Abstract
INTRODUCTION: While the KD holds promise as a therapeutic option for brain cancer patients, stringency of the diet impacts compliance. We have previously demonstrated that a high fat/low carbohydrate diet, similar to the Ketogenic Diet [KD], can reduce tumor progression and enhance survival in an orthotopic xenograft model. However, while this diet is less restrictive than the classic KD it still involves significant changes to a patient’s diet. Two of the primary physiological changes that occur when on the KD are a reduction in glucose and an increase in ketone bodies. These physiological changes are mimicked by providing ketone esters [KE] in the diet, and we [AMP, DPD], have recently shown that ketone esters can reduce glucose, elevate ketone bodies and enhance survival in a metastatic cancer model. HYPOTHESIS: We hypothesize that KE [1,3 butanediol acetoacetate diester] will reduce glucose, elevate ketones, reduce tumor progression and enhance survival in an orthotopic xenograft GBM model using a PDX model. APPROACH: NON/SCID animals implanted with patient-derived GBM cells were fed a standard diet [SD], or SD + KE [20%] till they reached endpoint. Body weight, plasma glucose, and ketones were measured weekly and overall survival assessed.
RESULTS
While the KE is bitter and can have poor compliance, we found that supplementing with 1% Stevia increased palatability based on food consumption and body weight. Comparing to SD, KE supplemented diet reduced plasma glucose (145.5 ± 5.3 vs 121.7 ± 5.7), increased ketone bodies [ß-hydroxybutarate, 0.7 ± 0.15 vs.1.3 ± 0.1] and enhanced median survival [47 ± 6.2 vs 60.8 ± 1.9, days]. CONCLUSION: Ketone esters can be effectively delivered orally together with a standard diet, and produce similar physiological changes [reduction in glucose and elevation in ketones] and enhance survival as the more restrictive KD in NON/SCID animals.