Alternative therapies are needed that can better manage brain tumors while permitting a decent quality of life. Surgical resection followed by radiation is the standard therapy for malignant gliomas today as it has been for over five decades. Chemotherapy has had little positive benefit on malignant glioma management and is often associated with adverse effects that diminish quality of life. It is also unlikely that therapeutic targeting of tumor-associated mutations will be effective in brain tumor management, as most tumor mutations arise as epiphenomena of tissue disorganization and their involvement with tumor initiation, promotion, or progression has not been conclusively established. We recently found that caloric restriction, a simple therapy that lowers glucose and elevates blood ketone levels, has powerful anti-angiogenic and pro-apoptotic effects on experimental mouse and human brain tumors. We are now defining the molecular mechanisms by which dietary caloric restriction can manage brain cancer. These studies will have direct translational benefit to the clinic.

Diet Therapy for Brain Cancer

We are studying the effect of dietary caloric restriction (DR) and the low carbohydrate, high fat, ketogenic diet on brain tumor growth, angiogenesis, and apoptosis. DR is produced from a total restriction of dietary nutrients and differs from starvation in that it reduces total caloric energy intake without causing anorexia or malnutrition. The KD, in addition to managing refractory pediatric epilepsy, is also the only known diet therapy effective against pediatric astrocytoma. It is recognized that the anti-tumor effects of DR result from caloric restriction per se and not from the restriction of any specific dietary component such as proteins, vitamins, minerals, fats, or carbohydrates. Besides inhibiting tumor growth, DR also produces a marked increase in general health. DR has documented beneficial effects on numerous diseases including cancer, but its mechanism of action is unknown.
Recently, we showed that DR has significant pro-apoptotic and anti-angiogenic effects on the inhibition of experimental brain tumor growth. Angiogenesis involves neovascularization or the formation of new capillaries from existing blood vessels and is associated with the processes of tissue inflammation, wound healing, and tumorigenesis. Apoptosis involves cell suicide in response to environmental stress. Both the ketogenic diet and DR may manage brain cancer by stressing the metabolic weakness of the tumor cells that are dependent almost exclusively on glucose for energy.

Gangliosides and Brain Cancer

We are also studying the role of gangliosides in brain tumor growth, angiogenesis, and metastasis. Gangliosides are complex glycolipids enriched on the outer surface of virtually all mammalian cells. Gangliosides may influence tumor growth and progression through modulation of adhesion, migration, and angiogenesis. We are interested in the effect of gene-linked alterations of ganglioside biosynthesis on brain tumor angiogenesis and invasion.