Abstract LB-238: Direct targeting of oncogenic transcription factors using next-generation oligonucleotides as a novel therapeutic strategy for translocation-positive sarcomas

Abstract

Abstract Many sarcoma subtypes including Ewing sarcoma (ES), alveolar rhabdomyosarcoma (ARMS), synovial sarcoma (SS), and desmoplastic small round cell tumor (DSRCT), are driven by oncogenic chimeric transcription factors. Outcomes for these diseases remain unacceptably poor despite intensification of standard therapies. Although these translocation positive sarcomas possess well-defined oncogenic drivers, as transcription factors that lack intrinsic enzymatic activity, they have been considered undruggable. We have developed a two-tiered pre-clinical therapeutic program 1) creating and characterizing faithful in vitro and in vivo models of these rare malignancies and 2) designing next generation antisense oligonucleotides (ASOs) to directly target the oncogenic chromosomal translocations underlying these multiple sarcoma subtypes. As proof of principle, we present here the program experience with DSRCT, a rare sarcoma for which there has been an overwhelming paucity of both biological tools for pre-clinical investigation, as well as clinical therapeutic options. We have extensively characterized two new DSRCT cell lines harboring the characteristic oncogenic EWSR1-WT1 t(11;22)(p13;q12) fusion, and have used these tools to develop orthotopic xenograft models. Utilizing these accurate model systems we have designed and evaluated a series of ASO compounds directly targeting the EWSR1-WT1 translocation product. Among the series of ASOs developed, we identified D2A, a selective and potent inhibitor of EWSR1-WT1. In vitro, we have shown D2A to abolish the EWSR1-WT1 fusion product with exquisite specificity in a dose-dependent fashion. D2A similarly exhibits efficacy in vivo, with anti-tumorigenic activity in our pre-clinical models resulting in an 80% reduction in xenograft tumor growth. With the aid of authentic in vitro and in vivo modeling systems, this ASO platform has wide-ranging implications for both biological as well as therapeutic advances. Citation Format: Emily Slotkin, Lee Spraggon, Julija Hmeljak, Luciano Martelotto, Romel Somwar, Elisa de Stanchina, Luca Cartegni, Marc Ladanyi. Direct targeting of oncogenic transcription factors using next-generation oligonucleotides as a novel therapeutic strategy for translocation-positive sarcomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-238.