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Summary form only given: Computational analysis of the recent onslaught of cancer molecular profile data is producing an unprecedented repertoire of genetic and epigenetic alterations contributing to tumorigenesis and progression. Yet, the direct impact of this knowledge on tumor treatment and prevention is still largely unproven. Loss of tumor suppressor function is difficult to target pharmacologically and, with a handful of exceptions, alterations providing potential drug targets are relatively infrequent in cancer patients and are thus unlikely to support clinical development. By computationally reconstructing and interrogating the regulatory logic of the cancer cell, which is responsible for integrating multiple aberrant signals in vivo, systems biology is starting to elucidate broad addiction mechanisms, both oncogene and non-oncogene based that are exquisitely specific to the cancer subtype. In this presentation, we will discuss recent result in the computational discovery and experimental validation of synergistic, non-oncogene addiction mechanisms in high-grade glioma, of the upstream genetic alterations causally related to their functional activation, and of candidate targets for combination therapy. This approach has been generalized to a number of additional tumor subtypes and provides a novel framework for cancer target discovery and development in patient centric fashion.