TMET-09. SEX DIFFERENCES IN SERINE-DERIVED GLYCINE BIOSYNTHESIS DRIVE RESPONSES TO COMBINED NUTRIENT DEPRIVATION AND PHARMACOLOGICAL INHIBITION IN GBM

Abstract

Abstract Glioblastoma (GBM) is the most common and deadly primary brain malignancy. Male GBM patients occur at higher incidence and display more aggressive disease than females. Ambiguity of molecular mechanisms driving sexually dimorphic outcomes in GBM limits the implementation of clinically effective treatments. Therefore, our group seeks to determine and target the metabolic bases of sex-biased GBM proliferation and progression. We have identified glucose utilization as a unique determinant of male but not female GBM patient outcomes. Utilizing a mouse model for mesenchymal GBM (Nf1-/-DNp53), we demonstrated a male-specific decrease in proliferation in response to glucose-deprived media and glycolytic inhibition. Following labeling with [13C] glucose, males had significantly higher de novo serine biosynthesis, measured by enrichment of serine and glycine. This was confirmed with significant upregulation of several serine biosynthetic pathway enzymes in male cells. These mouse model data were validated by metabolomics and enzyme data from human GBM and lung cancer, including pan-cancer gene expression data, underscoring the broad translational importance of these findings. We then sought to determine if sex-biased responses to serine and glycine deprivation were similar to those observed following glucose deprivation. Utilizing serine and glycine-deprived media conditions, we identified a male-specific decrease in proliferation following pharmacological inhibition of the serine biosynthetic pathway. More precisely, in the absence of exogenous glycine, we discovered that pharmacological inhibition of de novo synthesis of glycine from serine drove male-specific decreases in proliferation. Additionally, we discovered that under serine and glycine-deprived conditions, inhibition of de novo synthesis of glycine from serine sensitized female transformed astrocytes to antifolates. These data highlight that de novo glycine synthesis drives sex differences in GBM cell proliferation. As well, our work suggests that dietary restriction of serine and glycine, in combination with pharmacological inhibition of de novo glycine biosynthesis, represents a novel GBM treatment paradigm.