Evaluation of Pharmacokinetics and Pharmacodynamics of Palbociclib in in-vitro and in-vivo models of PDAC

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and deadly form of cancer. In recent years, advances in genomic sequencing have allowed for the identification of PDAC genomic subtypes and the development of targeted therapies specifically acting on mutated molecular pathways. The present study aims to optimize the treatment outcomes of the targeted CDK4/6 inhibitor Palbociclib against PDACs by using its innate autofluorescent properties to map the pharmacokinetic drug penetrance and tumour clearance in a spatiotemporally resolved manner using fluorescence lifetime imaging microscopy (FLIM). This study involves the use of genomically sequenced patient-derived TKCC cell lines of different RB status and their associated CAFs (cancer-associated fibroblasts) in vitro and in vivo. This is coupled with the pharmacodynamic evaluation of cell cycle states prior to and after Palbociclib treatment in 3D organotypic matrices and using intravital microscopy (IVM) employing optical imaging windows in primary pancreatic tumours. The findings suggest that Palbociclib FLIM signal can be detected in 2D, 3D and in vivo models of PDAC. In particular, IVM imaging data indicate that pharmacokinetic Palbociclib FLIM signal can be correlated to pharmacodynamic Palbociclib response in primary PDAC tumours.