Abstract
Simple SummaryThe lack of early diagnosis and the absence of suitable biomarkers coupled with resistance to available therapeutic options render pancreatic cancer one of the deadliest cancer types. Therefore, new therapeutic approaches are needed to be developed, taking into account the genetic and molecular profile of pancreatic tumors. Here, we critically review past and current efforts that have resulted in the development of potent and specific antitumor compounds that, if employed in the appropriate combination therapy, may change this recalcitrant cancer type into a manageable one.Cytotoxic chemotherapy remains the only treatment option for most pancreatic ductal adenocarcinoma patients. Currently, the median overall survival of patients with advanced disease rarely exceeds 1 year. The complex network of pancreatic cancer composed of immune cells, endothelial cells, and cancer-associated fibroblasts confers intratumoral and intertumoral heterogeneity with distinct proliferative and metastatic propensity. This heterogeneity can explain why tumors do not behave uniformly and are able to escape therapy. The advance in technology of whole-genome sequencing has now provided the possibility of identifying every somatic mutation, copy-number change, and structural variant in a given cancer, giving rise to personalized targeted therapies. In this review, we provide an overview of the current and emerging treatment strategies in pancreatic cancer. By highlighting new paradigms in pancreatic ductal adenocarcinoma treatment, we hope to stimulate new thoughts for clinical trials aimed at improving patient outcomes.
Highlights
Accepted: 10 February 2021Pancreatic ductal adenocarcinoma remains one of the deadliest malignancies with a 5-year overall survival (OS) of only 9% in 2020 [1]
Similar to human PCa, KRASG12D ; p53R172H ; Pdx-cre (KPC) mouse tumors are known to be refractory to therapy, suggesting that the combination of ATR with chemotherapy may be effective in a subset of human PCa patients
Accumulating evidence suggests that miRNAs by modulating key targets and pathways such as KRAS, PI3K/AKT, TP53, NF-κB, and Hedgehog signaling are associated with resistance of PDAC to chemotherapy
Summary
Pancreatic ductal adenocarcinoma (thereafter PCa) remains one of the deadliest malignancies with a 5-year overall survival (OS) of only 9% in 2020 [1] The reason for this lies on the fact that, due to the late diagnosis, about 80% of patients arriving to the clinic have already locally advanced and unresectable PCa as a result of local invasion of adjacent structures. MFOLFIRINOX or gemcitabine/nab-paclitaxel combination, followed by radiation therapy is recommended, and depending on the presence of alterations, including specific genetic mutations, mismatch repair deficiency, or high microsatellite instability, may receive additional targeted therapies. In such advanced stage and due to the aggressive cell biology of PCa with continuing therapy resistance, the available treatment options are not sufficient for curative outcomes. We critically summarize the latest targeted combination therapies for advanced/metastatic PCa and discuss new viewpoints for therapeutic approaches currently under preclinical evaluation
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