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ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand.
Rellinger EJ, Padmanabhan C, Qiao J, Appert A, Waterson AG, Lindsley CW, Beauchamp RD, Chung DH
(2017) Biochem Biophys Res Commun 491: 463-468
MeSH Terms: Antigens, CD, Antineoplastic Agents, Apoptosis, Cadherins, Caspase 3, Cell Cycle, Cell Line, Tumor, Drug Synergism, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Humans, Isoxazoles, Mesenchymal Stem Cells, Niacinamide, Poly(ADP-ribose) Polymerases, Sarcoma, Ewing, Signal Transduction, Small Molecule Libraries, TNF-Related Apoptosis-Inducing Ligand, Vimentin
Show Abstract · Added March 14, 2018
Ewing sarcomas are rare mesenchymal-derived bone and soft tissue tumors in children. Afflicted children with distant metastases have poor survival despite aggressive therapeutics. Epithelial-to-mesenchymal transition in epithelial carcinomas is associated with loss of E-cadherin and resistance to apoptosis. ML327 is a novel small molecule that we have previously shown to reverse epithelial-to-mesenchymal transition features in both epithelial and neural crest-derived cancers. Herein, we sought to evaluate the effects of ML327 on mesenchymal-derived Ewing sarcoma cells, hypothesizing that ML327 initiates growth arrest and sensitizes to TNF-related apoptosis-inducing ligand. ML327 induced protein expression changes, increased E-cadherin and decreased vimentin, consistent with partial induction of mesenchymal-to-epithelial transition in multiple Ewing Sarcoma cell lines (SK-N-MC, TC71, and ES-5838). Induction of epithelial features was associated with apoptosis, as demonstrated by PARP and Caspase 3 cleavage by immunoblotting. Cell cycle analysis validated these findings by marked induction of the subG cell population. In vitro combination treatment with TRAIL demonstrated additive induction of apoptotic markers. Taken together, these findings establish a rationale for further in vivo trials of ML327 in cells of mesenchymal origin both alone and in combination with TRAIL.
Copyright © 2017 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Lurbinectedin Inactivates the Ewing Sarcoma Oncoprotein EWS-FLI1 by Redistributing It within the Nucleus.
Harlow ML, Maloney N, Roland J, Guillen Navarro MJ, Easton MK, Kitchen-Goosen SM, Boguslawski EA, Madaj ZB, Johnson BK, Bowman MJ, D'Incalci M, Winn ME, Turner L, Hostetter G, Galmarini CM, Aviles PM, Grohar PJ
(2016) Cancer Res 76: 6657-6668
MeSH Terms: Animals, Camptothecin, Cell Line, Tumor, Female, Humans, Irinotecan, Mice, Mice, Nude, Oncogene Proteins, Oncogene Proteins, Fusion, Proto-Oncogene Protein c-fli-1, RNA-Binding Protein EWS, Sarcoma, Ewing
Show Abstract · Added June 27, 2017
There is a great need to develop novel approaches to target oncogenic transcription factors with small molecules. Ewing sarcoma is emblematic of this need, as it depends on the continued activity of the EWS-FLI1 transcription factor to maintain the malignant phenotype. We have previously shown that the small molecule trabectedin interferes with EWS-FLI1. Here, we report important mechanistic advances and a second-generation inhibitor to provide insight into the therapeutic targeting of EWS-FLI1. We discovered that trabectedin functionally inactivated EWS-FLI1 by redistributing the protein within the nucleus to the nucleolus. This effect was rooted in the wild-type functions of the EWSR1, compromising the N-terminal half of the chimeric oncoprotein, which is known to be similarly redistributed within the nucleus in the presence of UV light damage. A second-generation trabectedin analogue lurbinectedin (PM01183) caused the same nuclear redistribution of EWS-FLI1, leading to a loss of activity at the promoter, mRNA, and protein levels of expression. Tumor xenograft studies confirmed this effect, and it was increased in combination with irinotecan, leading to tumor regression and replacement of Ewing sarcoma cells with benign fat cells. The net result of combined lurbinectedin and irinotecan treatment was a complete reversal of EWS-FLI1 activity and elimination of established tumors in 30% to 70% of mice after only 11 days of therapy. Our results illustrate the preclinical safety and efficacy of a disease-specific therapy targeting the central oncogenic driver in Ewing sarcoma. Cancer Res; 76(22); 6657-68. ©2016 AACR.
©2016 American Association for Cancer Research.
