Researchers at Stanford University have identified a new way that the cancer drug candidate tegavivint kills cancer cells, which could lead to better treatments for patients who do not respond to existing therapies. The findings, published in Nature Chemical Biology, suggest that tegavivint triggers a unique type of cell death distinct from apoptosis, the process most current cancer drugs rely on.
“This could be a new weapon in the fight against cancer,” said Scott Dixon, associate professor of biology and senior author of the study. “We’ve shown a completely different way to attack the cancer by going after this new pathway. It remains to be established whether it ultimately is going to be useful, but certainly the door is open. We have a new opportunity here.”
Dixon’s lab at Stanford’s School of Humanities and Sciences has focused on finding molecular approaches to kill cancer cells. While working with CIL56, a related compound, Dixon’s team began investigating tegavivint after Mark Smith, director of medicinal chemistry at Stanford’s Sarafan ChEM-H, mentioned ongoing clinical trials with the drug.
Through genetic studies and comparisons with other compounds, researchers found that both CIL56 and tegavivint killed cancer cells without activating apoptosis or any other known forms of non-apoptotic cell death. Instead, they determined that these drugs likely work by causing palmitate—a common lipid found in dairy products and meat—to become toxic to cancer cells. The researchers have provisionally named this process lipid-dependent necrosis (LiDN).
The study involved collaboration across several departments at Stanford as well as institutions including the University at Buffalo; The State University of New York; University of California, Los Angeles; University of Massachusetts; Broad Institute of MIT and Harvard; University of Minnesota; and University of Toronto.
“Looking ahead, we hope that this makes doctors’ ability to use this drug even better,” Dixon said. “If they have a better understanding of how it’s really working, then maybe they’ll be able to pick patients more effectively or better understand the effects that they might see.”
Dixon credited foundational research and collaboration for enabling the discovery. “It’s really a combination of curiosity and serendipity that led us from CIL56 to this related molecule, tegavivint, which we realized had this unusual property,” he said. “Our main focus is understanding the details of how cells die, especially how cancer cells die. And just by spending a lot of time thinking about these problems, we could dissect something that might have been overlooked in earlier studies.”
The research was supported by organizations such as the National Institutes of Health, National Science Foundation, American Cancer Society, Lung Cancer Research Foundation, Manning Foundation/IALS Innovation Award, Mass Ventures Funds, and Canadian Institutes of Health Research.
Additional contributors from Stanford include Logan Leak, Ziwei Wang, Alby Joseph, Brianna Johnson, Alyssa Chang, Cassandra Decosto, Leslie Magtanong, Pin Joe Ko, Wavery Colleen Lee, Joan Ritho and Sophia Manukian.
None of the university researchers involved with this study are connected with the company developing tegavivint.
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