Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma
Tomás Duraj, Miriam Kalamian, Giulio Zuccoli, Joseph C. Maroon, Dominic P. D’Agostino, Adrienne C. Scheck, Angela M. Poff, Sebastian Winter, Jethro Hu, Rainer J. Klement, Alicia Hickson, Derek C. Lee, Isabella D. Cooper, Barbara Kofler, Kenneth A. Schwartz, Matthew Phillips, Colin E. Champ, Beth Zupec‐Kania, Jocelyn Tan-Shalaby, Fabiano Marcel Serfaty, Egiroh Omene, Gabriel Arismendi-Morillo, Michael A. Kiebish, Richard K. Cheng, Ahmed M. Elsakka, Axel Pflueger, E.H. Mathews, Donese Worden, Hanping Shi, Raffaele Ivan Cincione, Jean Pierre Spinosa, Abdul Kadir Slocum, Mehmet Salih Iyikesici, Atsuo Yanagisawa, Geoffrey J. Pilkington, Anthony Chaffee, Wafaa Abdel-Hadi, Amr K. Elsamman, Pavel Klein, Keisuke Hagihara, Zsófia Clemens, George W. Yu, Athanasios Evangeliou, Janak Nathan, Kris A. Smith, David Fortin, Jörg Dietrich, Purna Mukherjee, Thomas N. Seyfried
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.