Experimental drug drowns triple-negative breast cancer cells in toxic fats

An experimental drug slowed triple-negative breast cancer in mice by flooding tumour cells with toxic fats.

Triple-negative breast cancer lacks three common drug targets, making it one of the hardest-to-treat and most aggressive forms of the disease.

The compound, known as DH20931, appears to push cancer cells past their limits by triggering a surge in ceramides, fat-like molecules that place the cells under intense stress until they self-destruct.

In lab experiments, the drug also made standard chemotherapy more effective. When combined with 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 sharply increase production of these lipids and stress cancer cells. Healthy cells, by contrast, showed lower sensitivity to the drug in lab tests.

While the early results are promising, further preclinical and clinical trials would still be needed to determine the safety and effectiveness of DH20931 in humans.

Satya Narayan, a professor in the University of Florida’s College of Medicine, led the study with an international group of collaborators.

The researchers published their results on human-derived tumours on 21 April and presented their findings on combination therapy at the annual meeting of the American Association for Cancer Research in San Diego.

Narayan likened the drug’s effects to a home’s electrical system handling a power surge.

While healthy cells act like a properly grounded and installed circuit, cancer cells are more like a jumble of mismatched wires and faulty fuses. DH20931 overwhelms cells not with electricity, but with fats.

He said: “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.”

The compound was developed at the University of Florida in the lab of Sukwong Hong.

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 tumours into mice and treated them with DH20931.

The drug significantly slowed tumour 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 structures that produce a cell’s energy, ultimately leading to cell death.

Narayan said: “It does not just follow one pathway but it goes through multiple pathways. It’s a two-hit hypothesis.

“These pathways are common in all breast cancer types and other solid tumours, so we think this drug can be useful not only in triple-negative breast cancer but potentially other cancers as well.”