Cancer stem cells have an “energy addiction” scientists may be able to exploit

Scientists have uncovered an “energy addiction” in high-risk MDS stem cells that could become a powerful new target for blood cancer treatments.

Researchers at the University of Colorado Anschutz Cancer Center have uncovered a previously unknown metabolic vulnerability in the stem cells responsible for high risk myelodysplastic syndromes (MDS). The finding could eventually help scientists develop treatments that more precisely target the cells driving this aggressive blood cancer.

The study, published in Blood Cancer Discovery, found that high risk MDS stem cells depend unusually heavily on nicotinamide adenine dinucleotide (NAD), a molecule that plays an essential role in how cells produce energy. When researchers disrupted the pathway responsible for maintaining NAD, they were able to selectively weaken the disease driving stem cells. Healthy blood forming stem cells, by comparison, were better able to adjust.

"What we found is that these cells actually use energy in different ways than normal stem cells do," said Eric M. Pietras, PhD, associate professor in the Division of Hematology at the University of Colorado Anschutz, and co lead author of the study. "They were relying on a specific set of proteins and processes that created a vulnerability we could potentially target."

Myelodysplastic syndromes are blood cancers that interfere with the bone marrow's ability to make healthy blood cells. People with the disease can develop severe anemia, experience frequent infections, and need repeated blood transfusions. High risk MDS can also advance to acute myeloid leukemia (AML), an aggressive form of leukemia that remains difficult to treat.

MDS occurs mainly in older adults. An estimated 10,000 to 20,000 people are diagnosed with the disease in the United States each year.

Stem cells are central to both normal blood production and blood cancers. In high risk MDS, genetically mutated stem cells lose the ability to produce the healthy blood cells required to carry oxygen, form clots, and fight infections. Instead, they generate abnormal blood cells that cannot perform these essential jobs.

The researchers set out to identify biological differences between these cancer stem cells and their healthy counterparts.

Their experiments showed that MDS stem cells depend strongly on the NAD salvage pathway, a recycling process that helps cells maintain their supply of NAD. One enzyme in this pathway, nicotinamide phosphoribosyltransferase (NAMPT), stood out as a possible treatment target.

"These cells had developed a much greater need for this resource," Pietras said. "They appear to use NAD at a much higher rate than normal cells, which creates a vulnerability that we can exploit with new types of drugs."

The researchers describe this unusual dependence as an "energy addiction." Healthy blood forming stem cells can shift toward other ways of producing and managing energy when conditions change. MDS stem cells, however, appear to have much less flexibility.

When the researchers blocked NAMPT, NAD levels fell and the cancer stem cells entered an energy crisis. This selectively weakened the cells responsible for driving the disease while normal blood forming stem cells were better able to compensate.