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BET bromodomain inhibitors suppress EWS-FLI1-dependent transcription and the IGF1 autocrine mechanism in Ewing sarcoma.
Loganathan SN, Tang N, Fleming JT, Ma Y, Guo Y, Borinstein SC, Chiang C, Wang J
(2016) Oncotarget 7: 43504-43517
MeSH Terms: Animals, Antineoplastic Agents, Autocrine Communication, Azepines, Bone Neoplasms, Cell Line, Tumor, Cell Proliferation, Cell Survival, Epigenesis, Genetic, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Insulin-Like Growth Factor I, Mice, Mice, Nude, NIH 3T3 Cells, Oncogene Proteins, Fusion, Proteins, Proto-Oncogene Protein c-fli-1, Proto-Oncogene Proteins c-akt, RNA-Binding Protein EWS, Receptors, Somatomedin, Sarcoma, Ewing, Signal Transduction, Transcription, Genetic, Triazoles, Xenograft Model Antitumor Assays
Show Abstract · Added November 19, 2016
Ewing sarcoma is driven by characteristic chromosomal translocations between the EWSR1 gene with genes encoding ETS family transcription factors (EWS-ETS), most commonly FLI1. However, direct pharmacological inhibition of transcription factors like EWS-FLI1 remains largely unsuccessful. Active gene transcription requires orchestrated actions of many epigenetic regulators, such as the bromodomain and extra-terminal domain (BET) family proteins. Emerging BET bromodomain inhibitors have exhibited promising antineoplastic activities via suppression of oncogenic transcription factors in various cancers. We reasoned that EWS-FLI1-mediated transcription activation might be susceptible to BET inhibition. In this study, we demonstrated that small molecule BET bromodomain inhibitors repressed EWS-FLI1-driven gene signatures and downregulated important target genes. However, expression of EWS-FLI1 was not significantly affected. Repression of autocrine IGF1 by BET inhibitors led to significant inhibition of the IGF1R/AKT pathway critical to Ewing sarcoma cell proliferation and survival. Consistently, BET inhibitors impaired viability and clonogenic survival of Ewing sarcoma cell lines and blocked EWS-FLI1-induced transformation of mouse NIH3T3 fibroblast cells. Selective depletion of individual BET genes partially phenocopied the actions of BET inhibitors. Finally, the prototypical BET inhibitor, JQ1, significantly repressed Ewing sarcoma xenograft tumor growth. These findings suggest therapeutic potential of BET inhibitors in Ewing sarcoma and highlight an emerging paradigm of using epigenetic agents to treat cancers driven by fusion transcription factors.
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Three-dimensional Radiologic Assessment of Chemotherapy Response in Ewing Sarcoma Can Be Used to Predict Clinical Outcome.
Aghighi M, Boe J, Rosenberg J, Von Eyben R, Gawande RS, Petit P, Sethi TK, Sharib J, Marina NM, DuBois SG, Daldrup-Link HE
(2016) Radiology 280: 905-15
MeSH Terms: Adolescent, Adult, Bone Neoplasms, Child, Child, Preschool, Female, Humans, Imaging, Three-Dimensional, Infant, Kaplan-Meier Estimate, Magnetic Resonance Imaging, Male, Response Evaluation Criteria in Solid Tumors, Retrospective Studies, Sarcoma, Ewing, Treatment Outcome, Tumor Burden
Show Abstract · Added March 29, 2016
Purpose To compare the agreement of three-dimensional (3D) tumor measurements for therapeutic response assessment of Ewing sarcoma according to the Children's Oncology Group (COG) criteria, one-dimensional (1D) Response Evaluation Criteria in Solid Tumors (RECIST), and two-dimensional (2D) measurements defined by the World Health Organization (WHO) with tumor volume measurements as the standard of reference and to determine which method correlates best with clinical outcomes. Materials and Methods This retrospective study was approved by the institutional review board of three institutions. Seventy-four patients (mean age ± standard deviation, 14.5 years ± 6.5) with newly diagnosed Ewing sarcoma treated at three medical centers were evaluated. Primary tumor size was assessed on pre- and posttreatment magnetic resonance images according to 1D RECIST, 2D WHO, and 3D COG measurements. Tumor responses were compared with the standard of reference (tumor volume) on the basis of RECIST, COG, and WHO therapeutic response thresholds. Agreement between the percentage reduction measurements of the methods was assessed with concordance correlation, Bland-Altman analysis, and Spearman rank correlation. Agreement between therapeutic responses was assessed with Kendall tau and unweighted κ statistics. Tumor responses were compared with patient survival by using the log-rank test, Kaplan-Meier plots, and Cox regression. Results Agreement with the reference standard was significantly better for 3D measurement than for 1D and 2D measurements on the basis of RECIST and COG therapeutic response thresholds (concordance correlation of 0.41, 0.72, and 0.84 for 1D, 2D, and 3D measurements, respectively; P < .0001). Comparison of overall survival of responders and nonresponders demonstrated P values of .4133, .0112, .0032, and .0027 for 1D, 2D, 3D, and volume measurements, respectively, indicating that higher dimensional measurements were significantly better predictors of overall survival. Conclusion The 3D tumor measurements according to COG are better predictors of therapeutic response of Ewing sarcoma than 1D RECIST or 2D WHO measurements and show a significantly higher correlation with clinical outcomes. (©) RSNA, 2016 Online supplemental material is available for this article.
