Abstract 3409: Arsenic trioxide inhibits Ewing sarcoma growth by blocking Hedgehog/GLI pathway

Abstract

Abstract Ewing's Sarcoma Family of Tumors (ESFT) is an undifferentiated neoplasm of the bone and soft tissue. ESFT is characterized by a specific chromosomal translocation occurring between chromosome 22 and (in most cases) chromosome 11, which generates an aberrant transcription factor, EWS-FLI1. We have previously shown that GLI1 is a direct transcriptional target of EWS-FLI1, and is important for ESFT tumorigenicity. Thus, GLI1 is a potential therapeutic target in ESFT. Arsenic Trioxide (ATO) is an FDA approved drug used for the treatment of Acute Promyelocytic Luekemia (APL) as a second line of therapy for those patients who don't response or relapse on All-trans-retinoic acid therapy. We show that Arsenic Trioxide inhibits GLI1 transcriptional activity. Arsenic Trioxide can also decrease the expression of GLI target genes without affecting GLI1 protein levels. We also show that ATO can inhibit the growth of ESFT cell lines in vitro and in vivo in a mouse xenograft model. To further prove that ATO is causing tumor cell growth inhibition by affecting GLI, we treated a mouse medulloblastoma model that is driven by an activating Smoothened mutation SMOA1. We were able to significantly improve survival of these mice with ATO treatment. Our results establish ATO as a hedgehog pathway inhibitor, and warrant the investigation of ATO in clinical trials as a new therapy for ESFT, basal cell carcinoma and medulloblastoma patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3409.