New Combination Drug Controls Tumor Growth and Metastasis in Mice
Researchers at UC Davis, University of Massachusetts, and Harvard Medical School have developed a combination drug that controls both tumor growth and metastasis. By combining a cyclooxygenase (COX)-2 inhibitor, similar to celecoxib, and a soluble epoxide hydrolase (sEH) inhibitor, the drug controls angiogenesis and limits a tumor’s ability to grow and spread. The study by Zhang et al was published in the Proceedings of the National Academy of Sciences.
“We’ve been studying the effects of COX and sEH inhibitors, both by themselves and in combination, for several years,” said senior author and UC Davis Distinguished Professor Bruce Hammock, PhD. “We were surprised to find that the dual inhibitor was more active than higher doses of each compound, either individually or together. By combining the two molecules into one, we got much greater potency against several diseases and completely unique effects in terms of blocking tumor growth and metastasis.”
Both COX and sEH enzymes control lipid signaling, which has long been associated with inflammation, cell migration, proliferation, hypertension, and other processes. COX inhibitors block production of inflammatory and pain-inducing lipids, while sEH inhibitors preserve antihypertensive, anti-inflammatory, and analgesic compounds. Separate COX and sEH inhibitors were previously found to work together in reducing inflammation and neuropathic pain.
New Mechanism to Control Angiogenesis
After testing individual COX-2 and sEH inhibitors, the team synthesized the drug (PTUTB), the first combined COX-2/sEH inhibitor. They then tested the dual inhibitor against human lung and breast tumors, both in vitro and in mice. They found that PTUTB blocked angiogenesis, inhibiting the proliferation of endothelial cells, which are critical to blood vessel formation. This in turn limited tumor growth and metastasis, reducing lung and breast tumor growth by 70% to 83%.
“In breast and lung cancers, the dual inhibitor blocked angiogenesis, which blocked the growth of solid tumors,” said Dr. Hammock. “This represents a new mechanism to control blood vessel and tumor growth.”
Robert Weiss, MD, a coauthor and Professor of Nephrology at UC Davis, added that the combination drug achieved the results with minimal side effects and no cardiovascular or gastrointestinal effects.
“This is particularly important when administering COX-2 inhibitors, which have well-known cardiovascular risks,” he said. “However, the added sEH inhibitor appears to block COX-2’s side effects.”
Though the research was focused exclusively on cancer, researchers said the dual compound could benefit other conditions, such as macular degeneration.
“If we move beyond cancer, this drug combination could block a number of pathologies, ranging from cardiac hypertrophy to neuropathic pain,” said Dr. Hammock. “The compound looks quite powerful for a number of conditions.”
The research was supported in part by grants from the NIH, UC Davis, the Stop and Shop Pediatric Brain Tumor Fund, the C.J. Buckley Pediatric Brain Tumor Fund, the U.S. Department of Veterans Affairs, and the American Asthma Society.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
