Epigenetic Small Molecule Library Screen for Inhibition and Reversal of Acinar to Ductal Metaplasia in a Mouse Pancreas 3-Dimensional Organoid Model

We used in vitro mouse pancreatic 3-D organoid model to screen for possible compounds that inhibit or reverse Acinar-to-Ductal Metaplasia, which is a known intial stage of pancreatic ductal adenocarcinoma (PDAC). This model has higher translational value due to the harbored KRASG12D mutation which is common in PDAC patients and is considered a driving mutatrion for cancer development. Observed transcriptomic differences with select hit compounds compared to vehicle control could be very useful for future targeted therapy approach, as well as for further understanding of the driving mechanisms involved in pancreatic metaplasia and PDAC. Some of the hit compounds are already FDA approved drugs that could be easily re-purposed for PDAC treatment or prevention. Mouse 3D organoids harboring an KRASG12D mutation were grown in vitro and left to undergo acinar-to-ductal metaplasia for two days. Then organoids were treated with Largazole (10 µM and 1 µM), its stable homodimer (10 µM and 1 µM), FK228 (1 µM) or Chaetocin (1 µM) at two concentrations.