Metastasis, the dissemination of cancer cells from the primary tumor to distant organs, accounts for the majority of cancer-related mortalities. Despite rigorous treatments including surgery and chemotherapy, residual microscopic cancerous cells evade eradication and seed secondary tumors, complicating patient outcomes and posing a significant therapeutic challenge. Conventional strategies have struggled to selectively inhibit this metastatic cascade without causing systemic toxicity. The newly developed CO prodrug, designated CO-116, offers a promising avenue by releasing precisely controlled, low concentrations of carbon monoxide directly within the body, circumventing the risks associated with inhaled CO and metal-containing CO-releasing molecules.

Dr. Nancy Du, the senior author and associate professor of pathology and laboratory medicine at Weill Cornell Medicine, emphasizes the paradigm-shifting nature of this approach. Carbon monoxide, though infamous for its toxicity at high levels, is endogenously synthesized in mammalian systems as a critical signaling molecule. Harnessing this physiological production, CO-116 has been meticulously designed to deliver CO in a controlled manner, thereby leveraging its anti-metastatic properties while mitigating potential adverse effects. This balance is pivotal for transforming CO from a hazardous gas to a therapeutic agent.

The initial inspiration for this study stems from Dr. Du’s team’s prior work published in 2022, which demonstrated that low-dose carbon monoxide impedes metastatic dissemination in preclinical models. However, the translation of these findings into clinical practice was hindered by the difficulty in safely and effectively administering CO. Inhalation therapies present challenges in achieving precise dosing and bear inherent safety hazards. Past research explored metal-based carbon monoxide-releasing molecules (CORMs), but these approaches often left behind toxic metal residues, limiting their clinical viability.

To circumvent these obstacles, the team collaborated with Dr. Binghe Wang from Georgia State University, an expert in synthetic chemistry, to develop a metal-free prodrug capable of releasing carbon monoxide upon intravenous administration. This prodrug remains inert until metabolized in the body, ensuring targeted CO delivery. The molecular design of CO-116 optimizes pharmacokinetics and bioavailability while eliminating the risks associated with metal toxicity. Such chemical innovation marks a significant leap in the field of CO-based therapeutics.

Subsequent preclinical trials employing various murine models afflicted with pancreatic and triple-negative breast cancer revealed that CO-116 effectively curtailed the progression of metastatic tumors, particularly within intricately vascularized organs like the liver and lungs. Notably, these therapeutic benefits manifested without detectable systemic toxicity, weight loss, or behavioral alterations in treated animals, underscoring the safety profile of the prodrug. These findings underscore the clinical promise of CO-116 as a non-invasive metastasis inhibitor.

More intriguing was the discovery that the frequency and timing of CO-116 administration considerably influenced therapeutic outcomes. Administering smaller doses more frequently proved superior to an equivalent weekly bolus dose, indicating that dynamic CO delivery kinetics optimize anti-metastatic efficacy. This insight could reshape dosing paradigms for future clinical trials and influence the development of personalized CO-based therapeutic regimens tailored to tumor biology and patient physiology.

The researchers delved deeper into the mechanistic underpinnings driving CO-116’s anti-metastatic potency. Their investigations spotlighted the heme-responsive gene 1 (HRG1) protein, a pivotal transporter responsible for heme uptake in cancer cells. Heme, an iron-containing porphyrin complex, is indispensable for myriad cellular processes including oxygen transport and mitochondrial respiration. By attenuating HRG1 expression, CO-116 disrupts heme acquisition, thereby impairing cancer cell metabolic networks and metastatic capabilities.

Functional studies employing genetic manipulation of cancer cells elaborated on the relationship between HRG1 levels and CO sensitivity. Overexpression of HRG1 conferred increased metastatic aggressiveness and resistance to carbon monoxide therapy, whereas silencing HRG1 significantly impeded metastatic growth and enhanced responsiveness to the prodrug. These data suggest HRG1 not only functions as a therapeutic target but may also serve as a predictive biomarker, identifying patients who stand to benefit the most from CO-based treatments.

