The recent onslaught of molecular data, across multiple human malignancies, is producing an unprecedented repertoire of genetic and epigenetic alterations, both germline and somatic, contributing to tumourigenesisand progression. Yet, the direct impact of this knowledge on tumour treatment and prevention is still largely unproven. Loss of tumour 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 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 broadaddiction mechanisms, both oncogene and non-oncogene based that are exquisitely specific to the cancer subtype. In this presentation, we will discuss recent results in the discovery 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. Thisapproach has been generalised to a number of additional tumour subtypes and provides a novel framework for cancer target discovery and development in patient centric fashion as well as for the prioritisation of genetic variants fromcancerGWAS to elucidate mechanisms of genetic predisposition.