Searching for predictive markers and targets for personalized treatment of cancer

Recent work in the field of DNA damage recognition, signaling and repair identified multiple protein modifications that are coordinated by the ATM/ATR-regulated DNA damage response (DDR) machinery. This lecture will briefly introduce our most recent published and unpublished data documenting the biological and pathophysiological roles of the phosphorylation-dephosphorylation, ubiquitylation-deubiquitylation cascades, and their interplay with sumoylation, chromatin-remodelling and methylation-mediated signaling of DNA damage, in orchestration of cell cycle checkpoints, DNA repair and cell death pathways in human cells. The examples will include our results from pan-genomic RNAi-based screens for novel DDR components, the first dynamic global phosphoproteomic analysis and mechanistic insights into the cooperation between such dynamic phosphorylations, ubiquitylation and protein-protein inter-actions in response to DNA double strand breaks. Furthermore, the emphasis will be on our recent data that extend our concept of DDR as a barrier in human cancer development and selection pressure to favor growth of tumor cells with DDR defects. Finally, our efforts to exploit germ-line or tumor-specific DDR alterations in human carcinomas as predictive markers to guide individualized chemotherapy or radiotherapy, as well as to provide targets of synthetic lethality for optimized combined treatments, will be discussed.