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Scientists Develop Non-Toxic Strategy to Treat Leukemia

Harvard-led team kills cancer cells by disrupting their metabolism

A study comparing how blood stem cells and leukemia cells consume nutrients found that cancer cells are far less tolerant to shifts in their energy supply than are their normal counterparts. The results suggest that there could be ways to target leukemia metabolism so that cancer cells die but other cell types are undisturbed.

Scientists at the Harvard Stem Cell Institute led the work, which was published in the journal Cell, in collaboration with researchers at the Massachusetts Institute of Technology (MIT) and the Koch Institute for Integrative Cancer Research.

David Scadden, MD, and his colleagues examined blood stem cells and their direct offspring — blood progenitor cells, which have a more limited ability to differentiate. The researchers modified the way the cells take up nutrients in two ways: via a glucose on-off switch, and through subtle adjustments that raise or lower glucose, like a volume dial. The researchers found that turning off the glucose switch caused stem cells to die, whereas raising the glucose volume dial affected normal energy production in the offspring cells.

“That was an interesting distinction between these two cell types,” Scadden said. “They have very different functions, and you might imagine they’re going to use their nutrients very differently, but nobody had defined that before.”

The investigators next introduced genes that were corrupted to cause the parental blood stem cells and their offspring to become cancerous, giving rise to chronic and acute leukemia, respectively. The investigators then subjected the cancer cells to the same glucose manipulations as their normal counterparts.

The team found that regardless of which cell they started with, the leukemia cells were sensitive to both the glucose on-off switch and the volume dial.

“One of the major hurdles for cancer therapy is that while the drugs are effective in killing cancer cells, they are toxic to normal cells,” said first author Ying-Hua Wang, PhD. “In this study, we found a way to differentiate sensitivity between normal and malignant cells, suggesting a potential therapeutic angle.”

“Cancer cells are not like normal cells in a lot of ways, but one of them is that they get locked into a particular way of behaving,” Scadden said. “These cells are so singular in the way they handle glucose that they create a unique opportunity to intervene. Normal cells don’t get so disrupted because they have other energy mechanisms in place.”

Private companies have been developing drugs that target cancer metabolism, but primarily in solid tumors. Scadden hopes that the new study can open the door to industry partnerships and the generation of new treatments. More research will also be needed to determine whether non-blood cancers have similar differences in metabolism sensitivity.

Source: Harvard Stem Cell Institute; September 11, 2014.

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