The key lies within the mitochondria of tumor cells, where high levels of reactive oxygen species (ROS) accumulate as a result of rapid metabolism. Tumors protect themselves by producing antioxidant enzymes, including peroxiredoxin 3 (PRX3), which detoxifies harmful molecules to maintain cellular survival. Contrary to prior attempts aiming to increase antioxidants to slow tumor growth, the UVM team, led by Professor Brian Cunniff and postdoctoral scientist Victoria Gibson, chose to inhibit PRX3, saturate the tumor with oxidative stress, and induce cell death.

The drug, RSO-021, developed in collaboration with RS Oncology LLC, uses thiostrepton, a naturally occurring antibiotic, to disable PRX3. This inhibition leads to an accumulation of hydrogen peroxide in the mitochondria, triggering apoptosis selectively in cancer cells due to their elevated ROS production. Laboratory experiments demonstrated that removing PRX3 crippled mitochondrial function, arrested tumor growth, and prevented tumor formation in animal models, without adverse effects in healthy mice—addressing common concerns about targeting mitochondria.

A phase one clinical trial conducted in the UK enrolled patients with relapsed mesothelioma, delivering the drug directly into the chest cavity via a catheter. This local administration concentrates the therapy at the tumor site while limiting systemic toxicity. The trial met its safety endpoints, showed disease stabilization in 67% of patients, and, notably, indicated improved overall survival compared to existing treatments—a promising sign of clinical efficacy.

Beyond its cytotoxic effects, preliminary data suggest RSO-021 may also activate the immune system, potentially enhancing the body’s own response to tumors. These dual effects mark a significant advance in cancer therapeutics, blending targeted molecular attack with immunomodulation.

The success of the phase one trial has propelled the research into phase two, with results anticipated later this year. Meanwhile, efforts are underway to develop second-generation PRX3 inhibitors with improved solubility and oral bioavailability, facilitating broader applications across other cancer types. Victoria Gibson continues her work at UVM, expanding investigations into peritoneal and gastrointestinal malignancies.

This paradigm-shifting approach offers a beacon of hope for mesothelioma patients and exemplifies how challenging prevailing cancer treatment dogma can unlock new avenues for therapy with potential widespread impact.

Subject of Research: People
Article Title: Preclinical characterization and phase 1 clinical testing of targeting mitochondrial peroxiredoxin 3 in cancer
News Publication Date: 14-Jul-2026
Web References: http://dx.doi.org/10.1038/s41467-026-75153-y
Image Credits: Joshua Brown/UVM
Keywords: Mesothelioma, PRX3, reactive oxygen species, thiostrepton, mitochondria, cancer therapy, clinical trial, oxidative stress, immunomodulation

Mesothelioma, particularly diffuse pleural mesothelioma, remains a formidable clinical challenge. This aggressive malignancy, predominantly linked to asbestos exposure, has historically seen sparse improvements in survival outcomes. Immunotherapy, especially checkpoint inhibitors targeting PD-1 and CTLA-4 pathways, has revolutionized care for patients with inoperable disease, yet its utility in operable cases remained largely uncharted. The current study closes this gap by investigating neoadjuvant nivolumab, alone or combined with ipilimumab, followed by surgery and adjuvant nivolumab, demonstrating both safety and encouraging survival benefits.

The clinical trial enrolled patients with resectable mesothelioma, with over 80% successfully undergoing surgery within a predetermined window after receiving preoperative immunotherapy. Remarkably, those treated with the dual checkpoint blockade—nivolumab and ipilimumab—achieved a median overall survival of 28.6 months, significantly exceeding the historical average survival of 18 months for mesothelioma. Approximately 36% of these patients remained alive without recurrence at follow-up, underscoring the regimen’s potential to induce durable responses.

What sets this research apart is the comprehensive integration of tumor-informed, ultra-sensitive whole genome sequencing liquid biopsies to monitor circulating tumor DNA (ctDNA). This innovative approach addresses a critical limitation in mesothelioma management: the difficulty of tracking minimal residual disease using conventional imaging or mutation-based liquid biopsies due to the tumor’s low mutational burden. By sequencing the entire genome of tumor-derived DNA fragments in the bloodstream, clinicians can detect microscopic cancer persistence with unprecedented sensitivity.

