Abstract
Glioblastoma (GBM) is a lethal brain tumor that has a higher incidence and mortality in males compared to females. GBM tumors consume glucose and glutamine as the major fuels for growth and strategies have been developed that disrupt these nutrient utilization pathways. Both pre-clinical and clinical reports have identified the ketogenic diet (KD) as an approach which consists of high fat and low carbohydrates. It reduces circulating glucose and increases ketones resulting in restricted tumor growth. Because of published studies showing that carbohydrate utilization is higher in healthy males, we hypothesized that the KD would have greater inhibition of male GBM growth. We compared sex differences in response to the KD using an established GBM mouse model (Nf1-/-DNp53), which has previously yielded important insights into sex differences in GBM. Flank tumors were implanted and tumor size measurements were performed. Unexpectedly, the KD had no effect on male GBM tumor growth, but female tumors grew significantly slower in mice that were on the KD compared to control diet. To understand how male GBM tumors adapt their metabolism to the KD, we measured serial blood glucose and ketone levels. We discovered expected physiologic responses to the KD with decreased serum glucose and increased serum ketones, suggesting that males adapt to the KD through changes in cell-intrinsic metabolism. Using FDG-PET imaging to investigate glucose utilization, we found that FDG uptake was increased in both tumor and normal brain of male but not female mice that were on the KD compared to control diet. Taken together, our results show that the KD has a greater impact on female GBM tumor growth and that sex differences in metabolic adaptations such as increased glucose transport may underlie the male-specific resistance to the KD. This study has the potential to develop sex-specific metabolic treatment approaches for GBM.
Inhibition of Neuroblastoma Tumor Growth by Ketogenic Diet and/or Calorie Restriction in a CD1-Nu Mouse Model
