期刊
CLINICAL CANCER RESEARCH
卷 22, 期 16, 页码 4105-4118出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-15-2624
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资金
- Hyundai Hope on Wheels Program
- T32 training grant
- Vanderbilt Clinical Oncology Research Career Development K12
- Vanderbilt University Department of Pediatrics
- Lily's Garden Foundation
- Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]
Purpose: The goal of this study was to identify second-generation mithramycin analogues that better target the EWS-FLI1 transcription factor for Ewing sarcoma. We previously established mithramycin as an EWS-FLI1 inhibitor, but the compound's toxicity prevented its use at effective concentrations in patients. Experimental Design: We screened a panel of mithralogs to establish their ability to inhibit EWS-FLI1 in Ewing sarcoma. We compared the IC50 with the MTD established in mice to determine the relationship between efficacy and toxicity. We confirmed the suppression of EWS-FLI1 at the promoter, mRNA, gene signature, and protein levels. We established an improved therapeutic window by using time-lapse microscopy to model the effects on cellular proliferation in Ewing sarcoma cells relative to HepG2 control cells. Finally, we established an improved therapeutic window using a xenograft model of Ewing sarcoma. Results: EC-8105 was found to be the most potent analogue and was able to suppress EWS-FLI1 activity at concentrations nontoxic to other cell types. EC-8042 was substantially less toxic than mithramycin in multiple species but maintained suppression of EWS-FLI1 at similar concentrations. Both compounds markedly suppressed Ewing sarcoma xenograft growth and inhibited EWS-FLI1 in vivo. Conclusions: These results provide a basis for the continued development of EC-8042 and EC-8105 as EWS-FLI1 inhibitors for the clinic. (C) 2016 AACR.
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