Targeting RNA Processing Defects of Ewing Sarcoma

UT Health Science Center at San Antonio, San Antonio, TX

Ewing sarcoma (EwS) is a disease driven by the fusion of two genes, EWSR1 and FLI1, creating EWSR1-FLI1. In normal cells, EWSR1 has the ability to bind RNA and plays a role in RNA processing. EwS cells have problems properly processing RNA which is thought to be due to the fusion gene interfering with the normal function of EWSR1. We recently discovered that EWSR1 controls the activity of the RNA-producing machinery (RNA polymerase) and that in EwS cells this machinery is overactive, producing more RNA than in normal cells. We believe that EwS cells are unable to process the increased amount of RNA efficiently and therefore these cancer cells may be more sensitive than normal cells to agents that target RNA processing. We screened the whole genome, targeting each gene individually, and found that EwS are very sensitive to targeting RNA processing genes. This is a key finding that could lead to alternate targeted treatment options for this disease. We propose to further investigate the results, identify which RNA processes are particularly important for EwS and whether available pharmaceuticals targeting these processes can be used effectively to treat this disease. As with any strategy to specifically target cancer, the key is to identify how these cancers differ from the norm and then explore whether this difference can be therapeutically targeted. Clinically relevant RNA processing inhibitors currently exist and we will test them in preclinical models of EwS.