Acute myeloid leukemia (AML) is characterized by an expansion of abnormal undifferentiated myeloblast due to an acquired mutation in blood-forming cells from the bone marrow, resulting in impaired hematopoiesis. The typical treatment for AML is induction chemotherapy but refractory disease is common, and relapse can occur causing initial and subsequent treatments to fail. This is just one of indications that not all forms of cancer can be treated in the same way, as many specialized cancer cell types are able to resist current established therapies.
For decades, it has been documented that cancer cells rely on glycolysis for energy production instead of the more efficient process of oxidative phosphorylation. However, more recent studies counter this narrative, demonstrating that cancer stem cells from multiple tumor types are in fact dependent on oxidative phosphorylation. This complicated metabolic landscape suggests that understanding the unique metabolic properties of malignant stem cells may point to improved therapies.
In a recent study, scientists from the University of Boulder Colorado Cancer Center interrogated the metabolome of human acute myeloid leukemia (AML) stem cells to elucidate properties relevant to therapeutic intervention. Unlike normal healthy cells that typically do not need to metabolize protein, leukemia stem cells (LSCs) are reliant on amino acid metabolism for survival. Pharmacological inhibition of amino acid metabolism, via a combination of venetoclax with azacytidine, provides a targeted mechanism for targeting of LSCs. Because healthy cells do not depend on amino acid metabolism, the drugs killed LSCs without harming healthy cells.
The venetoclax and azacitidine treatment achieved high overall response rates in clinical trials with de novo patients otherwise ineligible for conventional chemotherapy. Importantly, LSCs derived from relapsed patients demonstrate a more complex metabolic profile and were less sensitive to venetoclax and azacitidine treatment. The LSCs from relapsed patients were able to metabolically compensate for amino acid loss following treatment by upregulating fatty acid metabolism, which was not observed in treatment-naive LSCs.
The findings indicate that metabolic targeting of LSCs is a promising therapeutic strategy, but such approaches must be tailored to distinct metabolic properties. This article titled “Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells” was published in Cancer Cell.