defactinib and fasudil

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the Western world with limited therapeutic options and dismal long-term survival. The neoplastic epithelium exists within a dense stroma, which is recognized as a critical mediator of disease progression through direct effects on cancer cells and indirect effects on the tumour immune microenvironment. The three dominant entities in the PDAC stroma are extracellular matrix (ECM), vasculature and cancer-associated fibroblasts (CAFs). The ECM can function as a barrier to effective drug delivery to PDAC cancer cells, and a multitude of strategies to target the ECM have been attempted in the past decade. The tumour vasculature is a complex system and, although multiple anti-angiogenesis agents have already failed late-stage clinical trials in PDAC, other vasculature-targeting approaches aimed at vessel normalization and tumour immunosensitization have shown promise in preclinical models. Lastly, PDAC CAFs participate in active cross-talk with cancer cells within the tumour microenvironment. The existence of intratumoural CAF heterogeneity represents a paradigm shift in PDAC CAF biology, with myofibroblastic and inflammatory CAF subtypes that likely make distinct contributions to PDAC progression. In this Review, we discuss our current understanding of the three principal constituents of PDAC stroma, their effect on the prevalent immune landscape and promising therapeutic targets within this compartment.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal; Extracellular Fluid; Extracellular Matrix; Focal Adhesion Protein-Tyrosine Kinases; Humans; Hyaluronic Acid; Hyaluronoglucosaminidase; Mice; Molecular Targeted Therapy; Pancreatic Neoplasms; Permeability; Pressure; Protein Kinase Inhibitors; Pyrazines; rho-Associated Kinases; Sulfonamides; Tumor Microenvironment