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Cancer Therapy: Preclinical

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 and Patrick J. Grohar
Christy L. Osgood
1Division of Pediatric Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee.
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Nichole Maloney
1Division of Pediatric Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee.
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Christopher G. Kidd
1Division of Pediatric Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee.
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Susan Kitchen-Goosen
2Van Andel Research Institute, Grand Rapids, Michigan.
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Laura Segars
1Division of Pediatric Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee.
3Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
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Meti Gebregiorgis
3Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
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Girma M. Woldemichael
4Basic Science Program, Leidos Biomedical Research Laboratory, Inc., Molecular Targets Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
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Min He
5Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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Savita Sankar
6Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri.
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Stephen L. Lessnick
7Center for Childhood Cancer and Blood Disorders, Nationwide Children's Hospital, Division of Pediatric Hematology/Oncology/BMT, The Ohio State University, Columbus, Ohio.
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Min Kang
8Texas Tech University Health Science Center, School of Medicine, Lubbock, Texas.
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Malcolm Smith
3Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
5Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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Lisa Turner
2Van Andel Research Institute, Grand Rapids, Michigan.
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Zachary B. Madaj
2Van Andel Research Institute, Grand Rapids, Michigan.
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Mary E. Winn
2Van Andel Research Institute, Grand Rapids, Michigan.
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Luz-Elena Núñez
9EntreChem S.L., Oviedo, Spain.
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Javier González-Sabín
9EntreChem S.L., Oviedo, Spain.
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Lee J. Helman
3Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
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Francisco Morís
9EntreChem S.L., Oviedo, Spain.
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Patrick J. Grohar
1Division of Pediatric Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee.
2Van Andel Research Institute, Grand Rapids, Michigan.
10Helen De Vos Children's Hospital, Grand Rapids, Michigan.
11Department of Pediatrics, Michigan State University School of Medicine, East Lansing, Michigan.
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  • For correspondence: patrick.grohar@vai.org
DOI: 10.1158/1078-0432.CCR-15-2624 Published August 2016
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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. Clin Cancer Res; 22(16); 4105–18. ©2016 AACR.

This article is featured in Highlights of This Issue, p. 3985

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received October 28, 2015.
  • Revision received February 17, 2016.
  • Accepted February 18, 2016.
  • ©2016 American Association for Cancer Research.
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Clinical Cancer Research: 22 (16)
August 2016
Volume 22, Issue 16
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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 and Patrick J. Grohar
Clin Cancer Res August 15 2016 (22) (16) 4105-4118; DOI: 10.1158/1078-0432.CCR-15-2624

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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 and Patrick J. Grohar
Clin Cancer Res August 15 2016 (22) (16) 4105-4118; DOI: 10.1158/1078-0432.CCR-15-2624
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