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...
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2024-12-01
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| Online Access: | https://doi.org/10.1186/s12916-024-03775-4 |
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| author | Tomás Duraj Miriam Kalamian Giulio Zuccoli Joseph C. Maroon Dominic P. D’Agostino Adrienne C. Scheck Angela Poff Sebastian F. Winter Jethro Hu Rainer J. Klement Alicia Hickson Derek C. Lee Isabella Cooper Barbara Kofler Kenneth A. Schwartz Matthew C. L. Phillips Colin E. Champ Beth Zupec-Kania Jocelyn Tan-Shalaby Fabiano M. Serfaty Egiroh Omene Gabriel Arismendi-Morillo Michael Kiebish Richard Cheng Ahmed M. El-Sakka Axel Pflueger Edward 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 E. Evangeliou Janak K. Nathan Kris Smith David Fortin Jorg Dietrich Purna Mukherjee Thomas N. Seyfried |
| author_facet | Tomás Duraj Miriam Kalamian Giulio Zuccoli Joseph C. Maroon Dominic P. D’Agostino Adrienne C. Scheck Angela Poff Sebastian F. Winter Jethro Hu Rainer J. Klement Alicia Hickson Derek C. Lee Isabella Cooper Barbara Kofler Kenneth A. Schwartz Matthew C. L. Phillips Colin E. Champ Beth Zupec-Kania Jocelyn Tan-Shalaby Fabiano M. Serfaty Egiroh Omene Gabriel Arismendi-Morillo Michael Kiebish Richard Cheng Ahmed M. El-Sakka Axel Pflueger Edward 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 E. Evangeliou Janak K. Nathan Kris Smith David Fortin Jorg Dietrich Purna Mukherjee Thomas N. Seyfried |
| author_sort | Tomás Duraj |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-f493bd6a9af94b99a15a8ff738e02f2b |
| institution | Kabale University |
| issn | 1741-7015 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj-art-f493bd6a9af94b99a15a8ff738e02f2b2024-12-08T12:33:07ZengBMCBMC Medicine1741-70152024-12-0122114910.1186/s12916-024-03775-4Clinical research framework proposal for ketogenic metabolic therapy in glioblastomaTomás Duraj0Miriam Kalamian1Giulio Zuccoli2Joseph C. Maroon3Dominic P. D’Agostino4Adrienne C. Scheck5Angela Poff6Sebastian F. Winter7Jethro Hu8Rainer J. Klement9Alicia Hickson10Derek C. Lee11Isabella Cooper12Barbara Kofler13Kenneth A. Schwartz14Matthew C. L. Phillips15Colin E. Champ16Beth Zupec-Kania17Jocelyn Tan-Shalaby18Fabiano M. Serfaty19Egiroh Omene20Gabriel Arismendi-Morillo21Michael Kiebish22Richard Cheng23Ahmed M. El-Sakka24Axel Pflueger25Edward H. Mathews26Donese Worden27Hanping Shi28Raffaele Ivan Cincione29Jean Pierre Spinosa30Abdul Kadir Slocum31Mehmet Salih Iyikesici32Atsuo Yanagisawa33Geoffrey J. Pilkington34Anthony Chaffee35Wafaa Abdel-Hadi36Amr K. Elsamman37Pavel Klein38Keisuke Hagihara39Zsófia Clemens40George W. Yu41Athanasios E. Evangeliou42Janak K. Nathan43Kris Smith44David Fortin45Jorg Dietrich46Purna MukherjeeThomas N. Seyfried47Biology Department, Boston CollegeDietary Therapies LLCNeuroradiology, Private PracticeDepartment of Neurological Surgery, University of Pittsburgh Medical CenterDepartment of Molecular Pharmacology and Physiology, University of South Florida Morsani College of MedicineDepartment of Child Health, University of Arizona College of MedicineDepartment of Molecular Pharmacology and Physiology, University of South Florida Morsani College of MedicineDepartment of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical SchoolCedars-Sinai Cancer, Cedars-Sinai Medical CenterDepartment of Radiotherapy and Radiation Oncology, Leopoldina Hospital SchweinfurtRayma HealthBiology Department, Boston CollegeAgeing Biology and Age-Related Diseases Group, School of Life Sciences, University of WestminsterResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical UniversityDepartment of Medicine, Michigan State UniversityDepartment of Neurology, Waikato HospitalExercise Oncology & Resiliency Center and Department of Radiation Oncology, Allegheny Health NetworkKetogenic Therapies LLCSchool of Medicine, University of Pittsburgh, Veteran Affairs Pittsburgh Healthcare SystemDepartment of Clinical Medicine, State University of Rio de Janeiro (UERJ)Department of Oncology, Cross Cancer InstituteDepartment of Medicine, Faculty of Health Sciences, University of DeustoBPGbio IncCheng Integrative Health CenterMetabolic Terrain Institute of HealthPflueger Medical Nephrologyand , Internal Medicine Services P.L.L.CDepartment of Physiology, Faculty of Health Sciences, University of PretoriaArizona State UniversityDepartment of Gastrointestinal Surgery and Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical UniversityDepartment of Clinical and Experimental Medicine, University of FoggiaIntegrative Oncology, Breast and Gynecologic Oncology SurgeryMedical Oncology, ChemoThermia Oncology CenterDepartment of Medical Oncology, Altınbaş University Bahçelievler Medical Park HospitalThe Japanese College of Intravenous TherapyUniversity of PortsmouthDepartment of Neurosurgery, Sir Charles Gairdner HospitalClinical Oncology Department, Cairo UniversityNeurosurgery Department, Cairo UniversityMid-Atlantic Epilepsy and Sleep CenterDepartment of Advanced Hybrid Medicine, Graduate School of Medicine, Osaka UniversityInternational Center for Medical Nutritional InterventionGeorge W, Yu Foundation For Nutrition & Health and Aegis Medical & Research AssociatesDepartment of Pediatrics, Medical School, Aristotle University of Thessaloniki, Papageorgiou Hospital, EfkarpiaDr. DY Patil Medical College, Hospital and Research CentreBarrow Neurological Institute, Dignity Health St. Joseph’s Hospital and Medical CenterUniversité de SherbrookeDepartment of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical SchoolBiology Department, Boston CollegeAbstract 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.https://doi.org/10.1186/s12916-024-03775-4CancerGlioblastomaMetabolismResearch designWarburg EffectGlutaminolysis |
| spellingShingle | Tomás Duraj Miriam Kalamian Giulio Zuccoli Joseph C. Maroon Dominic P. D’Agostino Adrienne C. Scheck Angela Poff Sebastian F. Winter Jethro Hu Rainer J. Klement Alicia Hickson Derek C. Lee Isabella Cooper Barbara Kofler Kenneth A. Schwartz Matthew C. L. Phillips Colin E. Champ Beth Zupec-Kania Jocelyn Tan-Shalaby Fabiano M. Serfaty Egiroh Omene Gabriel Arismendi-Morillo Michael Kiebish Richard Cheng Ahmed M. El-Sakka Axel Pflueger Edward 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 E. Evangeliou Janak K. Nathan Kris Smith David Fortin Jorg Dietrich Purna Mukherjee Thomas N. Seyfried Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma BMC Medicine Cancer Glioblastoma Metabolism Research design Warburg Effect Glutaminolysis |
| title | Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma |
| title_full | Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma |
| title_fullStr | Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma |
| title_full_unstemmed | Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma |
| title_short | Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma |
| title_sort | clinical research framework proposal for ketogenic metabolic therapy in glioblastoma |
| topic | Cancer Glioblastoma Metabolism Research design Warburg Effect Glutaminolysis |
| url | https://doi.org/10.1186/s12916-024-03775-4 |
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