Identification of Mithramycin Analogues with Improved Targeting of the EWS-FLI1 Transcription Factor
| العنوان: | Identification of Mithramycin Analogues with Improved Targeting of the EWS-FLI1 Transcription Factor |
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| المؤلفون: | Francisco Morís, Luz Elena Núñez, Javier González-Sabín, Christy L. Osgood, Min H. Kang, Savita Sankar, Christopher G. Kidd, Patrick J. Grohar, Lee J. Helman, Nichole Maloney, Laura E. Segars, Girma M. Woldemichael, Malcolm A. Smith, Zachary Madaj, Susan M. Kitchen-Goosen, Stephen L. Lessnick, Lisa Turner, Mary E. Winn, Min He, Meti Gebregiorgis |
| المصدر: | Clinical Cancer Research. 22:4105-4118 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Cell type, Oncogene Proteins, Fusion, Sarcoma, Ewing, Biology, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Molecular Targeted Therapy, Promoter Regions, Genetic, Transcription factor, Antibiotics, Antineoplastic, Proto-Oncogene Protein c-fli-1, Gene Expression Profiling, fungi, Plicamycin, Gene signature, medicine.disease, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, Gene expression profiling, Disease Models, Animal, 030104 developmental biology, Oncology, Cell culture, 030220 oncology & carcinogenesis, Toxicity, Immunology, Cancer research, Sarcoma, RNA-Binding Protein EWS, Transcription Factors |
| الوصف: | 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. Clin Cancer Res; 22(16); 4105–18. ©2016 AACR. |
| تدمد: | 1557-3265 1078-0432 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fbaed44365e349de0df143b92f375f69Test https://doi.org/10.1158/1078-0432.ccr-15-2624Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....fbaed44365e349de0df143b92f375f69 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573265 10780432 |
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