Ketogenic diet in cancer therapy

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The Ketogenic Diet (KD), a high-fat/low-carbohydrate/
adequate-protein diet, has recently been proposed as an
adjuvant therapy in cancer treatment [1]. KDs target the
Warburg effect, a biochemical phenomenon in which
cancer cells predominantly utilize glycolysis instead of
oxidative phosphorylation to produce ATP. Further-
more, some cancers lack the ability to metabolize
ketone bodies, due to mitochondrial embarrassment and
down-regulation of enzymes necessary for ketone
utilization [2]. Thus, the rationale in providing a fat-
rich, low-carbohydrate diet in cancer therapy is to
reduce circulating glucose levels and induce ketosis
such that cancer cells are starved of energy while
normal cells adapt their metabolism to use ketone
bodies and survive. Furthermore, by reducing blood
glucose also levels of insulin and insulin-like growth
factor, which are important drivers of cancer cell
proliferation, drop.
Numerous preclinical studies have provided evidence
for an anti-tumor effect of KDs [1] (Figure 1). For
example, our laboratory intensively studied the anti-
tumor effect of KDs in combination with or without
low-dose chemotherapy on neuroblastoma. We found
that the growth of neuroblastoma xenografts was
significantly reduced by a KD consisting of a 2:1 ratio
of fat to carbohydrate + protein when combined with
caloric restriction [2]. However, caloric restriction,
despite its anti-tumor effect and potential to sensitize
cancer cells to chemotherapy, would be contraindicated
in a range of cancer patients, particularly those with
cachexia. Thus, we further focused on optimizing the
KD composition to address this issue. We found that an
ad libitum KD (8:1) with a fat content of 25% medium-
chain triglycerides and 75% long-chain triglycerides
produced a stronger anti-tumor effect compared to a KD
(8:1) with all long-chain triglycerides, and was as
efficacious against neuroblastoma as the above-
described KD (2:1) combined with caloric restriction
[3]. These results stress the importance of an optimized
KD composition to suppress tumor growth and to
sensitize tumors to chemotherapy without requiring
caloric restriction.
In addition to neuroblastoma, various researchers have
investigated the efficacy of KDs as an adjuvant therapy
for other types of cancer. The strongest evidence (> 3
studies) for a tumor-suppressing effect has been reported
Editorial
for glioblastoma, whereas little or no benefit was found
for two other brain tumors (astrocytoma and medullo-
blastoma). Good evidence (2 - 3 studies) is available for
prostate, colon, pancreatic and lung cancer [1];
neuroblastoma also falls into this category (Figure 1).
Some of those studies report a tumor-suppressing effect
of KD alone and/or in combination with classic therapy
and/or caloric restriction. One study on prostate cancer
applied the KD in a preventive, instead of a therapeutic,
study setting. Only limited evidence (1 study) supports
the anti-tumor effect of an unrestricted KD on breast,
stomach, and liver cancer.
In contrast to the safe application of KDs reported in
various cancer models, our research group recently
reported that mice bearing renal cell carcinoma
xenografts and with signs of Stauffer’s syndrome
experienced dramatic weight loss and liver dysfunction
when treated with a KD [4]. Another study investigating
the effect of long-term KD treatment on kidney cancer
described a pro-tumor effect of the KD in a rat model of
tuberous sclerosis complex [5]. Most concerning is the
observation that, in a mouse model of BRAF V600E-
positive melanoma, tumor growth was significantly
increased under the KD [6]. Moreover, the study also
demonstrated that the ketone body acetoacetate
stimulated the oncogenic signaling of the BRAF
pathway. In contrast, the KD had no effect on the
progression of NRAS Q61K-positive or wild-type
melanoma xenografts [6]. Notwithstanding these obser-
vations, in a feasibility trial involving a limited number
of patients with advanced malignancies, a patient with
BRAF V600E-positive/BRAF-inhibitor resistant mela-
noma seemed to benefit from the KD [7].
Taken together, results from preclinical studies, albeit
sometimes contradictory, tend to support an anti-tumor
effect rather than a pro-tumor effect of the KD for most
solid cancers. However, even though pro-tumor effects
are rare, they cannot be ruled out per se. Most impor-
tantly, available preclinical evidence implies that the
feasibility of a KD as an adjuvant cancer therapy
strongly depends on the type of tumor and its genetic
alterations.
To date, evidence from randomized controlled clinical
trials is lacking, but needed, to answer the question of
whether an adjuvant KD would benefit specific cancer
patients. Human data pertaining to KDs and cancer are
Ketogenicdietincancertherapy
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DanielaDWeber,SepidehAminazdeh‐Gohari,BarbaraKofler
www.aging‐us.com    AG IING2018,Vol.10,No. 2
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mostly based on single case reports and a smattering of
preliminary clinical studies with small study cohorts,
heterogenous study designs, poor compliance to the
diet, noncomparable regimens, or without standardized
dietary guidance. Even so, results of the first clinical
studies support the hypothesis of an anti-tumor effect of
KDs. For example, 10 of the 24 (42%) clinical studies
included in a recent review [1] provide evidence for the
anti-tumor effect of KDs, whereas seven (29%) showed
no effect and only one study reported a pro-tumor effect
of the KD. The currently available medical literature
presents strong scientific evidence for the safe
application of a KD only in patients with glioblastoma.
However, a clear recommendation for adjuvant use of
the KD in glioblastoma patients still requires results
from ongoing randomized controlled clinical trials.
In conclusion, clinical application of KDs as an
adjuvant therapy for cancer patients first requires that
the KD be evaluated for its anti-tumor effect for each
single type/genetic subtype of cancer in a preclinical
setting, as the safety and efficacy of the KD strongly
depend on the tumor entity and its genotype. Based on
the results of rigorous preclinical and clinical studies
performed thus far, the KD would appear to be a
promising and powerful option for adjuvant therapy for
a range of cancers. Cancer-specific recommendations
await the findings of randomized controlled clinical
trials.
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https://doi:10.1186/s12986‐016‐0113‐y
BarbaraKofler:ResearchProgramforReceptor
BiochemistryandTumorMetabolism,UniversityHospital
forPediatricsoftheParacelsusMedicalUniversity,5020
Salzburg,Austria
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Correspondence:BarbaraKofler
Email:b.kofler@salk.at
Keywords:tumormetabolism,ketogenicdiet,adjuvant
therapy
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Copyright:Weberetal.Thisisanopen‐accessarticle
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AttributionLicense(CCBY3.0),whichpermitsunrestricted
use,distribution,andreproductioninanymedium,
providedtheoriginalauthorandsourcearecredited
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Received:January31,2018
Published:February11,2018
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Figure1.PreclinicalevidenceindicatingtheeffectofaKD
ontumorgrowthandprogression.Thebarchartshowsthe
numberofpreclinicalstudies,whichinvestigatedtheeffectofa
KDondifferenttypesofcancer.Colorsofthebarsrepresentthe
resultofeachstudyasindicatedinthecolorkey.StudiesonKD
andcancerwerecollectedbyaliteraturesearchcovering
throughtheendof2017.Rindicatesstudieswithacalorie‐
restrictedKD;TindicatesuseofaKDasanadjuvanttherapyto
classictherapy.