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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.