Candidate breast cancer drug overloads tumors with ‘surge’ of toxic lipids

An experimental drug targeting triple-negative breast cancer overwhelms cancer cells with toxic fats, according to new tests on human-derived tumors in mice. Triple-negative breast cancer lacks three common drug targets, making it one of the most aggressive forms of the disease. The compound, known as DH20931, appears to push cancer cells past their limits by triggering a surge in fat-like molecules called ceramides. Already under stress, the cells cannot cope and ultimately self-destruct. The findings are published in the journal Molecular Cancer Therapeutics.

In lab experiments, the drug also made standard chemotherapy more effective. When combined with the commonly used drug doxorubicin, researchers were able to reduce the dose needed to kill cancer cells by about fivefold.

The drug targets an enzyme known as CerS2 to dramatically increase the production of these lipids to stress cancer cells. Healthy cells, by contrast, showed lower sensitivity to the drug in lab tests.

While the early results are promising, it would take additional preclinical and clinical trials to determine the safety and effectiveness of DH20931 as a potential cancer drug for humans.

Satya Narayan, Ph.D., a professor in the University of Florida’s College of Medicine, led the study. Narayan and an international group of collaborators recently presented their findings on combination therapy at the annual meeting of the American Association for Cancer Research in San Diego.

Narayan likens the drug’s effects to a home’s electrical system handling a power surge. While a body’s healthy cells act like a properly grounded and installed circuit, cancer cells are more like a jumble of mismatched wires and bad fuses; except that DH20931 overwhelms cells not with electricity, but with fats.

“When that surge goes into the cancer cells, they cannot handle the amount of power they are getting. The fuses burn out, the cell can’t handle the surge and it dies,” said Narayan, who is also a member of the UF Health Cancer Institute.

The compound was developed at UF in the lab of Sukwong Hong, Ph.D. Hong, now a professor at the Gwangju Institute of Science and Technology in South Korea, created DH20931 as one of many drug candidates tested for efficacy in Narayan’s lab.

In the study, researchers implanted human triple-negative breast cancer tumors into mice and treated them with DH20931. The drug significantly slowed tumor growth without causing noticeable weight loss or signs of toxicity in the animals. In separate lab experiments, it also showed activity against other breast cancer subtypes.

In addition to increasing lipid levels, DH20931 triggers a second stress signal by flooding cells with calcium. Together, these effects disrupt the mitochondria—the cell’s energy-producing structures—ultimately leading to cell death.

“It does not just follow one pathway but it goes through multiple pathways. It’s a two-hit hypothesis,” Narayanan said. “These pathways are common in all breast cancer types and other solid tumors, so we think this drug can be useful not only in triple-negative breast cancer but potentially other cancers as well.”