A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma

Abstract

Purpose: Dysregulated energetics coupled with uncontrolled proliferation has become a hallmark of cancer, leading to increased interest in metabolic therapies. Glioblastoma (GB) is highly malignant, very metabolically active, and typically resistant to current therapies. Dietary treatment options based on glucose deprivation have been explored using a restrictive ketogenic diet (KD), with positive anticancer reports. However, negative side effects and a lack of palatability make the KD difficult to implement in an adult population. Hence, we developed a less stringent, supplemented high-fat low-carbohydrate (sHFLC) diet that mimics the metabolic and antitumor effects of the KD, maintains a stable nutritional profile, and presents an alternative clinical option for diverse patient populations. Experimental Design: The dietary paradigm was tested in vitro and in vivo, utilizing multiple patient-derived gliomasphere lines. Cellular proliferation, clonogenic frequency, and tumor stem cell population effects were determined in vitro using the neurosphere assay (NSA). Antitumor efficacy was tested in vivo in preclinical xenograft models and mechanistic regulation via the mTOR pathway was explored. Results: Reducing glucose in vitro to physiologic levels, coupled with ketone supplementation, inhibits proliferation of GB cells and reduces tumor stem cell expansion. In vivo, while maintaining animal health, the sHFLC diet significantly reduces the growth of tumor cells in a subcutaneous model of tumor progression and increases survival in an orthotopic xenograft model. Dietary-mediated anticancer effects correlate with the reduction of mTOR effector expression. Conclusions: We demonstrate that the sHFLC diet is a viable treatment alternative to the KD, and should be considered for clinical testing. Clin Cancer Res; 22(10); 2482–95. ©2015 AACR.

The Expanding Role of Ketogenic Diets in Adult Neurological Disorders

“…A similar synergistic effect was observed between KD and temozolomide in the GL-261 model [84]. Comparable effects of KDs on tumor growth and survival time have also been shown in glioma derived mouse models of metastatic cancer and in patient-derived GBM subcutaneous and orthotopic implantation models [85,86]. These and other studies suggest that KDs induce a metabolic shift in malignant brain tissue towards a pro-apoptotic, anti-angiogenic, anti-invasive and anti-inflammatory state accompanied by a marked reduction in tumor growth in vivo [70] via mechanisms that include:

Reduction in blood glucose and insulin growth factor-1 levels [79];

Attenuated insulin activated Akt/mTOR and Ras/mitogen-activated protein kinase (MAPK) signaling pathways [87,88];

Induction of genes involved in oxidative stress protection and elimination of ROS through histone deactylase inhibition and altered expression of genes related to angiogenesis, vascular remodeling, invasion potential and the hypoxic response [38,82,84];

Enhanced cytotoxic T cell anti-tumor immunity [89]; and

Reduced inflammation via ketone body inhibition of the NLRP3 inflammasome and a reduction in other circulating inflammatory markers [43,90].

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Infiltrative and drug‐resistant slow‐cycling cells support metabolic heterogeneity in glioblastoma

“…Maintaining mitochondrial OxPhos activities may confer SCCs broader metabolic capacities beyond those of aerobic glycolysis. We had previously shown that GBM cells were sensitive to glucose deprivation (Martuscello et al , ) and next examined whether GBM SCCs and FCCs displayed the same glucose dependencies. We tested the response of SCCs and FCCs to high (500 mg/dl) or lowered/physiological (90–110 mg/dl) glucose levels in normoxic conditions.…”

Targeting cancer stem‐like cells in glioblastoma and colorectal cancer through metabolic pathways

“…This suggests that activation of anaerobic metabolism in the rapidly growing brain cancer parenchyma may induce CSCs in an autologous fashion and that targeting the production of low pH generating metabolites may indirectly inhibit CSC development. Another study demonstrated that high‐lipid growth conditions with limited amounts of carbohydrates impairs GBM CSCs most probably due to suppressed mTOR signaling . This observation provides a possible molecular link between dietary status of a patient and their CSC condition.…”