Identification of mithramycin analogues with improved targeting of the EWS-FLI1 transcription factor

Christy L. Osgood, Nichole Maloney, Christopher G. Kidd, Susan Kitchen-Goosen, Laura Segars, Meti Gebregiorgis, Girma M. Woldemichael, Min He, Savita Sankar, Stephen L. Lessnick, Min Kang, Malcolm Smith, Lisa Turner, Zachary B. Madaj, Mary E. Winn, Luz Elena Núñez, Javier González-Sabín, Lee J. Helman, Francisco Morís, Patrick J. Grohar

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4105-4118
Number of pages14
JournalClinical Cancer Research
Volume22
Issue number16
DOIs
StatePublished - Aug 15 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Osgood, C. L., Maloney, N., Kidd, C. G., Kitchen-Goosen, S., Segars, L., Gebregiorgis, M., Woldemichael, G. M., He, M., Sankar, S., Lessnick, S. L., Kang, M., Smith, M., Turner, L., Madaj, Z. B., Winn, M. E., Núñez, L. E., González-Sabín, J., Helman, L. J., Morís, F., & Grohar, P. J. (2016). Identification of mithramycin analogues with improved targeting of the EWS-FLI1 transcription factor. Clinical Cancer Research, 22(16), 4105-4118. https://doi.org/10.1158/1078-0432.CCR-15-2624