Conférence scientifique : Unité collaborative en épigénétique moléculaire
Oncogenic Functions of Metabolic Defects Associated to Brain Cancer and Leukemia
Conférencier : Frédérick-Antoine Mallette, PhD
Professeur adjoint, Département de médecine, Université de Montréal, Centre de recherche de l'Hôpital Maisonneuve-Rosemont.
Résumé :
Gliomas and leukemias are devastating tumours that remain highly refractory to treatment, thus highlighting the need for new and improved therapeutic strategies. Mutations in the Krebs cycle enzymes isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are commonly observed in brain and blood cancers. Although the precise molecular underpinnings for this remain elusive, it has been shown IDH1/2 mutations confer altered metabolic function by increasing production of the recently described oncometabolite R-2-hydroxyglutarate (R-2HG) relative to the normal metabolite α-ketoglutarate (αKG). Here we characterize the molecular basis of our recent unexpected observation of modulation of oncogenic cellular signaling pathways by R-2HG, a totally novel concept in molecular oncology. The notion of oncometabolite-mediated cancer stimulation has recently been described but the molecular pathways regulated by R-2HG per se are largely unknown.
Our research aims to probe a novel molecular link between R-2HG and modulation of cellular signaling, offering completely fresh insight into the contribution of IDH1/2 mutations to glial transformation. Furthermore, we demonstrate that IDH1/2 mutations lead to telomere dysfunction such as telomere fragility, which is caused by telomeric DNA replication defects. Cancer cells exploit the metabolism differently than their normal counterparts. The proposed research project will investigate previously unsuspected oncogenic activities of metabolic defects associated to cancer.
