Preclinical characterization and phase 1 clinical testing of targeting mitochondrial peroxiredoxin 3 in cancer

Our plain-English summary of Preclinical characterization and phase 1 clinical testing of targeting mitochondrial peroxiredoxin 3 in cancer, by V. Gibson, J. Dzialo, T. Messier, et al (Nature Communications, 2026).

The study

• Authors: V. Gibson, J. Dzialo, T. Messier, A. Bzura, C. Poile, J. Rogel, J.C. Hahne, A. Habibovic, S. Stead, A. Saaman, K.G. Blyth, P.W. Szlosarek, S. Lord, F. Thistlethwaite, M. Zhang, A. Nakas, P. Wells-Jordan, K. Kutywayo, K.J. Butnor, N.H. Heintz, G.N. Naumov, M. Dungey, J.H. Colomina, B. Aktas, S. Dulloo, J. Spicer, D.A. Fennell, B. Cunniff
• Journal: Nature Communications
• Published: 2026;17(1)
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cancer cells counteract oxidative stress through upregulation of antioxidant networks. Peroxiredoxin 3 (PRX3), a mitochondrial antioxidant enzyme, regulates reactive oxygen species homeostasis and promotes tumor cell survival. The natural compound thiostrepton (TS) covalently inhibits PRX3, disrupting redox balance and selectively induces tumor cell death. Mesothelioma, an aggressive malignancy, has limited therapeutic options, particularly in relapsed or refractory settings. Here, we demonstrate genetic deletion of PRX3 impairs mitochondrial bioenergetics and suppresses mesothelioma growth, while pharmacological inhibition of PRX3 with TS induces apoptosis in patient-derived mesothelioma explants. In a phase 1 trial treating patients with relapsed pleural mesothelioma and malignant pleural effusion (NCT05278975), weekly local intrapleural treatment with the TS formulated drug product RSO-021 at 90 mg is well tolerated leading to disease control in 67% of patients at 12 weeks and is associated with tumor reductions. Primary endpoints of safety, tolerability and dose finding were met, and secondary endpoints of pharmacokinetics, objective response rate, disease control rate, and progression free survival are explored. Genomic screening identified Solute Carrier Family 7 member 11 (SLC7A11) as a mediator of TS resistance, suggesting combined targeting may further enhance the pro-oxidant activity of RSO-021.

© 2026. The Author(s).

