Disclosed are compositions for targeting 0TUD7A, the compositions having a component sufficient to block and/or reduce OTUD7A-mediated deubiquitination of EWS-FLI1 in a cell. The component can be 7Ai and variants thereof. The compositions can be used to treat Ewing sarcoma (EWS). Methods of using the disclosed compositions are also disclosed, including methods of treating EWS in a subject.t