Carefully designed metal-free carbon monoxide prodrugs could help prevent the spread of some of the deadliest cancers, Weill Cornell Medicine researchers say. A recent preclinical study published in Advanced Science proposes a new strategy to potentially reduce recurrence of pancreatic and triple-negative breast cancer in patients who initially respond to treatment.
Even after surgery or chemotherapy, microscopic cancer cells often survive and form new tumors in distant organs. Researchers have long sought treatments that can safely block this process.
“We are developing a unique approach to blocking metastases using metal-free prodrugs designed to release low levels of carbon monoxide in the body,” said lead author Nancy Du, PhD, Russweiler Family Fellow in Cancer Research and associate professor of pathology and laboratory medicine at Weill Cornell University. “Although carbon monoxide is known to be a toxic gas in large quantities, our bodies naturally produce it in small amounts.”
In 2022, Dr. Du’s team reported that low doses of carbon monoxide blocked metastatic progression in preclinical cancer models. The challenge was to find a safe and practical way to administer carbon monoxide as a treatment. Inhaled carbon monoxide is difficult to control and raises safety concerns. Other efforts have experimentally used carbon monoxide-releasing molecules containing metals such as ruthenium, manganese, and iron, but they leave behind byproducts that include toxic metals.
To overcome these limitations, researchers created metal-free prodrugs (inactive compounds that are converted to their active forms in the body). In this case, it releases carbon monoxide after intravenous administration. The synthesis of these molecules was led by Dr. Binghe Wang, Regents Professor of Chemistry and the Frank Hanna Professor at Georgia State University.
Next, they tested a prodrug called CO-116 at controlled doses in multiple mouse models of pancreatic cancer and triple-negative breast cancer. Treatment with CO-116 significantly reduced the growth of metastatic tumors in the liver and lungs without any signs of toxicity, weight loss, or behavioral changes.
Interestingly, the researchers found that smaller doses given more frequently were more effective than the same total dose given in larger doses once a week. “Determining when and how often to administer the prodrug is more important than the total dose and may guide future clinical development,” said Tiantian Zhang, Ph.D., a researcher in the Du lab and first author.
Inhibits cancer cell migration
In addition to demonstrating anti-metastatic activity, the research 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 uptake heme, an iron-containing molecule essential for many cellular functions. By reducing HRG1 levels, this prodrug disrupted the signaling pathway that promotes cancer cell migration and metastatic growth.
The researchers genetically engineered cancer cells to further investigate this link. Elevated HRG1 levels increased cancer cell aggressiveness and decreased cancer cell responsiveness to carbon monoxide-based therapy. 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 carbon monoxide prodrugs.
Although significant research is still needed to test this therapy in patients, CO-116 or related compounds could be developed as adjuvant therapy given after surgery or chemotherapy to reduce the risk of cancer recurrence. Future studies will need to assess long-term safety, determine the optimal dosing schedule, and establish whether anti-metastatic effects persist after treatment is discontinued.
“Our findings provide the first evidence that a non-inhalable, metal-free carbon monoxide prodrug can inhibit metastasis in multiple cancer models,” said Dr. Du. “This research opens new avenues for developing treatments aimed at preventing the spread of cancer, one of the biggest challenges in cancer.”
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Reference magazines:
https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202519898
