title: A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida. Interdisciplinary Program in Biomedical Sciences, Neuroscience, College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Regina T
authors.initials: RT
authors.lastname: Martuscello
authors.affiliation: Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida. Center for Movement Disorders and Neuro-restoration, University of Florida, Gainesville, Florida.
authors.forename: Vinata
authors.initials: V
authors.lastname: Vedam-Mai
authors.affiliation: Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: David J
authors.initials: DJ
authors.lastname: McCarthy
authors.affiliation: Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Schmoll
authors.affiliation: Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Musa A
authors.initials: MA
authors.lastname: Jundi
authors.affiliation: Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Louviere
authors.affiliation: Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Griffith
authors.affiliation: Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Colby L
authors.initials: CL
authors.lastname: Skinner
authors.affiliation: Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Oleg
authors.initials: O
authors.lastname: Suslov
authors.affiliation: Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida. b.a.reynolds@gmail.com loic.deleyrolle@neurosurgery.ufl.edu.
authors.forename: Loic P
authors.initials: LP
authors.lastname: Deleyrolle
authors.affiliation: Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida. Interdisciplinary Program in Biomedical Sciences, Neuroscience, College of Medicine, University of Florida, Gainesville, Florida. b.a.reynolds@gmail.com loic.deleyrolle@neurosurgery.ufl.edu.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000178:diet therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D050528:Diet, Carbohydrate-Restricted / Q000379:methods; D059305:Diet, High-Fat / Q000379:methods; D055423:Diet, Ketogenic / Q000379:methods; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000178:diet therapy* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D005947:Glucose