Aggressive brain cancer growth driven by metabolic enzyme

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An abnormal metabolic pathway drives the growth of cancer cells in a particular glioblastoma subtype, according to new research. This finding may lead to new therapies for a subset of patients with glioblastoma, which is the most common and lethal form of brain cancer.

The physician scientists sought to identify glioblastoma subtype-specific cancer stem cells. Genetic analyses have shown that high-grade gliomas can be divided into four subtypes: proneural, neural, classic and mesenchymal.   This study shows that the mesenchymal subtype is the most aggressive subtype, that it has the poorest prognosis among affected patients, and that cancer stem cells isolated from the mesenchymal subtype have significantly higher levels of the enzyme ALDH1A3 compared with the proneural subtype.

High levels of the enzyme ALDH1A3 drive tumor growth. The findings were published in Proceeding of the National Academy of Sciences (2013;110(21):8644-8649).

“Our study suggests that ALDH1A3 is a potentially functional biomarker for mesenchymal glioma stem cells, and that inhibiting that enzyme might offer a promising therapeutic approach for high-grade gliomas that have a mesenchymal signature,” said principal investigator Ichiro Nakano, MD, PhD, of The Ohio State University Comprehensive Cancer Center. “This indicates that therapies for high-grade gliomas should be personalized, that is, based on the tumor subtype instead of applying one treatment to all patients.”

Little is known about the metabolic pathways that drive the growth of individual glioblastoma subtypes, which is knowledge that is crucial for developing novel and effective targeted therapies that might improve treatment for these lethal tumors.

For this study, Nakano and his collaborators used cancer cells from 40 patients with high-grade gliomas, focusing on tumor cells with a stem-cell signature. The researchers then used microarray analysis and preclinical animal assays to identify two predominant glioblastoma subtypes, proneural and mesenchymal.

The mesenchymal glioma stem cells had significant upregulation of genes involved in glycolysis and gluconeogenesis, particularly ALDH1A3, compared with proneural stem cells. Also, the mesenchymal glioma stem cells had significantly higher radiation resistance and high expression of DNA-repair genes. Radiation induces the proneural glioma stem cells to be transformed into mesenchymal-like glioma stem cells that are highly resistant to radiation treatment. This resistance is reversed by inhibiting the ALDH1 pathway. The growth of mesenchymal glioma stem cells was slowed by inhibiting pathways mediated by ALDHA3, which may be a promising therapeutic approach for the subtype of glioblastomas with a mesenchymal signature.
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