TY - JOUR
T1 - Identification of mithramycin analogues with improved targeting of the EWS-FLI1 transcription factor
AU - Osgood, Christy L.
AU - Maloney, Nichole
AU - Kidd, Christopher G.
AU - Kitchen-Goosen, Susan
AU - Segars, Laura
AU - Gebregiorgis, Meti
AU - Woldemichael, Girma M.
AU - He, Min
AU - Sankar, Savita
AU - Lessnick, Stephen L.
AU - Kang, Min
AU - Smith, Malcolm
AU - Turner, Lisa
AU - Madaj, Zachary B.
AU - Winn, Mary E.
AU - Núñez, Luz Elena
AU - González-Sabín, Javier
AU - Helman, Lee J.
AU - Morís, Francisco
AU - Grohar, Patrick J.
N1 - Publisher Copyright:
© 2016 AACR.
PY - 2016/8/15
Y1 - 2016/8/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84971552083&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84971552083&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-15-2624
DO - 10.1158/1078-0432.CCR-15-2624
M3 - Article
C2 - 26979396
AN - SCOPUS:84971552083
SN - 1078-0432
VL - 22
SP - 4105
EP - 4118
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -