Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy

Abstract

Malignant brain tumors are devastating despite aggressive treatments such as surgical resection, chemotherapy and radiation therapy. The average life expectancy of patients with newly diagnosed glioblastoma is approximately ~18 months. It is clear that increased survival of brain tumor patients requires the design of new therapeutic modalities, especially those that enhance currently available treatments and/or limit tumor growth. One novel therapeutic arena is the metabolic dysregulation that results in an increased need for glucose in tumor cells. This phenomenon suggests that a reduction in tumor growth could be achieved by decreasing glucose availability, which can be accomplished through pharmacological means or through the use of a high-fat, low-carbohydrate ketogenic diet (KD). The KD, as the name implies, also provides increased blood ketones to support the energy needs of normal tissues. Preclinical work from a number of laboratories has shown that the KD does indeed reduce tumor growth in vivo. In addition, the KD has been shown to reduce angiogenesis, inflammation, peri-tumoral edema, migration and invasion. Furthermore, this diet can enhance the activity of radiation and chemotherapy in a mouse model of glioma, thus increasing survival. Additional studies in vitro have indicated that increasing ketones such as β-hydroxybutyrate (βHB) in the absence of glucose reduction can also inhibit cell growth and potentiate the effects of chemotherapy and radiation. Thus, while we are only beginning to understand the pluripotent mechanisms through which the KD affects tumor growth and response to conventional therapies, the emerging data provide strong support for the use of a KD in the treatment of malignant gliomas. This has led to a limited number of clinical trials investigating the use of a KD in patients with primary and recurrent glioma.

Keywords: beta-hydroxybutyrate; cancer; glioblastoma; glioma; ketogenic diet; ketones; metabolism.

Figure 1

An illustration of the interconnections between tumor metabolism with Hanahan and Weinberg’s Hallmarks of Cancer (Lewis and Abdel-Haleem, 2013).

Figure 2

Kaplan-Meier survival plot of animals implanted intracranially with GL261-luc2 malignant glioma cells and (A) maintained on KetoCal^® [KC, the 4:1 fat:carbohydrate plus protein formulation of the ketogenic diet (KD)] vs. standard diet (SD); (B) treated with 2x4Gy radiation vs. KC plus radiation, and (C) treated with 50 mg/kg temozolomide (TMZ) vs. KC plus TMZ. Animals on KC survived significantly longer when treated with KC alone, when KC was combined with radiation, and when KC was combined with TMZ (Scheck et al., ; Abdelwahab et al., 2012).