Oncology · Medical Literature
Preclinical characterization and phase 1 clinical testing of targeting mitochondrial peroxiredoxin 3 in cancer.
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.
Clinical relevance
In patients with relapsed pleural mesothelioma and malignant pleural effusion, is weekly intrapleural administration of RSO-021 (a clinical formulation of the PRX3 inhibitor thiostrepton) safe, tolerable, and associated with preliminary anti-tumor activity? __SNAPSHOT__ {"studyDesign":"Combined preclinical study and first-in-human Phase 1 open-label, non-randomized, multicenter, translational dose-escalation trial (MITOPE; NCT05278975)","setting":"Multiple centers in the United Kingdom; conducted under MHRA oversight (2022–2023)","sampleSize":"n=15 total enrolled (n=12 with pleural mesothelioma; n=3 with other solid tumors metastatic to pleura); 9–10 evaluable for efficacy at the recommended Phase 2 dose (90 mg)","population":"Adults with relapsed or refractory pleural mesothelioma (or other advanced solid tumors) with malignant pleural effusion managed via indwelling pleural catheter; heavily pre-treated population","intervention":"RSO-021 (clinical formulation of thiostrepton), administered as weekly intrapleural instillation via indwelling pleural catheter at dose levels of 90, 120, and 180 mg","comparator":"Not applicable (single-arm, dose-escalation study; no control arm)","primaryOutcome":"Safety, tolerability, and dose-finding (maximum tolerated dose/recommended Phase 2 dose); secondary endpoints included pharmacokinetics, objective response rate (ORR), disease control rate (DCR), and pharmacodynamic on-target activity","followUp":"Survival data cut-off at 80 weeks; partial response durability reported to week 30; median progression-free survival reported at recommended dose","fundingSource":"RS Oncology (private, clinical-stage biopharmaceutical company; the Chief Science Officer of RS Oncology is a named co-author and senior investigator)"}
Key findings
Primary endpoints of safety, tolerability, and dose-finding were met. The maximum tolerated dose (MTD) and recommended Phase 2 dose was established at 90 mg/week intrapleural. Three patients (20%) experienced dose-limiting toxicities (DLTs): Grade 3 dyspnea and Grade 3 acute inflammatory response at 120 mg/week, and Grade 3 dyspnea at 180 mg/week. No DLTs occurred at the 90 mg dose level, and no treatment-related deaths were reported. The most common all-grade treatment-related adverse events were fatigue (33%), pyrexia (20%), and elevated creatinine (20%); side effects at 90 mg were predominantly mild. Pro-inflammatory cytokines in pleural fluid correlated with inflammatory adverse events, and prophylaxis mitigated local inflammatory treatment-related adverse events. Pharmacokinetics at 90 mg demonstrated minimal systemic exposure with local pleural fluid drug concentrations increasing cumulatively with weekly dosing, supporting a loco-regional delivery strategy. On-target pharmacodynamic activity was confirmed: PRX3 covalent crosslinking was detected in patient-derived pleural effusion cell pellets 24 hours after the second dose. For efficacy at the recommended 90 mg dose, disease control was achieved in 6 of 9 evaluable mesothelioma patients at 12 weeks (67%; no confidence interval or p-value reported in the abstract). One patient achieved a confirmed partial response (59% reduction in target lesions by mRECIST v1.1), with response durability to week 30. Median progression-free survival at the MTD was 5.7 months (95% CI: 1.4 months–not reached). At 80 weeks' data cutoff, 7 of 12 mesothelioma patients remained alive. Preclinical data supporting the clinical program included: CRISPR-based genetic deletion of PRX3 impaired mitochondrial bioenergetics, suppressed tumor cell proliferation, and abrogated xenograft tumor formation in vivo; pharmacological PRX3 inhibition with thiostrepton induced apoptosis in patient-derived mesothelioma explants. SLC7A11 was identified as a putative biomarker of thiostrepton resistance, and combination of RSO-021 with an SLC7A11 inhibitor (erastin) increased cancer cell death in resistant models. Tumor genomic alterations in BAP1 and SETD2 were associated with apparent increased sensitivity to PRX3 inhibition, though formal statistical comparisons are not reported. An NNT cannot be calculated due to absence of a control arm.
Practice implications
This Phase 1 study established 90 mg/week intrapleural RSO-021 as safe and tolerable in a heavily pre-treated relapsed mesothelioma population, meeting all primary safety and dose-finding endpoints. Preliminary signals of anti-tumor activity—a 67% disease control rate at 12 weeks, one durable partial response, and a median PFS of 5.7 months at the MTD—are clinically notable given the absence of effective salvage therapies in relapsed pleural mesothelioma. However, the study did not establish efficacy: it was not powered or designed to determine whether RSO-021 improves outcomes versus any comparator. The survival data (7 of 12 alive at 80 weeks) are descriptive only; no comparison with historical controls was pre-specified or formally adjusted. Pharmacodynamic confirmation of on-target PRX3 binding in patient pleural effusion samples is a mechanistically important finding that strengthens the biological rationale. The trial population was restricted to patients with indwelling pleural catheters and malignant pleural effusion—a subgroup of the mesothelioma population—limiting generalizability to patients without pleural effusion or those managed without catheters. Patients with peritoneal or pericardial mesothelioma were not studied. Biomarker associations (BAP1/SETD2 mutations, SLC7A11 expression) are hypothesis-generating only. The partial response was notable but represents a single patient event in a very small cohort. Only an abstract and secondary source reporting were available for full quantitative review; the complete peer-reviewed manuscript was accessed via PMID 42448681, but granular subgroup data, full safety tables, and formal statistical analyses beyond those noted above were not available for independent verification. Phase 2 has been completed with results anticipated at a major oncology conference, which will be critical for a more definitive efficacy assessment. __LIMITATIONS__ Very small sample size (n=15 enrolled; n=9–10 evaluable at MTD) with no statistical power for efficacy conclusions,Single-arm, non-randomized design with no concurrent control group; disease control rate and survival data cannot be compared to a standard-of-care arm,Absence of a pre-specified comparator makes it impossible to attribute any survival benefit to RSO-021 versus natural disease course or supportive care,Restricted eligibility (indwelling pleural catheter required, malignant pleural effusion mandatory) severely limits generalizability to the broader mesothelioma population,Open-label design with inherent assessment bias for subjective endpoints,Intrapleural route of administration is feasible only in catheter-eligible patients; systemic or non-pleural disease sites are not directly exposed to drug,Industry sponsorship (RS Oncology) with a named co-author serving as Chief Science Officer introduces potential conflicts of interest,SLC7A11 resistance biomarker and BAP1/SETD2 sensitivity associations are exploratory and unadjusted for multiple comparisons,Efficacy data reported at the 12-week landmark only; longer-term disease control durability beyond one patient is not quantitatively described,Median PFS confidence interval lower bound is 1.4 months with upper bound not reached, reflecting extreme statistical uncertainty given sample size,Full safety table and complete adverse event grading data by dose level were not available from the abstract alone __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ RSO-021 (intrapleural thiostrepton) was well tolerated at 90 mg/week in relapsed pleural mesothelioma, with pharmacodynamic proof of on-target PRX3 inhibition, a 67% disease control rate at 12 weeks, and a median PFS of 5.7 months—signals that are clinically meaningful in a setting with no effective salvage options. These findings do not establish efficacy and should not alter current practice; RSO-021 remains investigational and is not approved outside clinical trials. Phase 2 results are expected imminently and will be essential to determine whether this first-in-class mitochondrial redox strategy warrants expedited development.