This recent publication describes six new PDX lines derived by direct implantation of tumor specimens, both from the liver (one primary and one recurrent tumor) and metastases. These facilitated the first reported large-scale screening of compounds for the ability to kill dissociated FLC tumor cells in short-term culture (72 hours). Active compounds were also assessed on cells obtained directly from patients, taken from lymph node metastases or ascitic fluid, and in vivo in mice bearing the PDX. A library of >5000 compounds, selected as suitable for drug repurposing, included clinically approved drugs, drugs in preclinical development, and other relevant bioactive species. The results revealed promising activity of several classes of inhibitors, including those for topoisomerase I (TOPOI) and histone deacetylase (HDAC). In addition, potent activity was observed for napabucasin and attributed to generation of reactive oxygen species (ROS) and decreased synthesis of certain proteins via inhibition of eukaryotic initiation factor-4A (eIF4A). Inhibitors of the anti-apoptotic protein Bcl-xL, but not BCL-2, synergized with other effective compounds. The data reported in this study may represent a major step towards clinical trials of the active molecules.
Click here to view Rockefeller University’s announcement of the publication and related comments by Sanford M. Simon, author of the study and head of Rockefeller University’s Laboratory of Cellular Biophysics.
The full article is listed below:
Licensed under a Creative Commons Attribution 3.0 License.