While the preclinical data are compelling, substantial research remains to translate these findings into human clinical practice. Future investigations must rigorously evaluate the long-term safety profile of CO-116, exploring potential cumulative effects and ensuring no latent toxicities arise over extended treatment durations. Additionally, optimizing dosing schedules through pharmacodynamic and pharmacokinetic studies will be essential to maximize efficacy while minimizing adverse events.

Furthermore, elucidating whether the anti-metastatic effects of CO-116 persist after cessation of therapy will determine its practicality as an adjuvant treatment. The ultimate goal is to integrate CO prodrugs as adjunctive interventions in cancer management, administered post-surgery or chemotherapy to thwart recurrence and improve survival outcomes for patients suffering from aggressive malignancies historically resistant to conventional therapies.

Dr. Du reflects on the broader implications of their discovery, highlighting the transformative impact of deploying a non-inhaled, metal-free carbon monoxide prodrug with demonstrable efficacy across multiple cancer models. This study not only validates CO’s therapeutic potential but also ignites a new frontier in cancer metastasis research, charting a course toward therapies that strike at the heart of cancer’s lethality—the spread and colonization of distant organs.

Supported in part by a Manhasset Women’s Coalition Against Breast Cancer Research Grant and bolstered through NIH funding for the prodrug synthesis in Dr. Wang’s laboratory, this research exemplifies cross-disciplinary collaboration and innovative chemistry driving precision medicine. The strides made herein herald a promising era wherein carbon monoxide’s dual nature is harnessed judiciously to save lives rather than threaten them.

In conclusion, the development of CO-116 represents a pioneering advancement in anti-metastatic treatment strategies, merging chemical ingenuity with biological insight to combat cancer’s deadliest trait. As research progresses and clinical trials emerge, this metal-free carbon monoxide prodrug could become an indispensable weapon in the arsenal against metastatic pancreatic and triple-negative breast cancers, offering renewed hope to patients worldwide confronting these formidable diseases.

Subject of Research: Development of a metal-free carbon monoxide prodrug to inhibit metastasis in pancreatic and triple-negative breast cancer.

Article Title: A Metal-Free Carbon Monoxide Prodrug Suppresses Metastatic Progression in Preclinical Models of Pancreatic and Triple-Negative Breast Cancer.

News Publication Date: March 20, 2026.

Web References:

• Original Study: https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202519898
• Prior Research: https://www.sciencedirect.com/science/article/abs/pii/S0304383522003159

Keywords: Carbon monoxide, CO prodrug, metastasis inhibition, pancreatic cancer, triple-negative breast cancer, HRG1, heme transporter, metal-free therapeutics, anti-cancer therapy, controlled drug delivery, preclinical cancer models, cancer metastasis

The innovative tactic devised by the Wake Forest team hinges on selectively inhibiting PRX3, thereby disrupting the cell’s antioxidative defense mechanism and triggering an intracellular buildup of toxic hydrogen peroxide. This method exploits the cancer cells’ altered redox balance and metabolic flux, effectively pushing them beyond their oxidative stress threshold and inducing cell death. Published in Science Advances, the research details how disabling this mitochondrial cleanup protein serves as a molecular “kill switch,” selectively targeting tumoral cells while sparing normal cells that maintain a lower baseline production of reactive oxygen species.

Central to this discovery is the natural molecule thiostrepton, a complex compound previously recognized for its anticancer potential but limited in clinical applicability due to its bulky structure and poor solubility. The investigative team, including experts in biochemistry and medicinal chemistry, systematically deconstructed thiostrepton into smaller fragments to isolate the minimal pharmacophore responsible for PRX3 inhibition. This meticulous structural dissection led to the identification of WF-242, a significantly reduced molecular fragment exhibiting potent anticancer activity akin to the parent compound but with improved drug-like characteristics, particularly solubility and specificity.

The significance of WF-242 lies not only in its efficacy but also in its diminished off-target effects, a critical consideration in drug development. Whereas intact thiostrepton interacts broadly with cellular components, often eliciting undesirable side effects, WF-242’s reduced complexity translates to increased specificity for PRX3, enhancing therapeutic precision and potentially mitigating cytotoxicity in non-cancerous tissue. This refined selectivity emerges from the fragment’s ability to covalently bind to PRX3, a biochemical interaction elucidated via high-resolution X-ray crystallography, which provided invaluable insights into the molecular interface between the inhibitor and its target protein.

