2026 Poster Presentations
P038: TARGETING METABOLIC VULNERABILITIES IN GLIOBLASTOMA: DISRUPTING GLYCOLYSIS, GLUTAMINOLYSIS, AND MITOCHONDRIAL FUNCTION
Jawad A Saad, BS; James Chung, BS; Ahmad Kafri, BS; Julien Rossignol, PhD; Maxwell Verbrugge, MD; Jesse Bakke, PhD; Central Michigan University College of Medicine
Introduction: Glioblastoma multiforme (GBM) is characterized by neoplastic cells that exhibit unique metabolic functioning, primarily demonstrated by a preferential shift toward aerobic glycolysis (the Warburg effect) for energy production. This metabolic reprogramming provides a substantial survival advantage and protects GBM cells from oxidative damage. Furthermore, GBM cells often develop metabolic inflexibility, increasing their reliance on glucose as a primary energy source. Given GBM’s reliance on these aberrant metabolic pathways, targeting them has emerged as a potential therapeutic approach to disrupt sustained growth and survival.
This abstract summarizes metabolic targeting strategies in GBM, aiming to provide an overview of approaches designed to disrupt aerobic glycolysis, glutaminolysis, and mitochondrial metabolism.
Methods: A narrative review was conducted, synthesizing 152 peer-reviewed publications from January 2000 to September 2025 across basic, translational, and clinical studies. Literature was identified through PubMed, Embase, and Web of Science using combinations of keywords including glioblastoma, metabolism, aerobic glycolysis, Warburg effect, Ketogenic Diet (KD), Pyruvate Kinase M2 (PKM2), pyruvate dehydrogenase kinase (PDK), dichloroacetate (DCA), glutaminolysis, glutaminase (GLS), mitochondrial dysfunction, T-cells, and immune microenvironment. Reference lists of key articles were also reviewed to capture additional publications. Eligible studies included English-language articles focused on GBM, encompassing preclinical models, translational work, and clinical trials, while excluding single case reports and non-primary brain tumor studies. Findings were synthesized thematically to highlight key therapeutic strategies and their mechanisms of action, with this section of the study focusing on dietary modifications (Ketogenic Diet), pharmacological inhibitors targeting glycolysis (PKM2, PDK), inhibitors of glutaminolysis (GLS, GDH), and strategies targeting mitochondrial dysfunction (VDAC1). The synthesis also addressed the impact of these strategies on GBM tumor-host interactions, including metabolic inflexibility and the modulation of the immunosuppressive tumor microenvironment.
Results: Preclinical mouse models demonstrated that KD can enhance the sensitivity of glioma cells to radiation and chemotherapy. Clinical data showed that a supervised KD was well tolerated in a Phase I trial alongside standard care, with stable or improved quality of life, yet survival benefits did not reach statistical significance. Targeting glycolysis has shown promise: DCA, by inhibiting PDK, maintains pyruvate dehydrogenase in its active form, reversing the Warburg effect in glioma cells and leading to increased mitochondrial function. PKM2 activators (like DMAMCL) suppress GBM proliferation by forcing maximal glycolytic flux and starving the tumor of anabolic building blocks. Furthermore, GLS inhibitors like CB-839 demonstrated a strong, dose-dependent anti-proliferative effect on multiple GBM cell lines. Targeting VDAC1 with inhibitors induced apoptosis and significantly decreased cellular ATP and tumor volume in mouse xenografts.
Conclusion: The use of dietary modifications (KD) and pharmacological agents targeting glycolysis, glutaminolysis, and VDAC1 provides compelling preclinical evidence for exploiting the metabolic vulnerabilities of GBM. Inhibitors of metabolic pathways, such as DCA and CB-839, show strong rationale for clinical translation due to their ability to disrupt key survival mechanisms in GBM cells, either by reversing the Warburg effect or starving the cells of precursors. Moving forward, clinical trials are necessary to translate these findings into demonstrable improvements in efficacy and survival outcomes for GBM patients.