Work

METB-08. Identification Of A Clinically-Actionable Sexual Dimorphism In Glioblastoma Glycolysis

Year: 2017

Type: article

Abstract: Sex differences are present in tumor incidence and mortality. In many cancers including GBM, males not only have a higher incidence but also exhibit poorer outcomes. The molecular basis of this phenomenon has not yet been elucidated. Because of increased glucose utilization in normal male development and the inverse correlation between glioma glucose uptake and patient survival, we hypothesized that male GBM would have enhanced glycolysis relative to female GBM. First, biochemical measurements of clinical samples disclosed significant enrichment of glycolytic activity in male GBM measured by pyruvate kinase activity and lactate levels. Next, to determine if a specific compartment in the GBM microenvironment was driving these sex differences in glycolysis, we performed metabolic reconstructions using the IVY glioblastoma atlas. We discovered significant overexpression (q<0.01, fold-change >2) of several glycolytic genes unique to the peri-necrotic compartment suggesting that male GBM had higher necrosis than female GBM. An analysis of clinical MRI datasets confirmed that although males had significantly higher necrosis than females, females were uniquely stratified into “high” and “low” necrosis groups where “high necrosis” females did significantly worse. To address the possibility that glycolysis could stratify females similarly to necrosis, we analyzed glycolytic pathway TCGA RNA-Seq data from male and female primary GBM. Similarly, we discovered that expression of the glycolytic transcriptome more robustly stratified females than males. We cross validated these findings with a small cohort of GBM patients with suspected recurrence who were imaged with FDG-PET. In keeping with female-specific stratification, we discovered that FDG uptake at the suspected recurrence also risk-stratified females. In summary, although male GBM is characterized by higher glycolytic activity, glycolysis has the ability to uniquely risk-stratify female GBM. Together, our findings represent a previously uncharacterized phenomenon that pave the way toward a “sex-based workflow” for GBM stratification employing integrated metabolism and imaging.

Source: Neuro-Oncology

DOI: 10.1093/neuonc/nox168.532