An experimental class of drugs alters cell metabolism and may prevent tumor growth

NYU's Andrew Chi

Researchers from the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center and Massachusetts General Hospital have discovered that a class of experimental drugs used for altering cell metabolism also works in mice to reduce cancers linked to changes in the same gene.

Mutations in the gene that codes for the protein isocitrate dehydrogenase 1 (IDH1 in brief) are found in blood, skin, soft tissue and cartilage cancer--and more importantly in a third of gliomas in the brain.

Senior authors Andrew Chi and Daniel Cahill published their findings this week in Cancer Cell.

By scanning a wide range of chemicals involved in metabolism in human and mouse mutant IDH1 cancer cells, the researchers found lower levels of an important metabolite called nicotinamide adenine dinucleotide. NAD is essential in cells for the conversion of sugars and other nutrients into energy, helping with DNA repair and indispensable for cell survival.

In IDH1 mutant soft tissue tumor (also known as fibrosarcoma) they found that treatment with NAMPT inhibitors, which similarly lower the level of NAD, halted the tumor. In mice with IDH1 mutant glioma brain cancer the finding was reproduced--mice given these class of drugs lived longer and showed no reported side effects.

In explanted cells from patients with the IDH1 brain tumor the researchers were again able to reduce NAD levels and cause the cells to die, due to the further loss of NAD activity and subsequent energy for the cell. In their control experiments--cancer cells without the mutant IDH1--they observed no change in cell death using NAMPT inhibitors.

Since no treatment exists for IHD1 mutant gliomas there is a need to develop a new therapy: hitting the cell that is already lower in NAD with NAMPT inhibitors may be the answer.

"Nearly all patients die from their [IDH1 mutant glioma] brain cancer," Chi said. "Our findings provide yet another example of the need to personalize cancer therapy, as based on our results, we would only expect NAMPT inhibitors to be effective against IDH1-mutated cancers."

Chi and his team are next asking why NAD levels are lower in IDH1 mutant cancer, with long term plans of taking this class of drugs to the clinic for IDH1 mutant cancer patients.

- here's the release
- here's the article abstract

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