Study of potential therapeutic targets within de NF-kB signaling pathway in human gliomas

Glioblastomas (GBMs) represent the most aggressive, resistant and frequent form of gliomas. We observe 200 to 400 new cases in Belgium each year. Actual protocole include maximal tumor resection followed by the administration of radio- and chemo-therapies. However, survival at 5 years has not progressed these 30 last years and does not reach 10%.The main goal of this work is to better comprehend mecanisms responsible for the treatment resistance and the tumorigenicity of GBMs. Among the factors that determine this strong resistance to therapies, anti-apoptotic signaling, for instance through constitutive NF-κ;B pathway activation, and altered DNA-damage response, are believed to play major roles. With the intention of translational research, I focused on the discovery of new therapeutic targets allowing to significantly improve patient survival. The principal study perfomed concerns the highlighting of a role of Iκ;Bζ, a new member of the Iκ;B family of proteins recently discovered, as a therapeutic molecular target for inhibitory strategies in GBMs. Actually, our results show for the first time that Iκ;Bζ can directly control the necroptotic cascade, allowing the escape of apoptosis resistance, and demonstrate the oncogenic role of this protein in GBMs via this mechanism. In addition, preliminary results encourage us to investigate the role of Iκ;Bζ in radiations induced DNA repair and its possible complementary mechanism with CK2, a serine-threonine kinase constitutively activated in these tumors, in order to design multiple therapies to overcome GBMs.