TMET-11. Altered serine metabolism in IDHm gliomas reveals a targetable metabolic vulnerability

Abstract Isocitrate dehydrogenase mutations (IDHm) occur in 70–80% of low-grade gliomas, a common, malignant adult cancer of the central nervous system. IDHm drives the production of oncometabolite D-2-hydroxyglutarate (D-2-HG), promoting tumorigenesis and treatment resistance in gliomas harboring this mutation. Consequently, IDHm gliomas are highly recurrent, incurable tumors with limited therapeutic options and unique metabolic phenotypes. Analysis of human tumor samples demonstrates reduced serine abundance in IDHm gliomas compared to IDH wild-type (IDHwt). Serine, which can be generated de novo from glucose or directly salvaged from the environment, is crucial for biomass generation and energy production. The mechanisms driving the discrepancy between IDHm and IDHwt glioma serine abundance are currently unknown. We hypothesize that D-2-HG disrupts both de novo serine synthesis and extracellular serine uptake, revealing a therapeutically targetable metabolic vulnerability in IDHm gliomas. To investigate this mechanism in patients, our laboratory conducted a first-ever human isotope tracing study comparing glucose flux in brain tumors and normal tissue. We observed reduced glucose-driven serine synthesis in IDHm tumors relative to IDHwt tumors, while levels in IDHm and IDHwt cortex are not significantly different. These findings suggest de novo serine synthesis is impaired in an IDHm-dependent manner. Additionally, IDHm cells exhibit reduced glycosylation of a key serine transporter. Glycosylation is essential for transporter function, implicating impaired serine uptake as a contributor to low serine abundance in IDHm tumors. In vitro growth assays further support serine uptake as a potential metabolic vulnerability in IDHm gliomas. Future studies will determine how D-2-HG specifically drives these phenotypes and test whether limiting serine availability in vivo enhances efficacy of standard-of-care treatments for IDHm gliomas. These findings may ultimately support therapeutic strategies involving dietary restriction of exogenous serine and glycine as a targeted approach for IDHm glioma treatment.