In plain English

This article combined laboratory experiments with an early-stage (phase 1) drug trial. It did not study asbestos exposure. The authors tested whether blocking PRX3, an antioxidant enzyme inside cells, could slow mesothelioma. Human mesothelioma cells with PRX3 genetically removed did not form measurable tumors when injected into the abdomens of immunodeficient mice (6 mice per group). The drug thiostrepton caused uneven amounts of cell death in tumor samples taken during surgery from 22 patients. In the trial, 15 patients with fluid around the lung received the thiostrepton product RSO-021 once a week through a tube placed in the chest. Twelve had relapsed pleural mesothelioma (all epithelioid), one had colorectal cancer and two had non-small cell lung cancer. No dose-limiting side effects occurred among seven patients at 90 mg. They occurred in two of six patients at 120 mg and one of two at 180 mg. At 12 weeks, disease was controlled in 6 of 9 evaluable patients (67%), including one partial response. In laboratory work, a gene called SLC7A11 was linked to resistance to the drug. The authors concluded that PRX3 is a tractable treatment target in mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Combined preclinical laboratory study (cell lines, mouse xenografts, patient-derived tumor explants) and a phase 1 dose-finding clinical trial using a 3 + 3 design (MITOPE, NCT05278975)
• Who was studied: Laboratory work used the human mesothelioma cell line H-MESO-1, immunodeficient (SCID) mice, and 22 mesothelioma patient-derived explants from the MEDUSA cohort. The trial treated 15 patients with malignant pleural effusion: 12 with pleural mesothelioma (all epithelioid, all having failed standard treatment), one with colorectal cancer and two with non-small cell lung cancer. The trial dates are not stated in the text.
• Exposure: Not asbestos. The exposures studied were genetic deletion of PRX3 in cells, and the drug thiostrepton (formulated as RSO-021). In patients, RSO-021 was given weekly into the pleural space through an indwelling pleural catheter at 90 mg, 120 mg or 180 mg.
• Main results:
  • In mice (6 animals per group), mesothelioma cells with PRX3 deleted did not form measurable tumors after 41 days, while control cells did.
  • In the 22 patient-derived explants, thiostrepton caused cell death markers to rise by differing amounts from sample to sample.
  • In the explants, losses, deletions and mutations in the BAP1 and SETD2 genes were more frequent in the responder group (p = 0.0124 for BAP1, p = 0.03 for SETD2).
  • Among the seven patients treated at 90 mg, no dose-limiting toxicities were seen.
  • At 120 mg, dose-limiting toxicities occurred in two of six patients (grade 3 acute inflammatory response and grade 3 shortness of breath). At 180 mg, one occurred in the two patients treated (grade 3 dyspnea).
  • By 12 weeks, disease control was seen in 6 of 9 evaluable patients (67%): one partial response and five with stable disease.
  • A partial response was reported in one of 10 evaluable patients (10%), described as in the 90 mg treatment cohort.
  • Among mesothelioma patients in the trial, median progression-free survival was 18 weeks (9 patients). Median overall survival was not reached by 80 weeks (12 patients).
  • In the first 24 hours after a dose given into the chest, drug levels in the blood were 1000-fold lower than the doses given.
  • In the trial, pleural fluid drainage fell from a median of 700 ml/week before treatment to a median of 175 ml/week at the end of treatment.
  • In cell experiments, silencing SLC7A11 made mesothelioma cells more sensitive to thiostrepton. The EC50 was 0.27 µM in silenced cells versus about 1 µM in control cells.
  • Before treatment, SLC7A11 expression was higher in the explants that responded poorly (non-responders) (adjusted p = 0.0021).
• The authors' conclusion: The authors concluded that PRX3 inhibition is a tractable therapeutic target in mesothelioma and that SLC7A11 confers resistance. They stated that the trial findings supported moving RSO-021 to phase 2 testing.
• Limitations the authors state:
  • The authors stated that the reduction in pleural fluid volume matched what is expected from the chest catheter itself, and was therefore not suggestive of a drug effect.
  • The authors noted that their earlier work, which reduced rather than deleted PRX3, gave conflicting results on mitochondrial measurements, and that this warrants further investigation.
  • The authors stated that baseline SLC7A11 expression explains only part of the variation in explant response.
  • No correction for multiple statistical testing was applied in most analyses.
  • The drug was given only into the pleural space. The authors stated that future studies are needed with forms of the drug that work throughout the body.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Oxidative Stress, Reactive Oxygen Species (ROS), Mesothelioma, Apoptosis, Pleural Mesothelioma, Pleural Effusion.

Related studies

• Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells — B. Cunniff, K. Benson, et al. (2013)
• Peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells — B. Cunniff, A.N. Wozniak, et al. (2014)
• Peroxiredoxin 3 is a redox-dependent target of thiostrepton in malignant mesothelioma cells — K. Newick, B. Cunniff, et al. (2012)
• Mechanism-based peroxiredoxin 3 inhibitors exploit a covalent warhead for cancer therapy — K.J. Nelson, T.L. Smalley, et al. (2025)
• Mitochondrial targeting of α-tocopheryl succinate enhances its anti-mesothelioma efficacy — J. Kovarova, M. Bajzikova, et al. (2014)
• The endoplasmic reticulum mitochondrial calcium cross talk is downregulated in malignant pleural mesothelioma cells and plays a critical role in apoptosis inhibition — S. Patergnani, C. Giorgi, et al. (2015)

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