Novel cancer-killing mechanism opens path to new treatments

A cancer drug currently undergoing clinical trials in human patients may work in a different way than previously understood.

A Stanford-led research team has discovered a new type of cell death that is triggered by the cancer drug candidate tegavivint. The cell death process is distinct from the primary way the body kills off old or abnormal cells, known as apoptosis. Many current cancer treatments activate apoptosis—and, until now, tegavivint was believed to work this way as well. 

The discovery, detailed in the journal Nature Chemical Biology, has the potential to not only improve the future use of tegavivint, but also help develop new treatments for killing cancer cells that are resistant to current therapies. 

Harrison Truong for Stanford University

“This could be a new weapon in the fight against cancer,” said Scott Dixon, associate professor of biology and the study’s senior author. “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.”

A new kind of cell death

Cancer occurs when abnormal cells divide and grow, circumventing the body’s normal cell death processes, so researchers are trying to find new and better ways to kill these resistant cells.  

Finding molecular cancer killers is the primary focus of Dixon’s lab in Stanford’s School of Humanities and Sciences. His team was working with a related chemical called CIL56 when colleague Mark Smith, director of medicinal chemistry at Stanford’s Sarafan ChEM-H, mentioned the tegavivint trials. Dixon’s team then started investigating how both compounds kill cancer cells. 

Through genetic investigations and comparisons to other cancer-killing compounds, they found evidence that both CIL56 and tegavivint caused cancer cells to die without triggering apoptosis. The two compounds also did not follow the pathways of any of the non-apoptotic types of cell death currently known.

Instead, the researchers found that these compounds likely caused cancer cell death by creating a killer out of a usually innocuous type of fat, a lipid called palmitate, which is found in many dairy products and meat. More research is needed to understand the exact process of this type of cell death, but the researchers have preliminarily named it lipid-dependent necrosis or LiDN. 

A foundational find

None of the university researchers involved with this study has any connection to the company behind tegavivint, yet if the drug candidate ultimately is approved, their findings may benefit future patients.

“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 credits the discovery to foundational research as well as collaboration with other researchers at Stanford, including Everett Moding, a co-author on the study and assistant professor of radiation oncology in the School of Medicine.  

“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.” 

Dixon is also a fellow at Stanford’s Sarafan ChEM-H and a member of Stanford Bio-X, the Stanford Cancer Institute, and the Wu Tsai Neurosciences Institute. 

Additional Stanford researchers on this study 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. Other collaborators include researchers affiliated with the University at Buffalo; The State University of New York; University of California, Los Angeles; the University of Massachusetts; the Broad Institute of MIT and Harvard; the University of Minnesota; and the University of Toronto. See the paper for full authorship details.

This research received support from 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.