Assembly and interrogation of regulatory networks elucidates synergistic dependencies in human malignancies (475.3)

The recent onslaught of molecular data, across multiple human malignancies, 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 reconstructing and interrogating the in vivo regulatory logic of distinct cancer cells, which integrates multiple aberrant signals resulting from genetic and epigenetic alterations, systems biology is starting to elucidate and mechanistically validate both oncogene and non‐oncogene addiction mechanisms. These mechanisms are exquisitely dependent on the molecular landscape of cancer subtypes, can be targeted pharmacologically, and are frequently synergistic, thus providing uniquely specific entry points for combination therapy. In this presentation, we will discuss recent result in the discovery of synergistic, non‐oncogene addiction mechanisms and their application to the stratification and treatment of prostate cancer, high‐grade glioma, and non‐small cell lung cancer. This approach is highly extensible and has been applied to a variety of additional tumor subtypes, to the study of stem cell differentiation, reprogramming, and pluripotency control, as well as to the study of neurodegenerative diseases, such as ALS.