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Title page for ETD etd-08072017-112041


Type of Document Dissertation
Author Harlow, Matthew L.
URN etd-08072017-112041
Title Optimizing Trabectedin Therapy for the Treatment of Ewing Sarcoma
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Wael El-Rifai Committee Chair
Michael Freeman Committee Member
Stephen Brandt Committee Member
William P. Tansey Committee Member
Keywords
  • Ewing sarcoma
  • trabectedin
  • lurbinectedin
Date of Defense 2017-07-27
Availability restricted
Abstract
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.
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