- Department of Neurosurgery, University of Pittsburgh Medical Center, Suite 5C, 200 Lothrop St., Pittsburgh, PA, USA
- Department of Biology, Boston College, 140 Commonwealth Ave., Chestnut Hill, MA, USA
Department of Neurosurgery, University of Pittsburgh Medical Center, Suite 5C, 200 Lothrop St., Pittsburgh, PA, USA
DOI:10.4103/2152-7806.155259Copyright: © 2015 Maroon JC This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
How to cite this article: Maroon JC, Seyfried TN, Donohue JP, Bost J. The role of metabolic therapy in treating glioblastoma multiforme. Surg Neurol Int 16-Apr-2015;6:61
How to cite this URL: Maroon JC, Seyfried TN, Donohue JP, Bost J. The role of metabolic therapy in treating glioblastoma multiforme. Surg Neurol Int 16-Apr-2015;6:61. Available from: http://sni.wpengine.com/surgicalint_articles/the-role-of-metabolic-therapy-in-treating-glioblastoma-multiforme/
Glioblastoma multiforme (GBM) is an aggressive and nearly uniformly fatal malignancy of the central nervous system. Despite extensive research and clinical trials over the past 50 years, very little progress has been made to significantly alter its lethal prognosis. The current standard of care (SOC) includes maximal surgical resection, radiation therapy and chemotherapy and temozolomide (TMZ), including the selective use of glucocorticoids for symptom control. These same treatments, however, have the potential to create an environment that may actually facilitate tumor growth and survival. Research investigating the unique metabolic needs of tumor cells has led to the proposal of a new metabolic treatment for various cancers including GBMs that may enhance the effectiveness of the SOC. The goal of metabolic cancer therapy is to restrict GBM cells of glucose, their main energy substrate. By recognizing the underlying energy production requirements of cancer cells, newly proposed metabolic therapy is being used as an adjunct to standard GBM therapies. This review will discuss the calorie restricted ketogenic diet (CR-KD) as a promising potential adjunctive metabolic therapy for patients with GBMs. The effectiveness of the CR-KD is based on the “Warburg Effect” of cancer metabolism and the microenvironment of GBM tumors. We will review recent case reports, clinical studies, review articles, and animal model research using the CR-KD and explain the principles of the Warburg Effect as it relates to CR-KD and GBMs.
Keywords: Adjunctive cancer therapy, calorie restriction, glioblastoma multiforme, ketogenic diet, metabolic cancer therapy
Glioblastoma multiforme (GBM) is a highly aggressive malignant tumor of the central nervous system that arises from astrocytes. Primary or de novo glioblastomas are the most common and aggressive form, while secondary forms are somewhat less aggressive. Despite billions of research dollars, innumerable clinical trials and untold associated morbidity, the prognosis of afflicted patients from the time of diagnosis to death remains dismal and virtually unchanged over the past 50 years. The standard of care (SOC) includes maximal safe resection followed by radiation therapy, which extends the median survival from 6 to 12.1 months. The addition of temozolomide (TMZ) adds another 2.5 months (median) to the survival time.[
GBM is a heterogeneous condition consisting of various subtypes with different genetic alterations and gene expression patterns. Thus, no single therapy as presently used will be efficacious across all subtypes. Wilson et al. recently concluded in their review article on the state of the art therapeutics for the treatment of GBM that “Failure of conventional treatments combined with its poor prognosis highlights the need for novel approaches for GBM.”[
For over 75 years it has been known that there is a fundamental metabolic and molecular difference between cancerous cells and normal somatic cells. One major metabolic difference is how cancer and normal cells undergo cellular respiration, glucose metabolism, and energy production. This insight to cancer energy metabolism has recently been exploited through the use of a novel adjunctive cancer therapy known as the calorie restricted ketogenic diet (CR-KD). In this article, we will review studies investigating the KD, CR-KD and cancer metabolism to provide a better understanding of cancer energy metabolism and the potential use of metabolic and dietary therapies for the future treatment of GBM.
