Scientists at Weill Cornell Medicine have created a metal-free prodrug that releases controlled doses of carbon monoxide in the body, significantly reducing the spread of pancreatic and triple-negative breast cancer in preclinical models — without toxic side effects.
Carbon monoxide has long been synonymous with danger, but researchers at Weill Cornell Medicine are turning that reputation on its head. A new preclinical study published in Advanced Science describes a metal-free prodrug that harnesses tiny, controlled amounts of the gas to block the spread of two of cancer’s most lethal forms: pancreatic cancer and triple-negative breast cancer.
The compound, called CO-116, represents a major step forward in the search for safe, practical anti-metastatic therapies. Even when surgery and chemotherapy successfully eliminate a primary tumor, microscopic cancer cells can survive and seed new tumors in distant organs — a process called metastasis that accounts for the vast majority of cancer deaths. Blocking that process has been one of oncology’s most persistent challenges.
Why Carbon Monoxide?
It might seem counterintuitive to use a gas best known for its role in accidental poisonings as a medicine. But senior author Nancy Du, an associate professor of pathology and laboratory medicine and the Rasweiler Family Research Scholar in Cancer Research at Weill Cornell, notes that the human body already produces small amounts of carbon monoxide on its own.
“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,” Du said in a news release. “Though carbon monoxide is known as a toxic gas at high doses, our bodies naturally produce small amounts of it.”
Du’s lab first demonstrated in 2022 that low-dose carbon monoxide could hamper metastatic progression in preclinical cancer models. The harder problem was delivery. Inhaling the gas is unpredictable and dangerous. Earlier experimental molecules that released carbon monoxide relied on metals like ruthenium, manganese or iron — elements that leave behind toxic byproducts in the body after the drug does its work.
Building a Cleaner Delivery System
To sidestep those problems, the team engineered an entirely metal-free prodrug — a compound that remains inactive until it reaches the body, where it then converts into its active form and releases carbon monoxide after intravenous administration. Binghe Wang, a Regents’ Professor of Chemistry and Frank Hannah Chair at Georgia State University, led the synthesis of these novel molecules.
The researchers tested CO-116 across multiple mouse models of pancreatic and triple-negative breast cancer. The results were striking: treatment with CO-116 substantially reduced the growth of metastatic tumors in the liver and lungs, and did so without any observable signs of toxicity, weight loss, or changes in behavior.
One of the more surprising findings concerned dosing strategy. Administering smaller doses more frequently proved significantly more effective than delivering the same total amount in one 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,” added first author Tiantian Zhang, a research associate in the Du lab.
Uncovering a Biological Mechanism
Beyond proving that CO-116 works, the team wanted to understand why it works. Their investigation pointed to a protein called HRG1, which helps cancer cells import heme — an iron-containing molecule critical for a wide range of cellular functions. CO-116 reduced HRG1 levels, disrupting a signaling pathway that normally encourages cancer cells to migrate and establish themselves in new tissue.
To confirm this link, the researchers genetically engineered cancer cells to express either more or less HRG1. Cells with elevated HRG1 became more aggressive and responded less robustly to carbon monoxide treatment. Cells with reduced HRG1 expression showed significantly slower metastatic growth in both pancreatic and breast cancer models. This suggests that HRG1 could serve a dual purpose going forward: as a therapeutic target in its own right, and as a biomarker to identify which patients are most likely to benefit from carbon monoxide-based treatment.
What This Means for Patients — and Future Research
The study authors envision CO-116 or similar compounds being developed as adjuvant therapies — treatments given after primary surgery or chemotherapy specifically to lower the risk of cancer coming back. That framing is significant for patients with pancreatic cancer and triple-negative breast cancer, both of which have high recurrence rates and relatively limited treatment options once they spread.
Still, substantial work lies ahead. Long-term safety data are needed, optimal dosing schedules must be established in humans, and researchers will need to determine whether the anti-metastatic effects are durable after treatment ends. Human clinical trials are not yet on the horizon.
“The findings provide the first evidence that a non-inhaled, metal-free carbon monoxide prodrug can suppress metastasis in multiple cancer models,” Du added. “The study opens a new avenue for developing treatments aimed at one of cancer’s greatest challenges, preventing its spread.”
Why It Matters for Students and Young Adults
Triple-negative breast cancer disproportionately affects younger women, and pancreatic cancer — while more common in older adults — carries a five-year survival rate of roughly 13%, largely because most cases are caught after the cancer has already spread. Research that specifically targets metastasis, rather than the primary tumor alone, could eventually reshape treatment protocols for both diseases.
For students pursuing careers in pharmacology, oncology, chemistry or biomedical engineering, this study also illustrates an important research principle: sometimes the most promising therapies come from reconsidering substances we thought we already understood. The fact that a gas long associated with toxicity could become a precision cancer-fighting tool underscores how much remains to be discovered at the intersection of chemistry and medicine.
Source: Weill Cornell Medicine