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Characterization and drug resistance patterns of Ewing's sarcoma family tumor cell lines.
May WA, Grigoryan RS, Keshelava N, Cabral DJ, Christensen LL, Jenabi J, Ji L, Triche TJ, Lawlor ER, Reynolds CP
(2013) PLoS One 8: e80060
MeSH Terms: Antineoplastic Agents, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p16, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Humans, Sarcoma, Ewing, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53
Show Abstract · Added February 8, 2016
Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT) will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32), two after chemotherapy and progressive disease (CHLA-10, CHLA-25), and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT) (CHLA-258, COG-E-352). The new lines were compared to widely studied EFT lines TC-71, TC-32, SK-N-MC, and A-673. These lines were extensively characterized with regard to identity (short tandem repeat (STR) analysis), p53, p16/14 status, and EWS/ETS breakpoint and target gene expression profile. The DIMSCAN cytotoxicity assay was used to assess in vitro drug sensitivity to standard chemotherapy agents. No association was found between drug resistance and the expression of EWS/ETS regulated genes in the EFT cell lines. No consistent association was observed between drug sensitivity and p53 functionality or between drug sensitivity and p16/14 functionality across the cell lines. Exposure to chemotherapy prior to cell line initiation correlated with drug resistance of EFT cell lines in 5/8 tested agents at clinically achievable concentrations (CAC) or the lower tested concentration (LTC): (cyclophosphamide (as 4-HC) and doxorubicin at CAC, etoposide, irinotecan (as SN-38) and melphalan at LTC; P<0.1 for one agent, and P<0.05 for four agents. This panel of well-characterized drug-sensitive and drug-resistant cell lines will facilitate in vitro preclinical testing of new agents for EFT.
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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
(2014) Clin Cancer Res 20: 1190-203
MeSH Terms: Animals, Antineoplastic Agents, Camptothecin, Cell Line, Tumor, DNA Breaks, Double-Stranded, DNA Damage, Dioxoles, Disease Models, Animal, 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, RNA Interference, RNA, Small Interfering, RNA-Binding Protein EWS, RecQ Helicases, Sarcoma, Ewing, Tetrahydroisoquinolines, Trabectedin, Werner Syndrome Helicase, Xenograft Model Antitumor Assays
Show Abstract · Added March 5, 2014
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
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30 MeSH Terms
Prospects and challenges for the development of new therapies for Ewing sarcoma.
Grohar PJ, Helman LJ
(2013) Pharmacol Ther 137: 216-24
MeSH Terms: Antineoplastic Agents, Bone Neoplasms, Camptothecin, Clinical Trials as Topic, Dioxoles, Epigenesis, Genetic, Humans, Molecular Targeted Therapy, Poly(ADP-ribose) Polymerase Inhibitors, Sarcoma, Ewing, Somatomedins, Tetrahydroisoquinolines, Trabectedin
Show Abstract · Added September 3, 2013
The Ewing sarcoma family of tumors or Ewing sarcoma (ES) is the second most common malignant bone tumor of childhood. The prognosis for localized Ewing sarcoma has improved through the development of intense multimodal therapy over the past several decades. Unfortunately, patients with recurrent or metastatic disease continue to have a poor prognosis. Therefore, a number of complementary approaches are being developed in both the preclinical and clinical arenas to improve these outcomes. In this review, we will discuss efforts to directly target the biologic drivers of this disease and relate these efforts to the experience with several different agents both in the clinic and under development. We will review the data for compounds that have shown excellent activity in the clinic, such as the camptothecins, and summarize the biological data that supports this activity. In addition, we will review the clinical experience with IGF1 targeted agents, ET-743 and epigenetically targeted therapies, the substantial amount of literature that supports their activity in Ewing sarcoma and the challenges remaining translating these therapies to the clinic. Finally, we will highlight recent work aimed at directly targeting the EWS-FLI1 transcription factor with small molecules in Ewing tumors.