A novel approach: The “Warburg Effect” and cancer glycolysis
In 1931, German scientist Otto Warburg won the Nobel Prize for his significant work in cellular respiration, specifically for “his discovery of the nature and mode of action of the respiratory enzyme.”[
Glycolysis, the breakdown of glucose into 2 pyruvate, 2 H+, 2 net Adenosine Triphosphate (ATP), two NADH and lactic acid, occurs in nearly all living organisms.[
It is important to recognize that all respiring cells use aerobic glycolysis to produce pyruvate, which is then completely oxidized in the mitochondria. Much of the pyruvate that is produced in tumor cells through aerobic glycolysis is fermented to lactate rather than oxidized in the mitochondria. It is aerobic fermentation that distinguishes the tumor cell from the normal cell.[
Tumor cells undergoing aerobic fermentation produce ATP in the cytosol and consume significantly more glucose than healthy cells, but much less efficiently. Aerobic fermentation produces a net 2 ATP compared with the approximately net 36 ATP produced from the CAC and OxPhos. Glycolytic rates 200 times higher than normal cells have been observed. This aberrant bioenergetics and dependency on glucose has become a hallmark of cancer.
Over the half-century following Warburg's hypotheses, significant research has been conducted into cancer mitochondrial activity, metabolism, and bioenergetics. Increased rates of glycolysis and aerobic fermentation have been observed in many cancer cell lines evidenced by increased expression of glycolytic enzymes, glucose transporters, lactate production, and glucose consumption.[
Prolonged dependence on glycolysis and fermentation (nonoxidative energy metabolism) has also been shown to induce genomic instability, which could further increase genomic mutations.[
Molecularly targeted therapies: Aiming at a moving target?
In their review, Wilson et al. focus on types of genetic alterations from GBM cells that lead to the overexpression of receptor protein kinases (RPKs) such as EGFR and PDGFR.[
The function of DNA repair enzymes, impaired in cancer cells, and the integrity of the nuclear genome are dependent on normal mitochondrial function and ATP production. Seyfried has proposed that genomic instability and hence the thousands of genetic abnormalities may be downstream epiphenomena of damaged or insufficient respiration and mitochondrial dysfunction.[
Research has elucidated relationships between specific tumor suppressor genes, oncogenes, and glucose metabolism.[
Are we pouring gasoline on a fire? The role of glucose and glutamine in brain tumor progression
Glucose serves as the primary metabolic fuel of GBM cells and is required in high amounts for tumor cell glycolysis. The metabolic shift to glycolysis renders these cancer cells even more dependent upon glucose. Indeed, human glioblastoma cells expressing constitutively active AKT undergo apoptotic death when deprived of glucose.[
With this is mind now consider how current GBM SOC may induce an environment that may actually facilitate tumor cell growth, tumor cell survival, and a greater likelihood of tumor recurrence [
Paradox of current standard of care
Traumatic surgical intervention, radiation therapy, and chemotherapy have all been extensively documented to increase tissue inflammation and blood glucose and glutamate levels.[
Elevated extracellular levels of glutamine contribute to tumor cell growth, proliferation, and cell transformation.[
In addition to glutamate levels, the current SOC may contribute to hyperglycemia, providing GBM cells with elevated glucose, the very fuel upon which they depend. Several laboratory and clinical studies have documented that persistent hyperglycemia in patients with GBM is directly correlated with decreased survival independent of the degree of disability, tumor grade, diabetes or prolonged dexamethasone use. In other words, the higher the blood sugar, the quicker the demise.[
The current SOC including steroids, surgical resection, radiation, and chemotherapy may provide some initial therapeutic, however, the incredibly poor prognosis indicates indisputably that new approaches must be evaluated to render a new efficacious SOC. A careful examination of the current SOC reveals a certain paradox; the treatments disrupt the blood–brain barrier, elevate glucose, glutamate and glutamine levels, and contribute to the inflammatory process—thus adding more “fuel” to the neoplastic fire. This paradox leaves treating physicians in a plight where the immediate treatment needs of the patient must be balanced with the pursuit of finding an efficacious long-term therapeutic management strategy for the treatment of GBM [
The metabolic management of glioblastomas: The ketogenic diet, ketones, and calorie restriction
The KD has been successfully used for over 90 years in the treatment of drug-resistant refractory seizures in children with epilepsy.[
In addition to a low carbohydrate KD, Seyfried et al. have proposed adding calorie restriction (CR) to further reduce cancer cellular metabolism. This CR-KD shifts energy production in the liver to ketones, an alternative energy source to glucose. Using this diet, Seyfried has reported inducing tolerable ketosis in mice, lowering blood glucose levels and profoundly reducing brain tumor size.[
Mammals have evolved to utilize ketones produced in the liver as an alternative energy source. Normal metabolic pathways can reconvert circulating ketone bodies (excluding acetone), derived from fatty acids in the liver, to acetyl CoA, which subsequently initiates the CAC in the mitochondria. GBM cancer cells cannot utilize ketones in this way, and remain largely dependent on glucose as their metabolic substrate.[
