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Published on: June 27, 2020
Combined transcriptional and translational targeting of EWS/FLI-1 in Ewing's sarcoma
Silvia Mateo-Lozano1, Prafulla C Gokhale, Viatcheslav A Soldatenkov
1Laboratory of Experimental Carcinogenesis, Department of Radiation Medicine, V.T. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia 20057-1482, USA.
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 the EWS/FLI-1 protein, cell proliferation, cell cycle distribution, apoptotic cell death, caspase activation, and tumor growth in EWS xenografts implanted in nude mice.
Results:
Simultaneous exposure of EWS cells in culture to an EWS/FLI-1-targeted suppression therapy using specific antisense oligonucleotides and rapamycin resulted in the activation of a caspase-dependent apoptotic process that involved the restoration of the transforming growth factor-beta-induced proapoptotic pathway. In vivo, individual administration of either antisense oligonucleotides or rapamycin significantly delayed tumor development, and the combined treatment with antisense oligonucleotides and rapamycin caused a considerably stronger inhibition of tumor growth.
Conclusions:
Concurrent administration of EWS/FLI-1 antisense oligonucleotides and rapamycin efficiently induced the apoptotic death of EWS cells in culture through a process involving transforming growth factor-beta. In vivo experiments conclusively showed that the combined treatment with antisense oligonucleotides and rapamycin caused a significant inhibition of tumor growth in mice. These results provide proof of principle for further exploration of the potential of this combined therapeutic modality as a novel strategy for the treatment of tumors of the Ewing's sarcoma family.
Insights
This study demonstrates that combining EWS/FLI-1 antisense oligonucleotides and rapamycin effectively kills Ewing
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ewing's sarcoma (EWS) is an aggressive bone and soft tissue cancer.
- The EWS/FLI-1 fusion protein is a key driver of EWS development and progression.
- Targeting EWS/FLI-1 offers a potential therapeutic strategy.
Purpose of the Study:
- To evaluate the efficacy of combined antisense oligonucleotides targeting EWS/FLI-1 and rapamycin.
- To assess the impact on EWS cell proliferation in vitro and tumor xenografts in vivo.
Main Methods:
- EWS cells were treated with EWS/FLI-1 antisense oligonucleotides and rapamycin.
- Evaluated endpoints included EWS/FLI-1 expression, cell proliferation, apoptosis, and tumor growth in mouse xenografts.
Main Results:
- Combined treatment induced caspase-dependent apoptosis in EWS cells.
- Restoration of the transforming growth factor-beta pathway was observed.
- In vivo, combination therapy significantly inhibited tumor growth more than individual treatments.
Conclusions:
- Concurrent administration of EWS/FLI-1 antisense oligonucleotides and rapamycin induces apoptosis in EWS cells.
- This combination therapy shows significant potential for treating Ewing's sarcoma family tumors.
- Further research is warranted to explore this novel therapeutic strategy.
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