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Clinical cancer research : an official journal of the American Association for Cancer Research
Aug 15, 2016;22 (16): 4105-18.

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
Author Information
  1. Christy L Osgood: Division of Pediatric Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee.
  2. Nichole Maloney: Division of Pediatric Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee.
  3. Christopher G Kidd: Division of Pediatric Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee.
  4. Susan Kitchen-Goosen: Van Andel Research Institute, Grand Rapids, Michigan.
  5. Laura Segars: Division of Pediatric Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee. Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
  6. Meti Gebregiorgis: Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
  7. Girma M Woldemichael: Basic Science Program, Leidos Biomedical Research Laboratory, Inc., Molecular Targets Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
  8. Min He: Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  9. Savita Sankar: Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri.
  10. Stephen L Lessnick: Center for Childhood Cancer and Blood Disorders, Nationwide Children's Hospital, Division of Pediatric Hematology/Oncology/BMT, The Ohio State University, Columbus, Ohio.
  11. Min Kang: Texas Tech University Health Science Center, School of Medicine, Lubbock, Texas.
  12. Malcolm Smith: Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland. Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  13. Lisa Turner: Van Andel Research Institute, Grand Rapids, Michigan.
  14. Zachary B Madaj: Van Andel Research Institute, Grand Rapids, Michigan.
  15. Mary E Winn: Van Andel Research Institute, Grand Rapids, Michigan.
  16. Luz-Elena Núñez: EntreChem S.L., Oviedo, Spain.
  17. Javier González-Sabín: EntreChem S.L., Oviedo, Spain.
  18. Lee J Helman: Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
  19. Francisco Morís: EntreChem S.L., Oviedo, Spain.
  20. Patrick J Grohar: Division of Pediatric Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee. Van Andel Research Institute, Grand Rapids, Michigan. Helen De Vos Children's Hospital, Grand Rapids, Michigan. Department of Pediatrics, Michigan State University School of Medicine, East Lansing, Michigan. patrick.grohar@vai.org.
PMID: 26979396 DOI: 10.1158/1078-0432.CCR-15-2624

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.

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Grants

  1. K12 CA090625/NCI NIH HHS
  2. Z01 SC006892-19/Intramural NIH HHS
  3. HHSN261200800001C/NCI NIH HHS
  4. Z99 CA999999/Intramural NIH HHS
  5. HHSN261200800001E/NCI NIH HHS

MeSH Term

Animals
Antibiotics, Antineoplastic
Cell Line, Tumor
Disease Models, Animal
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Mice
Molecular Targeted Therapy
Oncogene Proteins, Fusion
Plicamycin
Promoter Regions, Genetic
Proto-Oncogene Protein c-fli-1
RNA-Binding Protein EWS
Sarcoma, Ewing
Transcription Factors
Xenograft Model Antitumor Assays

Chemicals

Antibiotics, Antineoplastic
EWS-FLI fusion protein
Oncogene Proteins, Fusion
Proto-Oncogene Protein c-fli-1
RNA-Binding Protein EWS
Transcription Factors
Plicamycin
Journal Article
Article has an altmetric score of 30

Word Cloud

Created with Highcharts 10.0.0EWS-FLI1EwingsarcomaestablishedmithramycinconcentrationstoxicitysuppressionimprovedtherapeuticwindowusingmodelcellsxenograftEC-8105EC-8042PURPOSE:goalstudyidentifysecond-generationanaloguesbettertargettranscriptionfactorpreviouslyinhibitorcompound'spreventeduseeffectivepatientsEXPERIMENTALDESIGN:screenedpanelmithralogsestablishabilityinhibitcomparedIC50MTDmicedeterminerelationshipefficacyconfirmedpromotermRNAgenesignatureproteinlevelstime-lapsemicroscopyeffectscellularproliferationrelativeHepG2controlFinallyRESULTS:foundpotentanalogueablesuppressactivitynontoxiccelltypessubstantiallylesstoxicmultiplespeciesmaintainedsimilarcompoundsmarkedlysuppressedgrowthinhibitedvivo​CONCLUSIONS:resultsprovidebasiscontinueddevelopmentinhibitorsclinicClinCancerRes22164105-18©2016AACRIdentificationMithramycinAnaloguesImprovedTargetingTranscriptionFactor

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