A CR-KD takes advantage of evolutionary conserved traits enabling survival during times of food scarcity. The human body has evolved enduring mechanisms to convert fat stores in the liver to beta hydroxybutyrate and acetoacetate—the primary ketone bodies. Ketones can serve as an alternative source to glucose for human energy metabolism. Cancer cells, however, are glucose dependent, and lack this evolutionary versatility to survive on ketone bodies when glucose substrate is deficient.[
Cancer cell culture studies done thus far have confirmed that reduced levels of glucose as an energy substrate can “starve” human astrocytomas, reduce angiogenesis, and diminish production of inflammatory cytokines. Several clinical case studies investigating the use of KD as a metabolic approach to GBM have reported improved survival rates. At this time there are no randomized studies that have shown whether CR-KD can statistically enhance progression-free survival or preserve normal function in thus diagnosed with GBM. Klement and Kammerer in a recent review article have proposed a role for carbohydrate restriction in the treatment and prevention of cancer.[
CR, in addition to KD, can provide an additional advantage by activating sirtuin genes that have been shown to inhibit tumor proliferation. For example, SIRT 1 and Nrf-2 genes are both activated by CR. The SIRT 1 gene has been shown to inhibit neurodegeneration and neoplastic activity.[
In addition to CR, other dietary approaches have been shown to induce anticancer metabolic changes. Sulforphane is a sulfur-containing molecule found naturally in cruciferous vegetables, such as broccoli, brussel sprouts, andcabbage, which has been shown to have anticancer and antimicrobial properties. Dietary antioxidants, such as curcumin (from turmeric) and Resveratrol (from grapes and red wine) have also shown powerful anticancer properties.[
Implementation and challenges with the restricted calorie ketogenic diet
Despite seeming potential of the metabolic approach using glucose and CR, the practical application of this therapy has been difficult in the human case studies and clinical trials done thus far [
The CR-KD in practice would require frequent monitoring of blood glucose and ketone levels to maintain the targeted therapeutic levels. Additionally, enough calories and glucose are required to limit symptoms of hypoglycemia and ketoacidosis seen with blood ketone levels greater than 15 mM. In a recent clinical trial, subjects did experience fatigue and significant weight loss that required diet alterations.[
Clinical case reports using KD in human cancer
In 1995, Nebeling et al. reported on two female children with nonresectable advanced stage brain tumors. Both patients were previously treated with chemotherapy and radiation. They were placed on the KD only, using a MCT oil-based diet, which was reported to effectively manage tumor growth and enhance progression-free survival.[
In 2010, researchers published a case report on a single 65-year-old female patient with GBM that was placed on the CR-KD. The patient had already received standard radiation treatment and chemotherapy. She was restricted to 600 kcal/day and her glucocorticoids were stopped.[
In 2011, German researchers evaluated the CR-KD in 16 subjects with end-stage malignant tumors of various types who had exhausted all standard cancer therapies. Of the 16 subjects, 5 were able to complete the 3-month CR-KD treatment and all 5 experienced no tumor progression while on the diet.[
To make the CR-KD more tolerable for patients and improve compliance, drugs targeting energy metabolism are being proposed that could potentially allow higher carbohydrate consumption. 2-Deoxyglucose is a glucose mimetic that targets glucose metabolism and glycolysis by impeding the cellular uptake of glucose.[
Despite extensive research and clinical trials over the past 50 years, very little progress has been made to significantly alter the lethal prognosis of GBM brain tumors. This lack of an effective SOC obliges a reexamination of the disease and our current approach and has inspired the pursuit of novel therapeutics. In fact, current treatments may in part lead to enhanced tumor growth by increasing the metabolic fuel for cancer cells. Due to the current lack of effective long-term data we are not advocating the intervention as a standalone therapy, but we believe there is now a sound scientific basis for evaluating metabolic therapy as an adjunct for the treatment of malignant brain tumors. By recognizing the underlying unique energy production requirements of cancer cells, nutritional strategies are proposed to induce ketosis and reduce glucose levels to restrict cancer cell growth.
In this setting, clinicians specialized in metabolism and nutrition should be included with the neuro-oncology teams treating patients with GBM. This approach may be particularly worthy for patients who are nonsurgical by choice or because of technical reasons, and as an adjunct to radiation and chemotherapy treatments. Complimentary treatments using antiglycolytic drugs, selected tumor suppressing nutrients and the CR-KD should be considered in clinical trials as alternative or as adjunctive treatment to standard cancer therapies. Metabolic therapy, particularly the CR-KD, may enhance cancer treatment protocols by reducing glucose and glutamate levels, thus possibly extinguishing the neoplastic “fire” of GBM.
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