Jamming fat metabolism stops blood cancer cells

Targeted cancer therapies work by blocking specific, cancer-driving mutations. But in a new laboratory study, researchers show that cancers driven by several different mutations can all be stopped by a targeting a shared growth pathway that they use to fuel their nonstop cell division.

“This seems to be a common metabolic strategy that is exploitable as a target for cancer therapy,” says Daniel Liefwalker, Ph.D., the principal author of a paper in the journal Cancer & Metabolism describing the discovery. Liefwalker is a research assistant professor in the OHSU School of Medicine.

It’s long been known that cancer cells reprogram their metabolism to continue multiplying. For instance, cancer cells take up the sugar glucose at a high rate and can shift to a fermentation process for extracting energy from glucose. But many years of effort to target this process have not panned out as a way to stop cancer.

Daniel Liefwalker, Ph.D.

Liefwalker and colleagues looked at a different metabolic process: lipogenesis, the building of fatty acids. Liefwalker had analyzed masses of data on gene activity in cancer cells and that computational approach pointed to lipogenesis as a promising therapeutic target.

The researchers began by studying lipogenesis gene regulation in mouse models of lymphoma cancers and lymphoma cells derived from mice. Experiments showed that lipogenesis genes are upregulated not only in lymphoma cells driven by mutations in the gene MYC, but also in those driven by mutations in the genes RAS and BCR-ABL.

Those three types of lymphoma cells also proved sensitive to drugs that selectively inhibit lipogenesis. An inhibitor called TOFA reduced viable cell populations in all three oncogene-driven cells, in mouse and in human lymphoma cell lines. TOFA treatment also delayed cancer establishment and tumor progression in mice implanted with a form of leukemia.

But TOFA treatment did not increase cell death in experimental controls, mice that were not implanted with MYC-driven tumor cells. “When we treat with this lipogenesis inhibitor it specifically targets the cancer cells and leaves normal cells alone,” Liefwalker said. “Therapeutically this could have really nice implication: We could have a safe drug that targets circulating tumor cells while leaving non-tumor cells alone.”

Further reading:

Metabolic convergence on lipogenesis in RAS, BCR-ABL, and MYC-driven lymphoid malignancies by Daniel F. Liefwalker, Meital Ryan, Zhichao Wang, Khyatiben V. Pathak, Seema Plaisier, Vidhi Shah, Bobby Babra, Gabrielle S. Dewson, Ian K. Lai, Adriane R. Mosley, Patrick T. Fueger, Stephanie C. Casey, Lei Jiang, Patrick Pirrotte, Srividya Swaminathan and Rosalie C. Sears. Cancer & Metabolism (2021)

Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation by
Matthew G. Vander Heiden, Lewis C. Cantley and Craig B. Thompson. Science (2009)


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