Drug Repurposing, an Attractive Strategy in Pancreatic Cancer Treatment: Preclinical and Clinical Updates

SIMPLE SUMMARY: The purpose of this review is to provide an update on some of the most promising non-oncology drugs that are already approved and that could be useful also in the treatment of pancreatic cancer, one of the deadliest malignancies worldwide. Current chemotherapy options are unsatisfactory in this cancer and there is an urgent need for more effective and less toxic drugs to improve the dismal pancreatic cancer therapy. The use in cancer therapy of drugs approved for other indications (drug repurposing) is an attractive approach that has the potential to overcome several issues associated with de novo drug discovery, such as dose-finding and safety profiles, accelerating their clinical adoption. In this review, we report proposed mechanisms of action and biological targets of drugs that are candidates for repurposing in pancreatic cancer therapy, focusing on targets that appear to be relevant for their anticancer action. Finally, considering that cancer immunotherapy provides remarkable long-term remission in some responsive tumors and that this strategy is mostly ineffective in pancreatic cancer patients, we discuss recent developments regarding the ability of some repurposing drug candidates to activate anti-tumor immune response, which may be particularly relevant for their clinical effectiveness. ABSTRACT: Pancreatic cancer (PC) is one of the deadliest malignancies worldwide, since patients rarely display symptoms until an advanced and unresectable stage of the disease. Current chemotherapy options are unsatisfactory and there is an urgent need for more effective and less toxic drugs to improve the dismal PC therapy. Repurposing of non-oncology drugs in PC treatment represents a very promising therapeutic option and different compounds are currently being considered as candidates for repurposing in the treatment of this tumor. In this review, we provide an update on some of the most promising FDA-approved, non-oncology, repurposed drug candidates that show prominent clinical and preclinical data in pancreatic cancer. We also focus on proposed mechanisms of action and known molecular targets that they modulate in PC. Furthermore, we provide an explorative bioinformatic analysis, which suggests that some of the PC repurposed drug candidates have additional, unexplored, oncology-relevant targets. Finally, we discuss recent developments regarding the immunomodulatory role displayed by some of these drugs, which may expand their potential application in synergy with approved anticancer immunomodulatory agents that are mostly ineffective as single agents in PC.