Copyright © 2012 Elsevier Inc. All rights reserved.
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Identification of an inhibitor of the EWS-FLI1 oncogenic transcription factor by high-throughput screening.
Grohar PJ, Woldemichael GM, Griffin LB, Mendoza A, Chen QR, Yeung C, Currier DG, Davis S, Khanna C, Khan J, McMahon JB, Helman LJ
(2011) J Natl Cancer Inst 103: 962-78
MeSH Terms: Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Cell Survival, DNA Damage, Dose-Response Relationship, Drug, Gene Expression Regulation, Neoplastic, High-Throughput Screening Assays, Humans, Immunoblotting, Immunohistochemistry, Mice, Microscopy, Confocal, Oncogene Proteins, Fusion, Plicamycin, Protein Array Analysis, Proto-Oncogene Protein c-fli-1, RNA-Binding Protein EWS, Reverse Transcriptase Polymerase Chain Reaction, Sarcoma, Ewing, Transcription Factors, Transcription, Genetic, Translocation, Genetic, Transplantation, Heterologous
Show Abstract · Added March 5, 2014
BACKGROUND - Chromosomal translocations generating oncogenic transcription factors are the hallmark of a variety of tumors, including many sarcomas. Ewing sarcoma family of tumors (ESFTs) are characterized by the t(11;22)(q24;q12) translocation that generates the Ewing sarcoma breakpoint region 1 and Friend leukemia virus integration 1 (EWS-FLI1) fusion transcription factor responsible for the highly malignant phenotype of this tumor. Although continued expression of EWS-FLI1 is believed to be critical for ESFT cell survival, a clinically effective small-molecule inhibitor remains elusive likely because EWS-FLI1 is a transcription factor and therefore widely felt to be "undruggable."
METHODS - We developed a high-throughput screen to evaluate more than 50 000 compounds for inhibition of EWS-FLI1 activity in TC32 ESFT cells. We used a TC32 cell-based luciferase reporter screen using the EWS-FLI1 downstream target NR0B1 promoter and a gene signature secondary screen to sort and prioritize the compounds. We characterized the lead compound, mithramycin, based on its ability to inhibit EWS-FLI1 activity in vitro using microarray expression profiling, quantitative reverse transcription-polymerase chain reaction, and immunoblot analysis, and in vivo using immunohistochemistry. We studied the impact of this inhibition on cell viability in vitro and on tumor growth in ESFT xenograft models in vivo (n = 15-20 mice per group). All statistical tests were two-sided.
RESULTS - Mithramycin inhibited expression of EWS-FLI1 downstream targets at the mRNA and protein levels and decreased the growth of ESFT cells at half maximal inhibitory concentrations between 10 (95% confidence interval [CI] = 8 to 13 nM) and 15 nM (95% CI = 13 to 19 nM). Mithramycin suppressed the growth of two different ESFT xenograft tumors and prolonged the survival of ESFT xenograft-bearing mice by causing a decrease in mean tumor volume. For example, in the TC32 xenograft model, on day 15 of treatment, the mean tumor volume for the mithramycin-treated mice was approximately 3% of the tumor volume observed in the control mice (mithramycin vs control: 69 vs 2388 mm(3), difference = 2319 mm(3), 95% CI = 1766 to 2872 mm(3), P < .001).
CONCLUSION - Mithramycin inhibits EWS-FLI1 activity and demonstrates ESFT antitumor activity both in vitro and in vivo.
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25 MeSH Terms
Investigation of the insulin-like growth factor-1 signaling pathway in localized Ewing sarcoma: a report from the Children's Oncology Group.
Borinstein SC, Barkauskas DA, Krailo M, Scher D, Scher L, Schlottmann S, Kallakury B, Dickman PS, Pawel BR, West DC, Womer RB, Toretsky JA
(2011) Cancer 117: 4966-76
MeSH Terms: Adolescent, Adult, Age Factors, Child, Female, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Sarcoma, Ewing, Signal Transduction
Show Abstract · Added March 31, 2014
BACKGROUND - The insulin-like growth factor-1 (IGF-1) signaling pathway plays an important role in the pathology of Ewing sarcoma (ES). Retrospective studies have suggested that levels of IGF-1 and IGF binding protein 3 (IGFBP-3) are correlated with the outcome of patients with ES.
