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Updated: Jul 16, 2026
Analytical Determination of Mitochondrial Function of Excised Solid Tumor Homogenates
Published on: August 6, 2021
Preclinical characterization and phase 1 clinical testing of targeting mitochondrial peroxiredoxin 3 in cancer
Victoria Gibson1, Joanna Dzialo2, Terri Messier1
1Department of Pathology and Laboratory Medicine, University of Vermont Cancer Center, Larner College of Medicine, Burlington, VT, USA.
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.
Insights
Thiostrepton (TS) inhibits the antioxidant enzyme PRX3, selectively killing cancer cells. A phase 1 trial showed intrapleural RSO-021 (TS formulation) controlled mesothelioma in 67% of patients, with SLC7A11 identified as a resistance mediator.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Cancer cells utilize antioxidant networks to survive oxidative stress.
- Peroxiredoxin 3 (PRX3), a mitochondrial antioxidant enzyme, is crucial for tumor cell survival.
- Mesothelioma is an aggressive cancer with limited treatment options, especially in relapsed/refractory cases.
Purpose of the Study:
- To investigate the therapeutic potential of PRX3 inhibition in mesothelioma.
- To evaluate the safety and efficacy of intrapleural RSO-021 (thiostrepton formulation) in mesothelioma patients.
Main Methods:
- Genetic deletion of PRX3 to assess its role in mesothelioma growth.
- Pharmacological inhibition of PRX3 using thiostrepton (TS) in patient-derived explants.
- Phase 1 clinical trial (NCT05278975) of intrapleural RSO-021 in relapsed pleural mesothelioma patients.
- Genomic screening to identify mechanisms of TS resistance.
Main Results:
- Genetic PRX3 deletion impaired mitochondrial bioenergetics and suppressed mesothelioma growth.
- TS induced apoptosis in patient-derived mesothelioma explants.
- Intrapleural RSO-021 was well-tolerated, achieving disease control in 67% of patients at 12 weeks.
- Solute Carrier Family 7 member 11 (SLC7A11) was identified as a mediator of TS resistance.
Conclusions:
- PRX3 is a viable therapeutic target in mesothelioma.
- Intrapleural RSO-021 demonstrates promising safety and efficacy in relapsed mesothelioma.
- Combined targeting of PRX3 and SLC7A11 may enhance anti-tumor activity.
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