Targeting aberrant non-canonical NF-κB pathway activation in B-cell lymphomas
Christian Steidl
MD PhDBC Cancer, The University of British Columbia
Project Term: July 1, 2022 - June 30, 2025
The impact of biological heterogeneity on treatment outcomes is evidenced by a large proportion of lymphoma patients who experience relapsed/refractory disease. To address this knowledge gap, we sequenced primary lymphoma samples and found recurrent mutations in the non-canonical NF-kB pathway (NC NF-kB) and uncovered the NIK kinase as a targetable candidate. Our next steps focus on using advanced genetic modelling approaches to provide preclinical rationale for targeting NC NF-kB in lymphomas.
B-cell lymphomas are cancers of the antibody-producing cells of the immune system and remain the most common group of blood cancers in North America. Despite recent advances in early diagnosis and treatment of these diseases, a large number of patients are not cured or redevelop more severe ailment after initial treatment. Cell signaling entails a “cause-and-effect” series of events leading to a change in the way cells behave in response to a biochemical stimulus. Normally, nuclear factor of kappa B-cell (NF-κB) signaling is required for the growth and survival of B-cells during an immune response, but gene mutations can render it out of control leading to the development of cancer. Many open-ended questions regarding the varied clinical responses to drugs that block NF-κB signaling remain unanswered. To address these concerns, our lab has produced preliminary data suggesting a role of specific mutations driving NF-κB activity. Our overarching goal in this project is to develop experimental models and test for drugs that more potently kill these NF-κB-mutated lymphomas. In addition, we will use state-of-the-art genomics approaches to uncover novel biomarkers that will aid in identifying patients with NF-κB-active tumours. Building on this foundation, we hope that our translational research will guide targeted therapeutic treatment against these NF-κB-active B-cell lymphomas.