Despite advancements in treatment, acute myeloid leukemia (AML) remains a severe and challenging blood cancer to treat, affecting hundreds of adults in Sweden each year. Leukemia stem cells, which are responsible for AML's development and spread, are particularly to blame as they tend to develop resistance to standard treatments.
To address this issue and develop new targeting strategies, Lund University researchers set out to investigate the impact of different genes in leukemia stem cells using CRISPR-Cas9 screens, an advanced gene-editing tool, in animal models.
"We discovered that leukemia stem cells are reliant on a specialized protein, GLUT1, to transport glucose across their cell membranes," says Maria Rodriguez Zabala, first-author of the study and PhD student at Lund University. "By suppressing the activity of GLUT1, we were able to stop the cancer cells' ability to consume glucose, reducing their ability to survive, adapt and multiply."
When further exploring the role of GLUT1 in leukemia cells derived from patients with AML, inhibiting GLUT1 alone was not enough to bring energy production to a full stop.
Cancer cells can use a super-fast pathway called glycolysis to turn glucose into energy, as well as another pathway called oxidative phosphorylation (OXPHOS). This second option allows cancer cells to use different kinds of fuel like amino acids and fatty acids to make energy. The researchers used a combination of a GLUT1 inhibitor and an OXPHOS inhibitor to power down the two primary metabolic pathways that cancer cells use, which created a more challenging environment for leukemia cells to survive and thrive in.
"Although the patient group was small, this combination was promising in eliminating the leukemia cells in the patient samples, with the leukemia cells of patients with a certain AML subtype (RUNX1-mutated) being specifically vulnerable to this combined therapy," noted Maria Rodriguez Zabala.
However, the researchers noted a possible limitation in inhibiting GLUT1 through clinical applications, as it is present in nearly all human cells. “Nonetheless, experiments conducted on mice showed that the GLUT1 inhibitor had minimal effects on noncancerous cells. Instead, cancer cells were specifically targeted, likely due to their high energy needs and activity levels,” explains Marcus Järås, associate professor at Lund University and leader of the research group behind the study.
The impact of this research extends beyond the lab and is expected to add to the growing body of knowledge around metabolism-targeting therapies. This group of therapies are a new and exciting frontier in the field of cancer treatment, which aim to interrupt cancer cells' energy production processes, thereby making them more receptive to other anti-cancer treatments.
