Chemoresistance is a major impediment to succesful treatment of a growing number of cancer entitites. Circumventing this phenomenon demands highly selective and efficient targeting of cancer-specific pathways. We have recently discovered that MYC(N)-driven tumors show strong upregulation of genes involved in replicative stress-induced DNA damage repair. We thereby identified FOXM 1 as a central regulator. Our data suggest that FOXM1 driven DOR is an important determinant in the acquired drug resistance program. In this project we aim at confirming the pivotal role of FOXM1 in drug resistance and dissecting its pathway by integrating knowledge from molecular data sets from patients, primary cell cultures and zebrafish models. This way, we expect to identify novel targets for therapeutic intervention of aggressive or resistant tumors. Once we have established the most vulnerable targets, we will resort to semi-high-throughput screens for pinpointing the most suitable compounds. Subsequently, focused testing of drug combinations on model organisms will prove their in vivo performance and should result in the inclusion of the optimal formulation in phase I clinical trials on patients with highly resistant tumors. Thus, the goal of th is project is to devise new and iess toxic therapeutic strategies for more efficient kiiiing of tumors and for use in patients in which conventional methods no longer show effect. We thereby consider different MYC(N)driven tumor types such as neuroblastoma, medulloblastoma, T-cel acute lymphoblastic leukemia and Burkitt lymphoma, emphasising the translational value of our findings.