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.

Efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma

“…Thus, these case reports, along with numerous anecdotal observations, presented encouraging signs of metabolic reprogramming by the KD, along with the increased efficacy of standard of care treatment for malignant glioma (23,29). This preliminary evidence of the benefit of KD for cancer therapy is currently being validated in ongoing, controlled clinical trials, which include patients with malignant glioma (25).…”

“…It has been postulated that a ketogenic diet, i.e., a diet consisting of high fat, low carbohydrates and adequate protein, may be useful in the treatment of brain tumors (25)(26)(27)(28)(29)(30)(31). The present study was conducted to assess the therapeutic efficacy and safety of a KD concomitant with intranasal perillyl alcohol as a novel therapeutic strategy for recurrent GBM.…”

“…Previous preclinical studies demonstrated notable benefits of the KD in a variety of animal tumor models, including in malignant brain tumors (25) and in the meta-analysis by Klement et al (26). For example, among groups of mice with luciferase-labeled GL261 glioma cells implanted into their brains, median survival time was significantly extended in mice on a KD compared with mice on a standard diet; in addition, when such mice received two fractions of radiation (2x4 Gy of whole brain radiation), the bioluminescent signals from the intracranial tumors was diminished below the detectable limit in 82% of the mice, and no signs of tumor recurrence were observed for >200 days (27).…”

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

“…While epidemiological associations among obesity, cancer, and ketogenic diets are debated (Liskiewicz et al, 2016; Wright and Simone, 2016), a meta-analysis using ketogenic diets in animal models and in human studies suggested a salutary impact on survival, with benefits prospectively linked to the magnitude of ketosis, time of diet initiation, and tumor location (Klement et al, 2016; Woolf et al, 2016). Treatment of pancreatic cancer cells with ketone bodies ( d -βOHB or AcAc) inhibited growth, proliferation and glycolysis, and a ketogenic diet (81% kcal fat, 18% protein, 1% carbohydrate) reduced in vivo tumor weight, glycemia, and increased muscle and body weight in animals with implanted cancer (Shukla et al, 2014).…”

The Expanding Role of Ketogenic Diets in Adult Neurological Disorders

“…In the CT-2A malignant mouse astrocytoma model, a calorie-restricted KD decreased plasma glucose, plasma insulin-like growth factor and tumor weight when administered as a stand-alone therapy and elicited potent synergistic anti-cancer effects when administered in combination with glycolytic inhibitor 2-deoxy- d -glucose (2-DG) [79,80]. In the GL-261 malignant glioma model, KD fed mice had reduced peritumoral edema and tumor microvasculature, 20–30% increased median survival time and achieved complete and long-term remission when used concomitantly with radiation therapy [81,82,83]. A similar synergistic effect was observed between KD and temozolomide in the GL-261 model [84].…”