Session Speaker

Identification of Genotoxic Stress-Induced Target Structures for Therapeutic Intervention
Michael Naumann, Erik Messamore
Germany

Genotoxic stress, induced by a broad range of DNA damaging agents could lead to a variety of human diseases including cancer. DNA-damage is also therapeutically induced for cancer treatment with the aim to eliminate tumor cells. However, the effectiveness of radio- and chemotherapy is strongly hampered by resistance of tumor cells. A major reason for radio- and chemotherapeutic resistances is the simultaneous activation of cell survival pathways resulting in the activation of the transcription factor NF-κB (nuclear factor-kappa B). Here, we present a Boolean network model of the NF-κB signal transduction induced by genotoxic stress. For the representation and analysis of the model, we used the formalism of Logical Interaction Hypergraphs. By calculating Minimal Intervention Sets, we identified eg PIDD (p53-induced protein with a death domain) as a putative therapeutic target to abrogate NF-κB activation resulting in apoptosis. Experimental data confirmed the predictions. Targeting these structures therapeutically may potentiate the effectiveness of radio- and chemotherapy. Thus, the presented model allows a better understanding of the signal transduction in tumor cells and provides candidates as new therapeutic target structures.