Patrick Grohar
Faculty Member
Last active: 3/27/2014

Dual targeting of EWS-FLI1 activity and the associated DNA damage response with trabectedin and SN38 synergistically inhibits Ewing sarcoma cell growth.

Grohar PJ, Segars LE, Yeung C, Pommier Y, D'Incalci M, Mendoza A, Helman LJ
Clin Cancer Res. 2014 20 (5): 1190-203

PMID: 24277455 · PMCID: PMC5510643 · DOI:10.1158/1078-0432.CCR-13-0901

PURPOSE - The goal of this study is to optimize the activity of trabectedin for Ewing sarcoma by developing a molecularly targeted combination therapy.

EXPERIMENTAL DESIGN - We have recently shown that trabectedin interferes with the activity of EWS-FLI1 in Ewing sarcoma cells. In this report, we build on this work to develop a trabectedin-based combination therapy with improved EWS-FLI1 suppression that also targets the drug-associated DNA damage to Ewing sarcoma cells.

RESULTS - We demonstrate by siRNA experiments that EWS-FLI1 drives the expression of the Werner syndrome protein (WRN) in Ewing sarcoma cells. Because WRN-deficient cells are known to be hypersensitive to camptothecins, we utilize trabectedin to block EWS-FLI1 activity, suppress WRN expression, and selectively sensitize Ewing sarcoma cells to the DNA-damaging effects of SN38. We show that trabectedin and SN38 are synergistic, demonstrate an increase in DNA double-strand breaks, an accumulation of cells in S-phase and a low picomolar IC50. In addition, SN38 cooperates with trabectedin to augment the suppression of EWS-FLI1 downstream targets, leading to an improved therapeutic index in vivo. These effects translate into the marked regression of two Ewing sarcoma xenografts at a fraction of the dose of camptothecin used in other xenograft studies.

CONCLUSIONS - These results provide the basis and rationale for translating this drug combination to the clinic. In addition, the study highlights an approach that utilizes a targeted agent to interfere with an oncogenic transcription factor and then exploits the resulting changes in gene expression to develop a molecularly targeted combination therapy.

©2013 AACR

MeSH Terms (30)

Animals Antineoplastic Agents Camptothecin Cell Line, Tumor Dioxoles Disease Models, Animal DNA Breaks, Double-Stranded DNA Damage Doxorubicin Drug Resistance, Neoplasm Drug Synergism Exodeoxyribonucleases Female Gene Expression Regulation, Neoplastic Gene Silencing Humans Irinotecan Mice Oncogene Proteins, Fusion Phenotype Proto-Oncogene Protein c-fli-1 RecQ Helicases RNA, Small Interfering RNA-Binding Protein EWS RNA Interference Sarcoma, Ewing Tetrahydroisoquinolines Trabectedin Werner Syndrome Helicase Xenograft Model Antitumor Assays

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