Unlike healthy cells or mature cancer cells, the stem cells that sustain cancer rely on energy derived from protein or, more precisely, amino acids. This unique dietary preference, say scientists based at the University of Colorado Cancer Center, makes cancer stem cells uniquely vulnerable to drugs that inhibit amino acid uptake. Such drugs could kill cancer stem cells while leaving healthy cells unharmed. They could also be teamed with more conventional drugs that are effective against mature cancer cells.

The idea of slashing cancer’s extremities while also cutting it off at the knees was explored by Craig Jordan, Ph.D., and his colleagues at the University of Colorado Cancer Center. They evaluated a drug called venetolax for its ability to prevent leukemia stem cells from using amino acids for energy.

“In acute myeloid leukemia (AML), we’ve gotten pretty good at killing the bulk of cancer cells, but a small population of cancer stem cells are uniquely equipped to resist these therapies, and these stem cells often survive to restart the condition later,” said Dr. Jordan. “We’ve needed a way to specifically target cancer stem cells, and it looks like this might be it.”

Dr. Jordan and colleagues reported their findings November 12 in the journal Cancer Cell, in an article entitled, “Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells.” According to this article, amino acid uptake, steady-state levels, and catabolism are all elevated in the leukemia stem cell (LSC) population. The article also demonstrated that venetolax helps induce toxicity in leukemic stem cells taken from AML patients.

“LSCs isolated from de novo AML patients are uniquely reliant on amino acid metabolism for oxidative phosphorylation and survival,” the article’s authors wrote. “Pharmacological inhibition of amino acid metabolism reduces oxidative phosphorylation and induces cell death.”

The article also observed, however, that LSCs obtained from relapsed AML patients are not reliant on amino acid metabolism due to their ability to compensate through increased fatty acid metabolism. That is, only AML patients who were treated with venetoclax as their first treatment showed a dramatic response.

“When patients were treated with other therapies first, leukemia stem cells were pushed to diversify, and some adopted lipid metabolism,” explained Courtney Jones, Ph.D., a researcher in Dr. Jordan’s lab and the first author of the current study.

When those patients were subsequently treated with venetoclax, the drug killed the cancer stem cells that continued to depend on amino acid metabolism, but was ineffective against cancer stem cells that had switched to lipid metabolism. It was as if lipid metabolism provided an avenue of escape for these cells, and when even a small population of leukemia stem cells was able to resist therapy, they were able to later restart the growth of the disease.

Future work in Dr. Jordan’s lab will explore the possibility of inhibiting lipid metabolism along with amino acid metabolism for use with AML patients whose cancers have resisted or relapsed after previous therapies.

Dr. Jordan has spent more than 20 years laying the scientific groundwork for this attack against cancer stem cells, and now just in the past six months, with a flurry of important publications, the work from his team has led not only to increased understanding of these tenacious cells, but to treatments that may change the standard of care for acute myeloid leukemia and perhaps other cancers as well. In a recent clinical trial, patients with acute myeloid leukemia who were not candidates for bone marrow transplant were treated with the drug venetoclax, which blocks cells’ ability to uptake amino acids.

“Conventional chemotherapy is not effective for most patients with acute myeloid leukemia. The new results with venetoclax look very promising,” noted Dr. Jordan. Clinical trial results are also published in the journal Nature Medicine, with first author Daniel Pollyea, M.D., clinical director of leukemia services, University of Colorado School of Medicine. The current study circles back to pinpoint why the clinical trial was so successful.

“In the Cancer Cell paper, we report an important piece of science that describes a vulnerability of these leukemia stem cells, and in the Nature Medicine paper we describe a treatment that successfully exploits this vulnerability,” Dr. Jordan pointed out. “We believe this type of therapy is just the beginning of what may become an entirely new way of treating leukemia. Now our challenge is to optimize this treatment in acute myeloid leukemia, while possibly expanding it for use in other settings where cancer stem cells continue to drive the development, growth, and relapse of cancer.”

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