with poor patient outcomes. With this fellowship we will study further the components of the centrosome that are altered in myeloma, with great emphasis on finding ways to exploit these alterations for the purposes of developing new therapeutic strategies. There is potential for this work to lead to clinical trials of new drug treatments for myeloma in short order.
These results have been submitted for presentation at the 2006 meeting of the American Society of Hematology and will also be submitted for publication in a peer-review journal.
Title: Epigenetic Silencing of Putative Tumour Suppressor Gene PRDM1 in human DLBCL
Normal cells loose their protection against viral attack as they become more malignant. Exploiting this weakness has allowed researchers to develop a strategy using certain viruses to selectively infect and kill many types of cancer cells. Drs. Bell and Atkins aim to expand their knowledge of which viruses are the most active in killing lymphoma cells and to address the reasons, at a genetic level, of why some lymphomas are sensitive to viral attack and others are not.
Dr. Ben-David's study is the continuation of ongoing research and the goals of this study will provide important insight into the molecular mechanisms of B-lymphoproliferative disorder in humans as well as gaining insight into the roles of the Fli-1 gene in lymphoproliferative diseases towards clinical treatment.
The fellow will determine the patterns of gene expression in tumour cell lines exposed to antibodies that recognize novel cell surface markers (year 1). As well, the research will determine whether the genes encoding the proteins are amplified or mutated in Hodgkin's and Non Hodgkin's Lymphoma (year 2) and whether expression of the gene or protein in archived biopsies influence outcome.
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