Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors
Abstract
:Simple Summary
Abstract
1. Introduction
2. Drug Repositioning to Target the PD-1/PD-L1 Checkpoint
2.1. Repositioning of Liothyronine as a PD-L1 Binding Agent
2.2. Repositioning of Dihydropyridine Calcium Channel Blockers to Treat Cancer
2.3. Repositioning of Niclosamide as a STAT3-Dependent Regulator of the PD-1/PD-L1 Checkpoint
2.4. Albendazole and Flubendazole to Modulate the PD-1/PD-L1 Checkpoint
2.5. Other Repositioning Drug Candidates Affecting the PD-1/PD-L1 Checkpoint
- (i)
- The antidiabetic drug repaglinide is commonly used to stimulate insulin secretion from pancreatic beta cells. The drug has been shown recently to inhibit the transcription factor FOXO3 and to reduce cancer cell migration [119]. The drug has the capacity to down-regulate PD-L1 expression in glioblastoma cells [120].
- (ii)
- The dopamine antagonist pimozide, used to treat various psychiatric diseases, has been found to display interesting antileukemic and anticancer properties. The drug can reduce activation of STAT3 and STAT5 [121,122,123]. The combination of pimozide and an anti-PD-1 agent profoundly down-regulated expression of phospho-STAT5, leading to a major antitumor response in a model of melanoma. The drug enhanced PD-1 expression, rendering the tumor more sensitive to the anti-PD-1 agent [124].
- (iii)
- A repurposing of the lipid-lowering drug fenofibrate for the treatment of cancer has been proposed [125]. A recent work demonstrates that the drug can reprogram the immune microenvironment in a model of head and neck cancer. The drug was found to down-regulate PD-L1 expression in UMSCC47 cancer cells cultivated under hypoxic conditions (1% O2), probably due to a down-regulation of the upstream target hypoxia-inducible factor-1α (HIF1α) [126]. Fenofibrate has been tested in patients with multiple myeloma (NCT01965834), but not in association with an anti-PD-(L)1 mAb.
- (iv)
- In general, β-blockers are considered not to alter the antitumor response in patients with melanoma treated with anti-PD-1 therapy [127]. It has been reported that the use of β2-adrenergic receptor (βAR) antagonists (β-blockers) can improve overall survival in metastatic melanoma patients who received immunotherapy [128]. The βAR is a regulator of CD8+ T cell frequency and functional orientation within the tumor microenvironment [129]. The repurposing of β-blockers for the treatment of triple-negative breast cancer (TNBC) has been proposed previously, based on the high expression of βAR in TNBC cell lines and the capacity of β-blockers such as propranolol to reduce their proliferation, migration, and invasion [130]. β-blockers do not directly target the PD-1/PD-L1 system, but they exert useful antiangiogenic effects. Recent clinical trials have indicated that a combination of β-blockers with anti-PD-1/PD-L1 mAbs could be useful to improve progression-free survival in patients with NSCLC [131]. The β-blocker propranolol is particularly interesting, as it has been shown not only to upregulate PD-L1 expressed on tumor-associated macrophages (TAM), but also to enhance efficacy of an anti-CTLA4 therapy in soft tissue sarcoma [132]. A recent phase 1 trial in patients with metastatic melanoma has shown that the combination of propranolol and pembrolizumab (anti-PD1) is safe (no dose-limiting toxicity observed) and preliminary signs of activity were reported (increased interferon-γ, decreased interleukin-6) [133].
3. Discussion
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Thuru, X.; Magnez, R.; El-Bouazzati, H.; Vergoten, G.; Quesnel, B.; Bailly, C. Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors. Cancers 2022, 14, 3368. https://doi.org/10.3390/cancers14143368
Thuru X, Magnez R, El-Bouazzati H, Vergoten G, Quesnel B, Bailly C. Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors. Cancers. 2022; 14(14):3368. https://doi.org/10.3390/cancers14143368
Chicago/Turabian StyleThuru, Xavier, Romain Magnez, Hassiba El-Bouazzati, Gérard Vergoten, Bruno Quesnel, and Christian Bailly. 2022. "Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors" Cancers 14, no. 14: 3368. https://doi.org/10.3390/cancers14143368