Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma

Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a universally lethal prognosis despite maximal standard therapies. Here, we present a consensus treatment protocol based on the metabolic requirements of GBM cells for the two major fermentable fuels: glucose and glutamine. Glucose is a source of carbon and ATP synthesis for tumor growth through glycolysis, while glutamine provides nitrogen, carbon, and ATP synthesis through glutaminolysis. As no tumor can grow without anabolic substrates or energy, the simultaneous targeting of glycolysis and glutaminolysis is expected to reduce the proliferation of most if not all GBM cells. Ketogenic metabolic therapy (KMT) leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic flux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function. Suggested best practices are provided to guide future KMT research in metabolic oncology, offering a shared, evidence-driven framework for observational and interventional studies.

Keywords: Cancer; Glioblastoma; Glutaminolysis; Metabolism; Precision medicine; Research design; Warburg Effect.

Fig. 1

Simplified diagram of normal and cancer cell metabolism, with special emphasis on ATP synthesis (SLP and OXPHOS). All living cells must meet their ATP demands. Normal cells, including growth-regulated proliferating cells, generate the majority of ATP through the multi-step, ultrastructure-dependent process of OXPHOS. Cancer cells exhibit abnormalities in mitochondrial structure, function and/or number, as well as increased biosynthetic and redox demands, leading to a comparatively reduced efficiency of OXPHOS and compensatory upregulation of cytosolic and mitochondrial SLP. Cytosolic SLP is driven by glycolytic flux but is not synonymous with the Warburg effect (aerobic lactic acid fermentation). Oxidative metabolites can feed into the TCA cycle through catabolic pathways (glycolysis, glutaminolysis, lactate oxidation, β-oxidation, ketolysis), contributing to both SLP and OXPHOS; the total ATP yield is determined by nutrient availability and transport, as well as pathway flux, integrity, and efficiency. Cell division can be constrained by biosynthesis in the excess (assuming sufficient ATP), but energy is limiting for survival under nutrient depletion. The goal of KMT is to synergize with other therapies by targeting SLP flux in cancer cells and upregulating OXPHOS in normal cells, increasing metabolic stress and whole-body ecological competition

Fig. 2

Illustrative diagram of blood glucose, βHB, and GKI during different phases of dietary KMT. Note that the suggested glucose and ketone levels are representative of inter-individual and intra-individual variability, not prescriptive. In this example, after initiating a GKI-adjusted KD, glycemia is maintained below 5 mM and ketonemia above 1–2 mM. The proposed therapeutic zone has been achieved once glucose levels are less than two-fold ketone levels (e.g., 5 mM glucose, 2.5 mM βHB, GKI ≤ 2), and optimal when glucose levels are equal or lower than ketone levels (e.g., 4 mM glucose, 4 mM βHB, GKI ≤ 1). Absolute glucose levels should be at their physiological minimum. Dietary, stress, or therapy-induced excursions (e.g., corticosteroids) should be minimized. Exercise-induced gluconeogenesis is expected and offset via skeletal muscle demand. As a long-term therapeutic strategy, dietary KMT may continue as long as there is evidence of persistent disease or risk of recurrence. Real-time GKI tracking is recommended in research settings to avoid ambiguity regarding biological outcomes

Fig. 3

Overview of KMT implementation in high-grade glioma research, including both dietary KMT (GKI-adjusted KD/KD-R and fasting, aimed at increasing chronic metabolic pressure on cancer cells while favoring OXPHOS metabolism in normal tissues), as well as pharmacological KMT (targeting of glycolysis and glutaminolysis in a press-pulse design, in addition to cancer-associated pathways to normalize the tumor microenvironment)

Fig. 4

Prerequisites and potential experimental complexity of KMT. Any interested patient can initiate dietary KMT, ideally under the supervision of a trained dietitian. The resources and staff required for pharmacological KMT are dependent on the number of interventions and clinical settings (for example, a GKI-adjusted KD in addition to SOC, or research therapies such as glutaminolysis inhibition)

Fig. 5

Overview of potential drug treatments as part of KMT research. Strategies are divided into glucose targeting (red), glutamine targeting (green), and tumor microenvironment stabilization (blue). Safe administration of metabolic inhibitors will require physiological adaptation to a GKI-adjusted KD/KD-R, which can be accelerated by water-only fasting. Then, glycolysis targeting can be considered to further improve GKI and slow tumor progression (e.g., antidiabetic agents such as metformin or SGLT2 inhibitors, as well as research-phase glycolytic inhibitors). Glutaminolysis should be targeted at the same time (e.g., sodium phenylbutyrate, DON, or novel glutamine inhibitors). Finally, normalization of the tumor microenvironment can be explored in a modular fashion; for example, cell proliferation (mebendazole), inflammation (NSAIDs), hypoxia (HBOT), redox balance (DCA, intravenous vitamin C), immunotherapy, or combinatory approaches (e.g., CUSP9)