Next Viable Routes to Targeting Pancreatic Cancer Stemness: Learning from Clinical Setbacks

Pancreatic ductal adenocarcinoma (PDAC) is a devastating and highly aggressive malignancy. Existing therapeutic strategies only provide a small survival benefit in patients with PDAC. Laboratory and clinical research have identified various populations of stem-cell-like cancer cells or cancer stem cells (CSCs) as the driving force of PDAC progression, treatment-resistance, and metastasis. Whilst a number of therapeutics aiming at inhibiting or killing CSCs have been developed over the past decade, a series of notable clinical trial setbacks have led to their deprioritization from the pipelines, triggering efforts to refine the current CSC model and exploit alternative therapeutic strategies. This review describes the current and the evolving models of pancreatic CSCs (panCSCs) and the potential factors that hamper the clinical development of panCSC-targeted therapies, emphasizing the heterogeneity, the plasticity, and the non-binary pattern of cancer stemness, as well as the desmoplastic stroma impeding drug penetration. We summarized novel and promising therapeutic strategies implicated by the works of our groups and others' that may overcome these hurdles and have shown efficacies in preclinical models of PDAC, emphasizing the unique advantages of targeting the stroma-engendered panCSC-niches and metronomic chemotherapy. Finally, we proposed feasible clinical trial strategies and biomarkers that can guide the next-generation clinical trials.