This liquid biopsy strategy enabled the research team to uncover clinically meaningful insights unattainable through imaging alone. Patients exhibiting undetectable ctDNA levels after neoadjuvant therapy or a reduction of 95% or more during treatment experienced significantly better event-free and overall survival. Conversely, persistent ctDNA signaled impending disease progression, even when radiographic studies remained stable, facilitating earlier intervention decisions.

According to Dr. Valsamo “Elsa” Anagnostou, the study’s senior author and Alex Grass Professor of Oncology, the feasibility and potential efficacy of perioperative combination immune checkpoint blockade mirror successes seen in lung cancer. This parallel not only validates the approach but also opens a new therapeutic avenue for mesothelioma patients who have limited options. The incorporation of ultra-sensitive ctDNA monitoring further adds a layer of precision medicine that could transform individualized treatment decisions.

Technical challenges, such as the low somatic mutation count of mesothelioma tumors, historically hampered mutation-based liquid biopsy approaches. This study surmounts those obstacles by employing genome-wide sequencing that captures ctDNA irrespective of specific mutations, thereby enabling robust detection and dynamic treatment monitoring. Dr. Paul Lee, co-first author, highlighted that this advancement paves the way for clinically actionable, minimally invasive biomarkers that can guide real-time management of residual disease and relapse.

The trial exemplifies multidisciplinary collaboration among numerous academic cancer centers and leverages pharmaceutical partnership, with Bristol Myers Squibb sponsoring the study. Funding from a diverse array of agencies—including the Department of Defense, NIH, FDA, and multiple cancer research foundations—fueled the ambitious scope, ensuring rigorous study design and comprehensive molecular analyses.

In addition to survival metrics, the study illuminates the biologic underpinnings of treatment response and resistance. Monitoring ctDNA dynamics enabled the discernment of patients most likely to benefit from immunotherapy versus those who may require intensified or alternative interventions. This tailored approach holds promise for optimizing therapeutic efficacy while mitigating unnecessary toxicity.

While these findings mark a significant stride in mesothelioma treatment, the authors caution that further investigation is necessary to validate ctDNA as a surrogate marker and refine perioperative immunotherapy protocols. Nonetheless, the demonstrated safety and encouraging survival outcomes provide a compelling rationale for expanded clinical trials and potential integration into standard care.

The confluence of advanced immunotherapy and sensitive genomic monitoring heralds a new era of precision oncology in mesothelioma. This paradigm shift underscores the imperative of combining systemic therapies with molecular diagnostics to outsmart one of the most lethal thoracic malignancies.

As this work progresses, it may catalyze broader applications of perioperative immunotherapy and liquid biopsy surveillance in other low-mutation cancers, broadening the frontier of personalized cancer treatment. For a disease long devoid of substantial improvements, these findings offer renewed hope and a clear path forward for patients and clinicians alike.

Subject of Research: Combination perioperative immunotherapy and ctDNA monitoring in operable mesothelioma

Article Title: Perioperative Combination Immune Checkpoint Blockade and Ultra-Sensitive ctDNA Analysis in Resectable Mesothelioma

News Publication Date: September 8, 2025

Web References:

• Johns Hopkins Kimmel Cancer Center: https://www.hopkinsmedicine.org/kimmel-cancer-center
• Bloomberg-Kimmel Institute for Cancer Immunotherapy: https://www.hopkinsmedicine.org/kimmel-cancer-center/bloomberg-kimmel-institute-for-cancer-immunotherapy
• Original Study in Nature Medicine: https://www.nature.com/articles/s41591-025-03958-3

References: Study presented at the 2025 World Conference on Lung Cancer; multiple grants and institutional supports as detailed in the original publication.

Keywords: Cancer cells, Cancer genomics, Mesothelioma, Immunotherapy, Immune checkpoint blockade, Neoadjuvant therapy, Circulating tumor DNA, Liquid biopsy, ctDNA, Precision oncology, Ultra-sensitive sequencing, Perioperative treatment