Combined Transcriptional and Translational Targeting of EWS/FLI-1 in Ewing's Sarcoma

@article{MateoLozano2006CombinedTA,
  title={Combined Transcriptional and Translational Targeting of EWS/FLI-1 in Ewing's Sarcoma},
  author={Silvia Mateo‐Lozano and Prafulla C. Gokhale and Viatcheslav A. Soldatenkov and Anatoly Dritschilo and {\`O}scar Mart{\'i}nez Tirado and Vicente Notario},
  journal={Clinical Cancer Research},
  year={2006},
  volume={12},
  pages={6781 - 6790}
}
Purpose: To show the efficacy of targeting EWS/FLI-1 expression with a combination of specific antisense oligonucleotides and rapamycin for the control of Ewing's sarcoma (EWS) cell proliferation in vitro and the treatment of mouse tumor xenografts in vivo. Experimental Design: EWS cells were simultaneously exposed to EWS/FLI-1–specific antisense oligonucleotides and rapamycin for various time periods. After treatment, the following end points were monitored and evaluated: expression levels of… Expand
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References

SHOWING 1-10 OF 59 REFERENCES
Oncogene-targeted antisense oligonucleotides for the treatment of Ewing sarcoma
TLDR
A tumour inhibitory effect of oligonucleotides targeting the junction point has been demonstrated and other genes participating to the maintenance of the transformed phenotype of Ewing cells have been downregulated by antisense strategies. Expand
Rapamycin induces the fusion-type independent downregulation of the EWS/FLI-1 proteins and inhibits Ewing's sarcoma cell proliferation
TLDR
Data demonstrate that mTOR signaling plays a central role in ES cell pathobiology and strongly suggest that the use of rapamycin as a cytostatic agent may be an efficient tool for the treatment of ES patients. Expand
Therapeutic Potentialities of EWS‐Fli‐1 mRNA‐Targeted Vectorized Antisense Oligonucleotides
TLDR
With AON in nanospheres, it has been shown after 24 hours that the mRNA of EWS‐Fli‐1 was specifically down‐regulated, confirming the antisense activity of the targeted AON. Expand
EWS fli-1 antisense nanocapsules inhibits ewing sarcoma-related tumor in mice.
TLDR
Recently developed polyisobutylcyanoacrylate nanocapsules with an aqueous core were able to encapsulate efficiently high amounts of phosphorothioate oligonucleotides directed against EWS Fli-1 chimeric RNA to obtain inhibition of Ewing sarcoma-related tumor in mice. Expand
Small interfering RNAs expressed from a Pol III promoter suppress the EWS/Fli-1 transcript in an Ewing sarcoma cell line.
TLDR
This work achieves a greater than 80% reduction in the EWS/Fli-1 fusion transcript in an Ewing sarcoma cell line, and provides the first demonstration of expressed siRNAs downregulating an oncogenic fusion transcript. Expand
Potentials for RNAi in sarcoma research and therapy: Ewing's sarcoma as a model.
TLDR
In vitro suppression of EWS-FLI1 expression will allow to define the phenotypic characteristics of dormant tumor cells that may give rise to late relapses, enabling improved diagnosis and treatment even of minimal residual disease. Expand
EWS-Fli1 antisense oligodeoxynucleotide inhibits proliferation of human Ewing's sarcoma and primitive neuroectodermal tumor cells.
TLDR
It is shown that there might be a correlation between the expression levels of the EWS-Fli1 fusion gene and the proliferative activities of Ewing's sarcoma and primitive neuroectodermal tumor cells, and the E WS-Fali1 fusion RNA could be used as a target to inhibit the growth of Ewings' sarcomA and primitive Neuroectoder mal tumor with the specific antisense oligonucleotide. Expand
EWS/FLI-1 Silencing and Gene Profiling of Ewing Cells Reveal Downstream Oncogenic Pathways and a Crucial Role for Repression of Insulin-Like Growth Factor Binding Protein 3
TLDR
It is shown that EWS/FLI-1 can bind the IGFBP-3 promoter in vitro and in vivo and can repress its activity, which identifies the repression of IGF BP-3 as a key event in the development of Ewing's sarcoma. Expand
Regulation of apoptosis and proliferation in Ewing's sarcoma—opportunities for targeted therapy
TLDR
This review will focus on the regulation of major pathways of proliferation and apoptosis in tumors of the Ewing's sarcoma family and point out how modulation of these pathways might be of potential use for future therapy. Expand
The Insulin-like Growth Factor-I Receptor Is Required for EWS/FLI-1 Transformation of Fibroblasts*
TLDR
WF cells demonstrated a greater degree of ligand-stimulated insulin receptor substrate-1 phosphorylation when compared with W cells, suggesting that expression of the EWS/FLI-1 fusion protein alters the IGF-IR signaling pathway. Expand
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