Neuroblastoma is a pediatric tumor originating from the sympathetic nervous system responsible for 10-15% of all childhood cancer deaths. Half of all neuroblastoma patients present with high-risk disease and nearly 50% relapse and die of disease. In addition, cytotoxic standard therapies cause serious lifelong side-effects including growth retardation, delayed cognitive development, infertility and increased risk for secondary tumors. Options for a precision medicine approach for this group of patients are limited. Evidence is emerging that embryonal tumors such as neuroblastoma are marked by a blueprint of replicative stress resistance which protects them from DNA damage induced premature aging, an adaptation that can serve as key novel therapeutic vulnerability. Notably, CDK12 was recently discovered as a key regulator to ensure expression of various genes involved in the DNA damage response and therefore poses an innovative and novel entry point for combination therapies. In view of these observations, we identified a series of synergistic drug interactions with pharmacological CDK12 targeting. In this project, we aim to functionally dissect the molecular basis of these synergistic interactions in vitro and in vivo. Secondly, we will evaluate the impact of these synergistic drug combinations on the interaction of neuroblastoma tumor cells with the tumor micro-environment in vitro and in vivo using dedicated model systems.