Defining and targeting CIC::DUX4-dependent survival in fusion-positive sarcomas

Abstract The same intensity applied to identifying molecular targets, investing in research, and running clinical trials that is occurring now for adult cancers has not extended to the pediatric population, despite evidence that doing so in pediatric cancers will improve patient outcomes. An amenable context for targeted therapies is fusion- driven cancers, which are characterized by relatively quiet genomes with recurrent, balanced translocations that create fusion oncoproteins that drive oncogenesis. CIC::DUX4 sarcoma, a common member of the Ewing sarcoma family of pediatric and young adult cancers, is defined by a transcription factor fusion of the CIC and DUX4 genes. This is an especially aggressive disease and bears a significantly worse prognosis than classic Ewing sarcoma. A major limitation as to why no targeted therapies exist for this cancer is relatively little is known about the mechanisms by which CIC::DUX4 drives disease progression. In response, my team has developed and assembled the largest known collection of CIC::DUX4-driven human and mouse sarcoma models. I am working on studies combining these models with genomic and proteomic technologies to define, for the first time, the altered gene expression driven by this oncoprotein, how it alters cellular signaling, proliferation, survival, and differentiation state, and the network of proteins within the cell that regulate its oncogenic functions and associated survival dependencies. The purpose of this work is to shed light on consensus functions of the CIC::DUX4 fusion oncoprotein to better understand its molecular pathophysiology.