Cancer is a major health problem due to the failure of current therapies to effectively eradicate the disease. Alternative signaling pathways compensate for a therapeutically targeted pathway, a process referred to as 'evasive resistance'. The identities of the alternative signaling pathways and functional interconnections that underlie evasive resistance remain widely unknown. We propose to integrate cutting-edge clinical, molecular, and computational sciences to understand the signaling defects that allow tumors to evade therapy. With its synergistic, interdisciplinary approach, the proposed project is, to our knowledge, unique in Europe and possibly worldwide.Within the framework of rigorously designed clinical studies, a clinician will provide basic research scientists with diseased tissue isolated before therapy, during treatment or at the time of tumor progression. The tissue, chosen based on medical importance, accessibility to repeated sampling, and ethical considerations, will be from hepatocellular carcinoma. Tumor tissue will be obtained by needle biopsy and snap frozen to preserve in vivo properties. The basic research scientists and a computational biologist will determine, characterize and model the underlying signaling defects. Importantly, using longitudinal clinical samples in combination with mouse and cellular HCC model systems, we will seek to define treatment-related changes in cell signaling that allow tumors to circumvent therapy. This process will be iterative such that changes in treatment strategies will again be monitored in the same patient or experimental model. Insights gained will be used (i) to understand mechanisms of evasive resistance, (ii) to identify novel drug targets and predictive biomarkers, and (iii) to rationally design personalized medicine that ultimately increases therapeutic effectiveness and reduces financial burden. This innovative, comprehensive endeavor will improve diagnosis, treatment and clinical outcome.