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

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.

SUBMITTER: De Lellis L

PROVIDER: S-EPMC8394389 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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

De Lellis Laura L Veschi Serena S Tinari Nicola N Mokini Zhirajr Z Carradori Simone S Brocco Davide D Florio Rosalba R Grassadonia Antonino A Cama Alessandro A

Cancers 20210805 16

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 i ...[more]

PMID: 34439102

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Project description:BackgroundFor pancreatic adenocarcinoma (PDAC), no studies have established any association between earlier treatment initiation and long-term outcomes. In addition, an optimal type of initial treatment for the localized disease remains ill-defined.MethodsPatients in the National Cancer Database (2004-2015) with clinical stage I (CS-I) and II (CS-II) PDAC who underwent curative-intent resection were included. Optimal time from diagnosis-to-treatment including neoadjuvant chemotherapy, neoadjuvant chemoradiation, or upfront surgery was assessed. An optimal type of treatment was evaluated. The primary outcome was overall survival (OS).ResultsAmong 29 167 patients, starting any treatment within 0 to 6 weeks was associated with improved median OS compared with 7 to 12 weeks (21.0 vs 20.1 months; P = .004). This persisted when accounting for sex, race, and Charlson-Deyo score (hazard ratio [HR], 0.94; P = 0.02) and on subset analysis for CS-I (23.5 vs 21.8 months; P = .04) and CS-II (19.4 vs 18.3 months; P = .03). Neoadjuvant chemotherapy was associated with improved OS compared with neoadjuvant chemoradiation (25.6 vs 22.7 months; P < .0001) or US (25.6 vs 20.1 months; P < .0001) even when accounting for sex, race, and Charlson-Deyo score (neoadjuvant chemoradiation: HR, 0.86; P < .001; US: HR, 0.79; P < .001). This improvement persisted in subset analysis with NC compared with neoadjuvant chemoradiation (CS-I: 28.6 vs 25.0 months; CS-II: 25.0 vs 22.9 months; both P < .0001) and to US (CS-I: 28.6 vs 22.9 months; CS-II: 24.7 vs 18.4 months; both P < .0001). On multivariable analysis for each CS-I/CS-II, NC remained associated with 20% improved survival compared with neoadjuvant chemoradiation or upfront surgery.ConclusionsFor PDAC, initiation of therapy within 6 weeks from diagnosis is associated with improved survival, with neoadjuvant chemotherapy associated with the best survival compared with neoadjuvant chemoradiation or upfront surgery.

Dataset Information

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

Publications

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

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