Abstract
Advances in our understanding of glioma biology has led to an increase in targeted therapies in preclinical and clinical trials; however, cellular heterogeneity often precludes the targeted molecules from being found on all glioma cells, thus reducing the efficacy of these treatments. In contrast, one trait shared by virtually all tumor cells is altered (dysregulated) metabolism. Tumor cells have an increased reliance on glucose, suggesting that treatments affecting cellular metabolism may be an effective method to improve current therapies. Indeed, metabolism has been a focus of cancer research in the last few years, as many pathways long associated with tumor growth have been found to intersect metabolic pathways in the cell. The ketogenic diet (high fat, low carbohydrate and protein), caloric restriction, and fasting all cause a metabolic change, specifically, a reduction in blood glucose and an increase in blood ketones. We, and others, have demonstrated that these metabolic changes improve survival in animal models of malignant gliomas and can potentiate the anti-tumor effect of chemotherapies and radiation treatment. In this review we discuss the use of metabolic alteration for the treatment of malignant brain tumors.
Highlights
Advances in our understanding of glioma biology has led to an increase in targeted therapies in preclinical and clinical trials; cellular heterogeneity often precludes the targeted molecules from being found on all glioma cells, reducing the efficacy of these treatments
A recent study suggests that hydroxybutyrate, the major ketone that is increased in the blood in animals and patients on the unrestricted KD (UKD), can alter the epigenetic landscape in mammalian cells by inhibiting histone deacetylase [65]
A therapy for diabetes mellitus, and the analog phenformin are becoming a focus in the cancer metabolism research community due to their anti-tumor activity in a variety of in vitro and in vivo cancer models, including brain tumors [75]; they have not been investigated in combination with caloric restriction (CR) or the ketogenic diet (KD)
Summary
Glioblastoma multiforme (GBM), the most aggressive type of brain tumor, represents one of the greatest challenges in the management of cancer patients worldwide. Despite aggressive surgery followed by radiation and chemotherapy, patients with newly diagnosed GBM have an average life expectancy of 12–18 months and less than 10% survive 5 years [1, 2]. Brain tumors are highly infiltrative, and surgery rarely removes all tumor cells, . Manuscript received 6 January 2014 and in revised form 5 February 2014.
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