Cancer cells consume large amounts of sugar to fuel their rapid growth, prompting many scientists to develop drugs that disrupt this process by cutting off their sugar supply.
Researchers at The University of Texas at Austin have taken a different approach. Instead of starving cancer cells, they have developed a drug that tricks these cells into consuming even more sugar than usual while simultaneously blocking their backup fuel source: fat.
Dual-action strategy
By targeting both fuel sources simultaneously, the experimental drug places cancer cells under significant stress, leading to the death of many of them. The research team demonstrated the drug’s effectiveness in treating an aggressive form of melanoma in mice.
“I like to think of this technology like a two-headed dragon,” said Xiaolu (Lulu) Lim Ang Cambronne, an associate professor of molecular biosciences at UT and co-corresponding author. “We are putting one part of the cell into overdrive while simultaneously weakening another part. It appears to be extremely potent.”
In laboratory experiments, the drug proved effective against several types of human cancer cells, including melanoma, leukemia, breast cancer, lung cancer, liver cancer, and neuroblastoma. In mice with melanoma, most cancer cells died, while non-cancerous cells were significantly less affected.
Chemical alternative to ADCs
Drugs that attack cancer with a dual-action strategy are not entirely new. A growing class of compounds called antibody-drug conjugates (ADCs) uses antibodies to target cancer cells and deliver chemotherapy directly to tumors. However, ADCs have limitations.
“Antibodies are difficult to make, and because they’re so large they’re only able to target proteins in the surface of cancer cells,” said Ken Hsu, an associate professor of chemistry at UT and co-corresponding author. “We think of this new compound as a fully chemical counterpart to ADCs. They are much easier to manufacture. And because they are smaller, they are able to target even proteins that are inside cells.”
This research received support from the National Institutes of Health, the National Institute of General Medical Sciences, the Cancer Prevention and Research Institute of Texas (CPRIT), the University of Washington Beckman Cryo-EM Center, West Virginia University’s Visual Sciences CoBRE program, the Melanoma Research Alliance, the Mark Foundation for Cancer Research, The Welch Foundation, and Tito’s Handmade Vodka.
Unconventional mechanism
The drug consists of two components. The targeting agent, a molecule called XJ-4-85, acts on an enzyme known as PFKL, accelerating glycolysis—the process of sugar breakdown—inside cancer cells. Once XJ-4-85 binds, it releases its payload, a compound that targets another enzyme called CPT2. CPT2 typically aids cells in breaking down fatty acids for energy. By disrupting both major energy sources simultaneously, the drug halts cancer growth.
“The way this drug works was totally unexpected,” said Xiaoding Jiang, a postdoctoral fellow in the Hsu Lab who designed the molecule. “A lot of research was required to figure out what it was doing on the molecular level. We were also surprised to see how selectively it binds to cancer cells.”
The research is still in its early stages. Although the results are promising, much more laboratory testing is needed before the drug can be studied in people.
