Exploring the Effect of PAK Inhibition in a 3D Pancreatic Cancer Invasion Model

Abstract

: Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive cancer, with over half of patients presenting with metastatic PDAC at diagnosis. Most patients receive conventional chemotherapy which invariably faces resistance, and a key facilitator in this is the PDAC stroma which acts as a functional mediator of disease progression through bilateral crosstalk between stromal cells and cancer cells. ‘Migrastatics’ are a new drug class which target cell migration pathway effector proteins to attenuate cancer cell invasion. Improvement in PDAC treatment strategy is well-overdue and migrastatics as adjuvant therapy is one avenue gaining traction. The p21-activated kinase (PAK) family is frequently overexpressed and/or amplified in PDAC where it regulates cytoskeletal actin contractility as well as transcription. Pre-clinical PAK inhibitors have shown reduced PDAC cell invasion in vitro, yet it is unknown how the PDAC stromal cells would respond to a PAK inhibitor and how this could consequently affect PDAC invasion. My PhD project investigates the Pancreatic stellate cell response to PAK inhibition.