Ewing sarcoma is a highly aggressive pediatric bone tumor that is characterized EWS/FLI1 transcription factor. Ewing sarcoma tumors require the continued activity of EWS/FLI1 to sustain a gene signature that promotes proliferation and blocks differentiation leading to tumorigenesis and disease progression. Inhibition of EWS/FLI1 activity is not compatible with cell proliferation, which creates an attractive drug target. While no EWS/FLI1 targeted therapies have been translated into the clinic, trabectedin has demonstrated activity in early phase clinical trials. In this report, we optimize trabectedin therapy for the treatment of Ewing sarcoma. We identify the mechanism by which trabectedin inhibits EWS/FLI1 activity and demonstrate that inhibition can be achieved at clinically relevant concentrations. We use this novel mechanism of action to further optimize the schedule of administration and show that maximum EWS/FLI1 inhibition is obtained following a short term, high concentration treatment with trabectedin. Additionally, we characterize a second-generation analog of trabectedin, lurbinectedin, which has an improved pharmacokinetic profile that allows much higher serum concentrations to be achieved. In addition to being a bonafide EWS/FLI1 inhibitor, lurbinectedin can be combined with SN38 (in vitro) or irinotecan (in vivo) to augment the suppression of EWS/FLI1 target genes. Ultimately, we show that this combination strategy decreases tumor growth, extends lifespan, and leads to the differentiation of xenograft mouse models of Ewing sarcoma.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-08072017-112041 |
| Date | 29 August 2017 |
| Creators | Harlow, Matthew |
| Contributors | William P. Tansey, Wael El-Rifai, Stephen Brandt, Michael Freeman |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-08072017-112041/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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