Molecular Therapeutics of Pancreatic Ductal Adenocarcinoma: Targeted Pathways and the Role of Cancer Stem Cells. (December 2020)

• Record Type: Journal Article
• Authors: Stoica, Andrei-Florian; Chang, Chao-Hui; Pauklin, Siim
• Is Part Of: Trends in pharmacological sciences. Volume 41:Number 12(2020)
• Page Start: 977
• Page End: 993
• Publication Date: 2020-12
• Subjects: pancreatic ductal adenocarcinoma -- cancer therapy -- cancer stem cells -- signalling pathways -- tumour stroma -- cancer hallmarks; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2020.09.008
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans due to late detection and highly metastatic characteristics. PDAC cells vary in their tumorigenic capabilities with the presence of a subset of PDAC cells known as pancreatic cancer stem cells (CSCs), which are more resistant to currently used therapeutics. Here, we describe the role of CSCs and tumour stroma in developing therapeutic strategies for PDAC and suggest that developmental plasticity could be considered a hallmark of cancers. We provide an overview of the molecular targets in PDAC treatments, including targeted therapies of cellular processes such as proliferation, evasion of growth suppressors, activating metastasis, and metabolic effects. Since PDAC is an inflammation-driven cancer, we also revisit therapeutic strategies targeting inflammation and immunotherapy. Lastly, we suggest that targeting epigenetic mechanisms opens therapeutic routes for heterogeneous cancer cell populations, including CSCs. Highlights: Pancreatic ductal adenocarcinoma (PDAC) is among the most metastatic and lethal cancers in humans. PDAC cells are heterogeneous and dedifferentiation leads to the formation of stem cell-like cells known as cancer stem cells (CSCs). These cells can easily metastasise, are more resistant to conventional therapeutics, and can lead to cancer relapse. As an inflammation-driven cancer, PDAC has a large stromal component that is hypovascularised, reducing access of therapeutics to cancer cells. Current therapeutics include FOLFIRINOX, gemcitabine, erlotinib, and nab-paclitaxel, while targeted therapeutics are being explored for signalling pathways that govern the different cancer hallmarks such as proliferation, activating metastasis, metabolic effects, and inflammation. The combined targeting of multiple features of PDAC, including stroma, non-CSCs, and CSCs, is expected to provide improved efficiency. In particular, the targeting of the regulators of phenotypic plasticity in CSCs is an increasingly attractive research avenue.