Applying Small Molecule Signal Transducer and Activator of Trancription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics
Menée in vitro et in vivo sur des modèles de cancer du pancréas, cette étude évalue l'activité antitumorale d'un inhibiteur de STAT3
Constitutively activated Signal Transducer and Activator of Transcription 3 (STAT3) protein has been found to be a key regulator of pancreatic cancer and a target for molecular therapeutic intervention. In this study PG-S3-001, a small molecule derived from the SH-4-54 class of STAT3 inhibitors, was found to inhibit patient-derived pancreatic cancer cell proliferation in vitro and in vivo in the low µM range. PG-S3-001 binds the STAT3 protein potently, Kd = 324 nM by SPR, showed no effect in a kinome screen (> 100 cancer-relevant kinases). In vitro studies demonstrated potent cell killing as well as inhibition of STAT3 activation in pancreatic cancer cells. To better model the tumor and its microenvironment, we utilized 3-Dimensional (3D) cultures of patient-derived pancreatic cancer cells in the absence and presence of cancer-associated fibroblasts (CAFs). In this co-culture model, inhibition of tumor growth is maintained following STAT3 inhibition in the presence of CAFs. Confocal microscopy was used to verify tumor cell death following treatment of 3D co-cultures with PG-S3-001. The 3D model was predictive of in vivo efficacy as significant tumor growth inhibition was observed upon administration of PG-S3-001. These studies showed that the inhibition of STAT3 was able to impact the survival of tumor cells in a relevant 3D model, as well as in a xenograft model using patient-derived cells.
http://mct.aacrjournals.org/content/early/2016/02/12/1535-7163.MCT-15-0003.abstract 2016