Cell metabolism linked to deadly tumors

DUKE (US) — The discovery that genetic mutations found in brain tumors can alter tumor metabolism could pave the way for targeted anti-cancer drug designs.

“What we and other researchers are learning now is that certain changes in cellular metabolism are probably a hallmark of cancer,” says study leader Hai Yan, an associate professor in the pathology department at Duke University.

Yan says that malignant glioma appear to be at least two large subclasses of diseases—”one that involves mutations in the IDH1 and IDH2 genes and one that doesn’t,” continues Yan. “The IDH mutation can serve as a biomarker to help single out individuals who are likely to have better outcomes and who might then receive a particular type of treatment based on their tumor IDH mutation status.”

The study was published in the journal Proceedings of the National Academy of Sciences.

Earlier work by Yan and colleagues showed that a mutation that disrupts the isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) genes was common in some types of incurable brain tumors, including astrocytomas, oligodendrogliomas, and glioblastomas.

Their work suggested that these tumors require the gene to go awry at some point during cancer development. Though key IDH discoveries have been made around the world, a reason that IDH gene mutations could have such a profound influence on brain cancer has remained elusive.

In the current study, Yan’s group solved the connection to metabolism. The IDH1 and IDH2 genes are known to play an important role in cell metabolism—the conversion of nutrients into energy and into building blocks to manufacture new cells.

The researchers examined concentrations of hundreds of metabolites—including sugar, protein, and fat molecules—in cancer cells that they were able to grow in their laboratory.

The analysis revealed that more than 100 metabolites had altered concentrations in cells with the defective IDH1 or IDH2 genes compared to cells without the defective genes.

One very common metabolite in the human brain—N-acetyl-aspartyl-glutamate—was found to be 50 times less common in cells that had that IDH1 mutation compared to those that did not, says Zach Reitman, a graduate student at Duke.

“The fact that defective genes can alter the metabolism of cancer cells could mean that altering cellular metabolism is an important step in brain tumor development,” says Reitman.

“The study emphasized that cellular metabolism could potentially be an ‘Achilles heel’ for brain tumors, and it points to several promising avenues for future research into new treatments for brain tumors in particular,” says Genglin Jin, a key author and postdoctoral research fellow in Yan’s lab.

The work was supported by the American Cancer Society, the Pediatric Brain Tumor Foundation Institute, the Virginia and D.K. Ludwig Fund for Cancer Research, and National Institutes of Health grants.

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