Sex differences in glycine biosynthesis drives sex-specific responses to combined nutrient deprivation and pharmacological inhibition in brain tumors
Camryn Marquez, Jianyun Lu, Kevin Cho, Shanshan Zhang, Jingqin Luo, Joshua B Rubin, Gary J Patti, Joseph E IppolitoAbstract
Background
Glioblastoma (GBM) is the deadliest brain tumor. Generally, male GBM occur at higher incidence and demonstrate shorter overall survival compared to females. Targetable drivers of this phenomenon remain undisclosed, preventing the integration of sex differences into the design of targeted therapeutics.
Methods
Here, we utilized metabolite tracing, pharmacological blockade, and nutrient deprivation to profile and target putative sex differences in cellular proliferation driven by the synthesis of glycine and nucleotides from glucose.
Results
Utilizing an established murine model of GBM (Nf1-/-DNp53), we observed male biases in de novo glycine biosynthesis and in the cellular response to inhibition of this pathway in nutrient-replete media. Additionally, we illustrated that removal of exogenous glycine or nucleotide salvage metabolites enhanced inhibition efficacy in both male and female tumor cells. Collectively, our paradigm targets sex differences in the endogenous synthesis of glycine, which coordinates with cellular uptake of exogenous glycine or nucleotide salvage metabolites, to stall nucleotide biosynthesis and cellular proliferation.
Findings
These data suggest inhibition of de novo glycine biosynthesis may elicit a sex-biased therapeutic response in GBM. Additionally, this work opens the doors to future studies involving dietary restriction of glycine in combination with pharmacological inhibition of de novo glycine biosynthesis as a means to improve outcomes in patients with brain tumors.