Main content

Contributors:
  1. Sandy Simon

Date created: | Last Updated:

: DOI | ARK

Creating DOI. Please wait...

Create DOI

Category: Data

Description: Here we investigated whether approved or late phase therapeutics could be repurposed for FLC. We generated a collection of FLC patient-derived xenografts (PDX). Resected tumor tissue was implanted without interim cell culture. The PDX were validated for expression of the fusion transcript and protein, and a histopathology and transcriptome that recapitulated the tumor of origin. We tested a repurposing library of >5000 drugs on cells dissociated from the PDX. The top hits included napabucasin, inhibitors of epigenetic modulators, topoisomerase 1 and anti-apoptotic proteins. The efficacy of these hits was further validated on PDX implanted in mice. Cells taken directly from freshly resected patient tumors provided additional validation. We show the activity of napabucasin is mediated through inhibition of translation intiation and by activation of reactive oxygen species. We also demonstrate that drug sensitivity inversely correlates with expression of the anti-apoptic protein Bcl-xL, and that inhibitors of Bcl-xL synergize with other drugs. This is the first large scale drug screen for FLC using PDX made from fresh tissue without interim cell culture. This screen identifies four novel classes of therapeutics for FLC, and synergistic drug combinations. Finally, our direct from patient drug screening provides a rapid assay for the personalized profile of therapeutic efficacy against a solid tumor. Results PDX

Files

Loading files...

Citation

Tags

Recent Activity

Loading logs...