Evaluating Glutamine Metabolism in Pediatric High-Grade Gliomas With the H3K27M Mutation

Cancer cells fuel growth and proliferation through the catabolism of two main substrates: glucose (Glu) and glutamine (Gln). Glutamine metabolism has been reported to exceed the use of other nonessential amino acids in cancer cells. Gln is the most abundant plasma amino acid and promotes cancer cell proliferation and survival likely through the generation of the TCA cycle intermediate alpha-ketoglutarate (α-KG), a process referred to as anaplerosis. Furthermore, Gln-derived alpha-ketoglutarate (α-KG) is a critical co-factor for histone lysine demethylases, including JMJD3 (a Jumonji C family of histone lysine demethylase responsible for demethylating H3K27me3). Importantly, H3K27M tumors show global reduction in H3K27 methylation that abundant Gln may help facilitate.

Dr. Daniels' research team in the Experimental Drug and Therapeutics for Pediatric Brain Tumor Lab aims to determine the impact of Gln deprivation in H3K27M tumors. The research team is also exploring the altered Gln metabolism in H3K27M tumor cells that feed the TCA cycle and regulate the activity of the α-KG dependent enzyme JMJD3. Regulating Gln metabolism may represent a novel therapeutic approach for tumors with this mutation.