METHODS - The IGF-1 signaling pathway was investigated prospectively in 269 patients who had localized, previously untreated ES. Serum samples were obtained at diagnosis, and concentrations of IGF-1 and IGFBP-3 were determined by enzyme-linked immunosorbent assays. In addition, immunohistochemistry (IHC) was performed to assay for phosphorylated p70S6 kinase, protein kinase B (Akt), and forkhead box protein O1 (FOXO1) and to determine the presence of protein tyrosine phosphatase-L1 (PTPL1). IHC findings along with IGF-1 and IGFBP-3 concentrations were correlated with age, tumor location, sex, event-free survival, and overall survival.
RESULTS - Patients aged >18 years tended to have higher levels of IGF-1 (P = .10), lower levels of IGFBP-3 (P = .16), and decreased IGFBP-3:IGF-1 ratios (P = .01). No correlations were observed between sex, tumor location, or outcomes and concentrations of IGF-1 or IGFBP-3. Phosphorylation of p70S6 kinase, Akt, and FOXO1 was detected in the majority of patient tissues but was not associated with age, sex, or tumor location. PTPL1 was present in >80% of tumors and also was not correlated with age, sex, or tumor location. There was no difference in survival with respect to the presence of phosphorylated p70S6 kinase, phosphorylated FOXO1, phosphorylated Akt, or PTPL1.
CONCLUSIONS - The baseline IGFBP-3:IGF-1 ratio was correlated with age but did not affect the outcomes of patients with ES. The authors concluded that additional investigation of the IGF-1 pathway is warranted in patients with ES, and especially in those who have received treatment with IGF-1 receptor antibody inhibitors.
Copyright © 2011 American Cancer Society.
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11 MeSH Terms
Ecteinascidin 743 interferes with the activity of EWS-FLI1 in Ewing sarcoma cells.
Grohar PJ, Griffin LB, Yeung C, Chen QR, Pommier Y, Khanna C, Khan J, Helman LJ
(2011) Neoplasia 13: 145-53
MeSH Terms: Antineoplastic Agents, Alkylating, Bone Neoplasms, Cell Line, Tumor, Child, DAX-1 Orphan Nuclear Receptor, Dioxoles, Europe, Gene Expression Regulation, Neoplastic, Humans, Oncogene Proteins, Fusion, Promoter Regions, Genetic, Proto-Oncogene Protein c-fli-1, RNA-Binding Protein EWS, RNA-Binding Protein FUS, Sarcoma, Sarcoma, Ewing, Tetrahydroisoquinolines, Trabectedin, Transcription Factor CHOP
Show Abstract · Added September 3, 2013
ET-743 (trabectedin; Yondelis) is approved in Europe for the treatment of soft tissue sarcomas. Emerging phase 1 and 2 clinical data have shown high response rates in myxoid liposarcoma in part owing to the inhibition of the FUS-CHOP transcription factor. In this report, we show that modulation of specific oncogenic transcription factors by ET-743 may extend to other tumor types. We demonstrate that, among a panel of pediatric sarcomas, Ewing sarcoma family of tumors (ESFTs) cell lines bearing the EWS-FLI1 transcription factor are the most sensitive to treatment with ET-743 compared with osteosarcoma, rhabdomyosarcoma, and synovial sarcoma. We show that ET-743 reverses a gene signature of induced downstream targets of EWS-FLI1 in two different ESFT cell lines (P = .001). In addition, ET-743 directly suppresses the promoter activity of a known EWS-FLI1 downstream target NR0B1 luciferase reporter construct without changing the activity of a constitutively active control in ESFT cells. Furthermore, the effect is specific to EWS-FLI1, as forced expression of EWS-FLI1 in a cell type that normally lacks this fusion protein, HT1080 cells, induces the same NR0B1 promoter, but this activation is completely blocked by ET-743 treatment. Finally, we used gene set enrichment analysis to confirm that other mechanisms of ET-743 are active in ESFT cells. These results suggest a particular role for ET-743 in the treatment of translocation-positive tumors. In addition, the modulation of EWS-FLI1 makes it a novel targeting agent for ESFT and suggests that further development of this compound for the treatment of ESFT is warranted.
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19 MeSH Terms