A carefully designed metal-free carbon monoxide prodrug – an inactive compound that is converted into its active form in the body – may help prevent some of the deadliest forms of cancer from spreading, according to researchers at Weill Cornell Medicine.

The recent preclinical study, published in Advanced Science, offers a new strategy to potentially reduce the recurrence of pancreatic and triple-negative breast cancer in patients who initially respond to treatment. 

Even after surgery and chemotherapy, microscopic cancer cells often survive and establish new tumors in distant organs. Researchers have long pursued treatments that can safely block this process.

“We are developing a unique approach to block metastasis, using a metal-free prodrug designed to release low, controlled levels of carbon monoxide in the body,” said senior author Nancy Du, associate professor of pathology and laboratory medicine and the Rasweiler Family Research Scholar in Cancer Research at Weill Cornell. “Though carbon monoxide is known as a toxic gas at high doses, our bodies naturally produce small amounts of it.” 

In 2022, Du’s team reported that low-dose carbon monoxide hindered metastatic progression in preclinical cancer models. The challenge has been finding a safe and practical way to deliver carbon monoxide as a therapy. Inhaled carbon monoxide is difficult to control and raises safety concerns. Other efforts used experimental carbon monoxide-releasing molecules containing metals such as ruthenium, manganese or iron, but they leave behind toxic metal-containing byproducts.

To overcome these limitations, the researchers created a metal-free prodrug – in this case, releasing carbon monoxide after intravenous administration. Binghe Wang, Regents’ Professor of Chemistry and Frank Hannah Chair at Georgia State University, led the synthesis of these molecules.

They then tested the prodrug, called CO-116, with controlled dosing in multiple mouse models of pancreatic and triple-negative breast cancer. Treatment with CO-116 significantly reduced the growth of metastatic tumors in the liver and lungs without signs of toxicity, weight loss or behavioral changes.

Interestingly, the researchers found that giving smaller doses more frequently was more effective than administering the same total amount in a single larger weekly dose. “Determining when and how often the prodrug is given is more important than the total dose, which could help guide future clinical development,” said Tiantian Zhang, research associate in the Du lab, and first author.

Disrupting cancer cell migration

Beyond demonstrating antimetastatic activity, the team identified a biological mechanism that appears to drive CO-116’s effects on metastasis. CO-116 reduced levels of HRG1, a protein that helps cancer cells import heme, an iron-containing molecule essential for many cellular functions. By lowering HRG1 levels, the prodrug disrupted a signaling pathway that promotes cancer cell migration and metastatic growth.

The researchers genetically manipulated cancer cells to investigate this connection further. Increasing HRG1 levels made cancer cells more aggressive and reduced their responsiveness to carbon monoxide-based treatment. Conversely, reducing HRG1 expression significantly slowed metastatic growth in both pancreatic and breast cancer models. These findings suggest that HRG1 may be a promising therapeutic target and a potential biomarker for identifying patients most likely to benefit from a carbon monoxide prodrug.

While significant work is still needed before the therapy can be tested in patients, CO-116 or related compounds could potentially be developed as adjuvant therapies – treatments given after surgery or chemotherapy to reduce the risk of cancer recurrence. Future studies will need to evaluate long-term safety, determine optimal dosing schedules and establish whether the antimetastatic effects persist after treatment stops.

“The findings provide the first evidence that a non-inhaled, metal-free carbon monoxide prodrug can suppress metastasis in multiple cancer models,” Du said. “The study opens a new avenue for developing treatments aimed at one of cancer’s greatest challenges, preventing its spread.”

This work was partially supported by a Manhasset Women’s Coalition Against Breast Cancer Research Grant. The development of the CO prodrugs in Dr. Wang’s laboratory was supported by the National Institutes of Health (R01DK119202 and R01DK128823).

Karen Hopkin is a freelance writer for Weill Cornell Medicine.