Molecular Therapeutics of Pancreatic Ductal Adenocarcinoma: Targeted Pathways and the Role of Cancer Stem Cells

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. 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. 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. a protein that binds chiefly to a receptor on endothelial cells and promotes the maturation and stability of blood vessels. the leakage of blood, lymph, or other fluid, such as an anticancer drug, from a blood vessel or tube into the tissue around it. a large glycoprotein that acts as a host defence mechanism. a substance made by the body that functions to regulate cell division and cell survival. an acid mucopolysaccharide that acts as the binding and protective agent of the ground substance of connective tissue. a fibrous glycoprotein forming a major component of basement membranes and serving as an adhesive surface for epithelial cells. cancer that has spread from where it started to nearby tissue or lymph nodes. a common combination of insulin resistance and type 2 diabetes with central obesity. antibody made from cloned organisms (i.e., all with identical DNA). The main uses of monoclonal antibodies are in specific anticancer therapy and immunosuppression. a gene that is a mutated (changed) form of a gene involved in normal cell growth. Oncogenes may cause the growth of cancer cells. the length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive. the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. a normal gene that helps a cell grow. a type of unstable molecule that contains oxygen and that easily reacts with other molecules in a cell. A build-up of reactive oxygen species in cells may cause damage to DNA, RNA, and proteins and may cause cell death. the percentage of patients whose cancer shrinks or disappears after treatment. fibrous connective tissue or other intercellular material that forms the structural framework of an organ. death of cells caused by concomitant perturbations in the expression of two genes, each of which is nonlethal by itself. the transplant of an organ, tissue, or cells to an individual of another species.