Abstract

Glioblastoma (GBM) is the most common and deadly high-grade glioma (HGG) and remains incurable utilizing the sole standard protocol known to significantly improve patient survival. [1, 2] Patients administered this protocol— concomitant chemoradiation therapy and subsequent tumor-treating fields (instituted in 2005 and 2015, respectively)— survive a median of 16 months post-treatment.[3–5] Notably, GBM exhibits sex differences in all three parameters mentioned: cancer incidence, response to treatment, and post-treatment survival.[6, 7] More specifically, GBM incidence is 1.6X higher and mean survival time 4-5 months shorter in males than females.[6, 7] Similar observations of higher male cancer incidence and lethality have been observed for almost all non-reproductive cancers.[8] In GBM, these differences have been found to be mediated, in part, by greater responsiveness of female tumors to surgery accompanied by standard therapy.[9] Collectively, these observations intuit that cryptic mechanisms driving disease origination, progression, and therapeutic susceptibility modulate with sex. Knowledge about the mechanistic basis of sex differences in cancer can be used to inform more effective targeting of GBM in males and females. Therefore, my thesis seeks to disclose and target these mechanisms toward this end. Previously, we have identified that metabolism may mediate significant sex differences in multiple cancers.[10, 11] Our published metabolomics analyses of primary cancer tissues excavated putative, male-biased therapeutic vulnerabilities in brain and lung cancer metabolism.[10, 11] Our studies of male and female lung cancer cells uncovered targetable sex differences in the de novo synthesis of serine and glycine from glucose, which may exist in other cancers.[10] Our data suggest male-biased upregulation of transcripts encoding proteins mediating de novo synthesis of serine, glycine, and nucleotides from glucose to drive cellular proliferation.[10] These data led us to hypothesize that inhibition of the synthesis of serine and glycine from glucose would more significantly compromise cellular proliferation of male cancer cells than female cancer cells. Utilizing a murine model of HGG which exhibits sex differences in proliferation, we first tested if male HGG cells synthesize more serine and glycine from glucose than females. Next, we pharmacologically inhibited the de novo synthesis of serine and glycine from glucose to determine if male HGG cell number was more significantly reduced than females. Leveraging knowledge from the literature to refine our approach, we molecularly dissected the hypothesis that sex differences in inhibitor-mediated reductions in HGG cell number modulate with the presence or absence of exogenous metabolites.[12] Then, we performed pharmacological blockade of de novo serine or glycine biosynthesis in the presence or absence of serine, glycine, and/or nucleotide precursors to determine its effects on cell number and proliferation index. Utilizing these approaches and our murine model of HGG, we report several observations. First, relative to female HGG cells, murine male HGG cells more robustly generate serine and glycine from glucose. Second, pharmacological blockade of the biosynthesis of glycine, but not serine, more significantly reduced the number of murine male HGG cells than female HGG cells, relative to the vehicle. Third, inhibitor-mediated reductions in cell number were significantly reduced further in both sexes by the absence of exogenous glycine or an alternative nucleotide precursor (hypoxanthine). Concordantly, removal of exogenous nucleotide precursors (hypoxanthine or thymidine) improved inhibitor-mediated reductions in cell number using multiple inhibitors of nucleotide biosynthesis. Mechanistically, these inhibitors significantly reduced biosynthesis of their targeted nucleotide category— purines or pyrimidines—resulting in murine male-biased reductions in cell number and proliferation index. From these studies, we conclude that sex differences in glycine biosynthesis and nucleotide metabolism exist in our murine model and may exist in human GBM. Further, the mechanisms disclosed here may mediate significant sex differences in human male and female GBM response to inhibition of de novo glycine biosynthesis. Revelations of differences of this nature are rare, essential, and underlie the discovery of novel therapeutics that consider sex as a biological variable.

Committee Chair

Joseph Ippolito

Committee Members

Alexander Stegh; Jason Weber; Jim Skeath; Kristen Kroll

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Cancer Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

8-12-2026

Language

English (en)

Download

Available for download on Friday, August 11, 2028

Included in

Biochemistry Commons

Share

COinS