Cancer as a Mitochondrial Metabolic Disease

Most, if not all, cancers express abnormalities in the number, structure, and function of mitochondria. As structure is linked to function, these mitochondrial abnormalities would compromise energy metabolism through oxidative phosphorylation. Glucose and glutamine are recognized as the major fermentable fuels that drive cancer growth through glycolysis and glutaminolysis, respectively. 

In this presentation, Prof. Thomas Seyfried describes how he and his colleagues used the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON), administered together with ketogenic metabolic therapy (calorically restricted ketogenic diet, KD-R), to treat late-stage orthotopic growth in two syngeneic mouse models of glioblastoma (GBM): the highly invasive mesenchymal tumor VM-M3 and the high-grade stem cell glioma CT-2A. DON targets glutaminolysis while the KD-R reduces glucose and at the same time elevates neuroprotective and non-fermentable ketone bodies. 

This diet/drug therapeutic strategy caused massive tumor cell death or mitotic arrest while reversing disease symptoms and improving overall survival without toxicity. The therapeutic strategy also reduced edema, hemorrhage, and inflammation associated with rapid tumor growth. Moreover, the KD-R diet facilitated DON delivery to the brain and allowed a lower nontoxic dosage to achieve therapeutic effect. 

Seyfried also presents data from human case reports. These findings support the importance of glucose and glutamine in driving GBM growth and provide a plausible therapeutic strategy for the nontoxic metabolic management of GBM and any cancer with mitochondrial defects.

Speaker bio:

Thomas N. Seyfried is Professor of Biology at Boston College and received his Ph.D. in genetics and biochemistry from the University of Illinois, Urbana, in 1976. He completed his undergraduate work at the University of New England, where he recently received the distinguished Alumni Achievement Award. He also holds a master’s degree in genetics from Illinois State University, Normal, Illinois. Seyfried served with distinction in the United States Army’s First Cavalry Division during the Vietnam War and received numerous medals and commendations.

He was a postdoctoral fellow in the Department of Neurology at the Yale University School of Medicine and then served on the faculty as an Assistant Professor in Neurology. Other awards and honors have come from such diverse organizations as the American Oil Chemists Society, the National Institutes of Health, The American Society for Neurochemistry, and the Ketogenic Diet Special Interest Group of the American Epilepsy Society. Seyfried previously served as chair of the Scientific Advisory Committee for the National Tay-Sachs and Allied Diseases Association. He recently received a Lifetime Achievement Award from the Academy of Complementary and Integrative Medicine and the Uncompromising Science Award from the American College of Nutrition for his work on cancer.

Seyfried presently serves on several editorial boards, including those for Nutrition & Metabolism, Neurochemical Research, the Journal of Lipid Research, and ASN Neuro. He has over 180 peer-reviewed publications and is author of the book Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer (Wiley Press). His full list of peer-reviewed publications can be found on PubMed.

Learning objectives:

1. Recognize that cancer is primarily a mitochondrial metabolic disease and not a genetic disease. 
2. Recognize that cancer is a disease of defective respiration with compensatory fermentation regardless of the cellular or genetic heterogeneity involved.
3. Recognize that ketogenic metabolic therapy (KMT) is a cost-effective, nontoxic therapeutic strategy that targets and kills tumor cells while protecting and enhancing the energy efficiency in normal cells.

Disclosures relevant to the speaker:

The individuals involved in course planning have no relevant financial or non-financial disclosures to report related to the planning or presentation of this course.