This structural elucidation empowers rational drug design, facilitating the fine-tuning of chemical properties to optimize stability and bioavailability—an essential step toward clinical viability. Current efforts focus on enhancing WF-242’s pharmacokinetic profile to render it suitable for intravenous administration, thereby expanding its therapeutic reach beyond localized applications such as direct lung delivery currently under exploration for mesothelioma treatment. This expansion holds promise for addressing metastatic and systemic malignancies, including ovarian, lung, prostate, brain, and hematologic cancers, which demonstrated susceptibility to PRX3 inhibition in cell-based assays.

The strategic elevation of oxidative stress in tumors marks a paradigm shift from traditional antioxidant-centric cancer therapies. Instead of mitigating oxidative damage, this approach leverages the inherently precarious redox equilibrium within cancer cells, deliberately amplifying oxidative stress to cytotoxic levels. Given that cancer cells operate near the brink of oxidative tolerance due to their hypermetabolic state, they are uniquely predisposed to this mode of intervention. This therapeutic exploitation of tumor biology underscores the precision and rationality of targeted cancer treatment modalities poised to improve clinical outcomes.

Mesothelioma, a notoriously aggressive malignancy with limited systemic treatment options and poor prognostic outlooks, serves as a key application target for this technology. While thiostrepton’s application has been constrained to localized lung delivery, WF-242’s favorable physicochemical properties open avenues for broader systemic therapies. The molecule’s ability to circumvent solubility and delivery challenges could transform the management of this devastating disease by providing a novel class of chemotherapeutic agents capable of intravenous administration.

The development trajectory of WF-242 embodies the quintessential pathway from natural product derivatization to precision pharmacology. This process illustrates how fundamental biochemical insights combined with advanced structural techniques and medicinal chemistry can yield transformative therapeutic candidates. The ongoing refinement and preclinical evaluation phases are critical milestones preceding human clinical trials, typically requiring several years of meticulous research and optimization to ensure safety, efficacy, and regulatory compliance.

Funding for this pioneering endeavor has been provided by the Wake Forest Innovations Catalyst Fund, Atrium Health Wake Forest Baptist Comprehensive Cancer Center, and the Center for Redox Biology and Medicine. Their support underscores the imperative of investing in innovative redox biology approaches to surmount longstanding challenges in cancer management. Should clinical translation prove successful, this research portends a new era in cancer treatment, where manipulation of intracellular oxidative environments becomes a frontline strategy in combating diverse malignancies.

The discovery also highlights the interdisciplinary collaboration essential to contemporary drug development, integrating biochemistry, structural biology, pharmacology, and clinical oncology. The insights gained from visualizing drug-protein interactions provide a roadmap for subsequent medicinal chemistry efforts aimed at enhancing drug specificity and minimizing off-target toxicities. This iterative process epitomizes the modern drug discovery paradigm, driven by mechanistic understanding and technological innovation.

Ultimately, this research at Wake Forest University School of Medicine epitomizes the potential of targeted redox modulation in oncology. It develops a sophisticated molecular weapon that can disable cancer cells’ defenses, induce cytotoxic oxidative stress, and overcome the limitations of previous treatment modalities. As clinical validation progresses, WF-242 and its derivatives may emerge as vital components in the arsenal against cancers that have long evaded effective systemic therapies.

Subject of Research: Targeted inhibition of peroxiredoxin-3 (PRX3) to induce oxidative stress and kill cancer cells.

Article Title: Mechanism-based peroxiredoxin 3 inhibitors exploit a covalent warhead for cancer therapy

News Publication Date: 4-Nov-2025

Web References:
https://school.wakehealth.edu/
https://www.science.org/doi/10.1126/sciadv.ady4492
http://dx.doi.org/10.1126/sciadv.ady4492

Keywords: Cancer, Cancer treatments, Biochemistry, Structural analysis, Cancer cells, Mesothelioma, Drug development