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Cancer Therapy: Preclinical

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

Regina T. Martuscello, Vinata Vedam-Mai, David J. McCarthy, Michael E. Schmoll, Musa A. Jundi, Christopher D. Louviere, Benjamin G. Griffith, Colby L. Skinner, Oleg Suslov, Loic P. Deleyrolle and Brent A. Reynolds
Regina T. Martuscello
1Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
2Interdisciplinary Program in Biomedical Sciences, Neuroscience, College of Medicine, University of Florida, Gainesville, Florida.
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Vinata Vedam-Mai
1Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
3Center for Movement Disorders and Neuro-restoration, University of Florida, Gainesville, Florida.
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David J. McCarthy
1Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
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Michael E. Schmoll
1Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
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Musa A. Jundi
1Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
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Christopher D. Louviere
1Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
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Benjamin G. Griffith
1Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
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Colby L. Skinner
1Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
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Oleg Suslov
1Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
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Loic P. Deleyrolle
1Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
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  • For correspondence: b.a.reynolds@gmail.com loic.deleyrolle@neurosurgery.ufl.edu
Brent A. Reynolds
1Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida.
2Interdisciplinary Program in Biomedical Sciences, Neuroscience, College of Medicine, University of Florida, Gainesville, Florida.
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  • For correspondence: b.a.reynolds@gmail.com loic.deleyrolle@neurosurgery.ufl.edu
DOI: 10.1158/1078-0432.CCR-15-0916 Published May 2016
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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.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received April 15, 2015.
  • Revision received October 30, 2015.
  • Accepted November 12, 2015.
  • ©2015 American Association for Cancer Research.
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Clinical Cancer Research: 22 (10)
May 2016
Volume 22, Issue 10
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A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma
Regina T. Martuscello, Vinata Vedam-Mai, David J. McCarthy, Michael E. Schmoll, Musa A. Jundi, Christopher D. Louviere, Benjamin G. Griffith, Colby L. Skinner, Oleg Suslov, Loic P. Deleyrolle and Brent A. Reynolds
Clin Cancer Res May 15 2016 (22) (10) 2482-2495; DOI: 10.1158/1078-0432.CCR-15-0916

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A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma
Regina T. Martuscello, Vinata Vedam-Mai, David J. McCarthy, Michael E. Schmoll, Musa A. Jundi, Christopher D. Louviere, Benjamin G. Griffith, Colby L. Skinner, Oleg Suslov, Loic P. Deleyrolle and Brent A. Reynolds
Clin Cancer Res May 15 2016 (22) (10) 2482-2495; DOI: 10.1158/1078-0432.CCR-15-0916
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