Glioblastoma (GBM), similar to most cancers, is dependent on fermentation metabolism
for the synthesis of biomass and energy (ATP) regardless of the cellular or genetic
heterogeneity seen within the tumor. The transition from respiration to fermentation
arises from the documented defects in the number, the structure, and the function
of mitochondria and mitochondrial-associated membranes in GBM tissue. Glucose and
glutamine are the major fermentable fuels that drive GBM growth. The major waste products
of GBM cell fermentation (lactic acid, glutamic acid, and succinic acid) will acidify
the microenvironment and are largely responsible for drug resistance, enhanced invasion,
immunosuppression, and metastasis. Besides surgical debulking, therapies used for
GBM management (radiation, chemotherapy, and steroids) enhance microenvironment acidification
and, although often providing a time-limited disease control, will thus favor tumor
recurrence and complications. The simultaneous restriction of glucose and glutamine,
while elevating non-fermentable, anti-inflammatory ketone bodies, can help restore
the pH balance of the microenvironment while, at the same time, providing a non-toxic
therapeutic strategy for killing most of the neoplastic cells.
