Pancreatic cancer is the third leading cause of cancer death in the USA, and pancreatic ductal adenocarcinoma (PDA) constitutes 85% of pancreatic cancer diagnoses. PDA frequently metastasizes to the peritoneum, but effective treatment of peritoneal metastasis remains a clinical challenge. Despite this unmet need, understanding of the biological mechanisms that contribute to development and progression of PDA peritoneal metastasis is sparse. By contrast, a vast number of studies have investigated mechanisms of peritoneal metastasis in ovarian and gastric cancers. Here, we contrast similarities and differences between peritoneal metastasis in PDA as compared with those in gastric and ovarian cancer by outlining molecular mediators involved in each step of the peritoneal metastasis cascade. This review aims to provide mechanistic insights that could be translated into effective targeted therapies for patients with peritoneal metastasis from PDA.

Mesothelin (MSLN) is a cell surface glycoprotein normally expressed only on serosal surfaces, and not found in the parenchyma of vital organs. Many solid tumors also express MSLN, including mesothelioma and pancreatic adenocarcinoma. Due to this favorable expression profile, MSLN represents a viable target for directed anti-neoplastic therapies, such as recombinant immunotoxins (iToxs). Pre-clinical testing of MSLN-targeted iTox’s has yielded a strong body of evidence for activity against a number of solid tumors. This has led to multiple clinical trials, testing the safety and efficacy of the clinical leads SS1P and LMB-100. While promising clinical results have been observed, neutralizing anti-drug antibody (ADA) formation presents a major challenge to overcome in the therapeutic development process. Additionally, on-target, off-tumor toxicity from serositis and non-specific capillary leak syndrome (CLS) also limits the dose, and therefore, impact anti-tumor activity. This review summarizes existing pre-clinical and clinical data on MSLN-targeted iTox’s. In addition, we address the potential future directions of research to enhance the activity of these anti-tumor agents.