Sex differences in glycine biosynthesis drives sex-specific responses to combined nutrient deprivation and pharmacological inhibition in brain tumors
Abstract
Background: Glioblastoma (GBM) is the deadliest brain tumor. Generally, male GBM occurs at higher incidence and demonstrates 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 door 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.
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BibTeX
@article{marquez2026differences,
title = {{Sex differences in glycine biosynthesis drives sex-specific responses to combined nutrient deprivation and pharmacological inhibition in brain tumors}},
author = {Camryn Marquez and Jianyun Lu and Kevin Cho and Shanshan Zhang and Jingqin Luo and Joshua B Rubin and Gary J Patti and Joseph E Ippolito},
journal = {Neuro-Oncology Advances},
year = {2026},
month = sep,
doi = {10.1093/noajnl/vdag245},
url = {https://doi.org/10.1093/noajnl/vdag245},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Sex differences in glycine biosynthesis drives sex-specific responses to combined nutrient deprivation and pharmacological inhibition in brain tumors
AU - Camryn Marquez
AU - Jianyun Lu
AU - Kevin Cho
AU - Shanshan Zhang
AU - Jingqin Luo
AU - Joshua B Rubin
AU - Gary J Patti
AU - Joseph E Ippolito
PY - 2026
DA - 2026/09/22
JO - Neuro-Oncology Advances
DO - 10.1093/noajnl/vdag245
UR - https://doi.org/10.1093/noajnl/vdag245
AB - Background: Glioblastoma (GBM) is the deadliest brain tumor. Generally, male GBM occurs at higher incidence and demonstrates 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 door 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.
SN - 2632-2498
ER -