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CURATOR
A pinboard by
Endre Szvetnik

I write for Sparrho and work with Curators to translate and disseminate research to the public.

I believe scientific thinking fosters progress and is beneficial to society.

PINBOARD SUMMARY

Scientists used cancer drugs' side effects to make them more potent by regulating insulin levels.

In 10 seconds? Researchers have given a new lease of life to a group of poorly performing cancer drugs that cost a lot of money to develop. They've thwarted the process that reduces their efficiency and the key to this was a diet that suppresses insulin levels.

What's the deal with insulin? Spikes in insulin levels are a side effect of cancer drugs called PI3K inhibitors. These aim to block Pl3K enzymes that promote cell growth in some tumours, helping them to survive. But it turns out that higher insulin levels reactivate the very enzymes that the drugs are designed to disable.

And how did they make the drug work? Well, by limiting insulin levels, of course! Scientists put the lab mice they were observing on a ketogenic diet, which is high in fat, low in carbs and involves normal levels of protein. As a result, insulin levels dropped and the drug started performing much better, slowing down tumour growth.

Is there any other evidence that this approach works? Yes – in recent years, we’ve seen a number of papers on the subject. They suggest that this sort of diet can make cancer cells more vulnerable to conventional therapies, while protecting normal cells from side effects.

What kind of cancers can be treated like this? Studies indicate that combined with cancer drugs, the ketogenic diet can prevent unwanted cell growth and increase survival times in a number of cancers, including pancreatic, prostate, gastric, colon, brain, lung and neuroblastoma.

So now fat is the new magic formula? Not so fast! We're still waiting for the results from human trials. And doctors stress that there are a lot of unfounded claims about the ketogenic diet replacing chemo or radiotherapy. The results with lab mice suggest that the diet helps only in conjunction with drugs. However, if clinical trials return positive results, treatment efficacy could be significantly increased for a great number of cancer patients.


Calorie restriction also does the trick

Researchers have found that limiting calorie intake can extend the lives of patients with cancer, diabetes, cardiovascular and neurodegenerative diseases.

They tested the potential of calorie restriction (CR) to enhance the efficacy of chemotherapy, radiation therapy and novel immunotherapies.

However, it is very difficult to make cancer patients stick to a strict CR-regime, so researchers have suggested intermittent fasting, some diet regimes (such as ketogenic) and drugs mimicking the effects of calorie restriction.

For instance, intermittent fasting has already been shown to boost the effects of both chemotherapy and radiation therapy.

17 ITEMS PINNED

Suppression of insulin feedback enhances the efficacy of PI3K inhibitors

Abstract: Mutations in PIK3CA, encoding the insulin-activated phosphoinositide-3-kinase (PI3K), and loss of function mutations in PTEN, a phosphatase that degrades the phosphoinositide lipids generated by PI3K, are among the most frequent events in human cancers1,2. However, pharmacological inhibition of PI3K has resulted in variable clinical responses, raising the possibility of an inherent mechanism of resistance. Since the PIK3CA-encoded enzyme, p110α, mediates virtually all cellular responses to insulin, targeted inhibition of this enzyme disrupts glucose metabolism in multiple tissue types. For example, blocking insulin signalling promotes glycogen breakdown in the liver and prevents glucose uptake in the skeletal muscle and adipose tissue, resulting in transient hyperglycemia that occurs within a few hours of PI3K inhibition. The effect is usually transient because compensatory insulin release from the pancreas (i.e. insulin feedback) restores normal glucose homeostasis3. However, the hyperglycemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, requires discontinuation of therapy3–6. We hypothesized that insulin feedback induced by PI3K inhibitors may be reactivating the PI3K-mTOR signalling axis in tumours, compromising their effectiveness7,8. Here, we show in several model tumours, that systemic glucose-insulin feedback caused by targeted inhibition of this pathway is sufficient to activate PI3K signalling, even in the presence of PI3K inhibitors. We demonstrate that this insulin feedback can be prevented using dietary or pharmaceutical approaches, which greatly enhance the efficacy/toxicity ratios of these compounds. These findings have direct clinical implications for the multiple p110α inhibitors that are in clinical trials and provide a means to significantly increase treatment efficacy for patients with a myriad of tumour types.

Pub.: 04 Jul '18, Pinned: 13 Jul '18

Effects of a Ketogenic Diet on [ 18 F]FDG-PET Imaging in a Mouse Model of Lung Cancer.

Abstract: Myocardial uptake can hamper visualization of lung tumors, atherosclerotic plaques, and inflammatory diseases in 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) studies because it leads to spillover in adjacent structures. Several preparatory pre-imaging protocols (including dietary restrictions and drugs) have been proposed to decrease physiological [F]FDG uptake by the heart, although their effect on tumor glucose metabolism remains largely unknown. The objective of this study was to assess the effects of a ketogenic diet (as an alternative protocol to fasting) on tumor glucose metabolism assessed by [F]FDG positron emission tomography (PET) in a mouse model of lung cancer. PET scans were performed 60 min after injection of 18.5 MBq of [F]FDG. PET data were collected for 45 min, and an x-ray computed tomograph (CT) image was acquired after the PET scan. A PET/CT study was obtained for each mouse after fasting and after the ketogenic diet. Quantitative data were obtained from regions of interest in the left ventricular myocardium and lung tumor. Three days on a ketogenic diet decreased mean standard uptake value (SUVmean) in the myocardium (SUVmean 0.95 ± 0.36) more than one night of fasting (SUVmean 1.64 ± 0.93). Tumor uptake did not change under either dietary condition. These results show that 3 days on high-fat diets prior to [F]FDG-PET imaging does not change tumor glucose metabolism compared with one night of fasting, although high-fat diets suppress myocardial [F]FDG uptake better than fasting.

Pub.: 04 Jul '18, Pinned: 12 Jul '18

Can Nutrition Lower the Risk of Recurrence in Breast Cancer?

Abstract: The impact of diet on breast cancer prognosis is poorly understood. Therefore, we conducted a literature search summarizing the current evidence on the effect of diet on breast cancer recurrence and mortality. The PubMed database was searched for original studies, reviews, and meta-analyses published between 2010 and 2017. Studies related to diet, dietary patterns, special diets or specific dietary factors, and breast cancer recurrence or mortality were included. Adherence to high diet quality indices (relative risk (RR) 0.74, 95% confidence interval (CI) 0.60-0.90) and a prudent/healthy dietary pattern (RR 0.76, 95% CI 0.60-0.95) may have a beneficial effect on breast cancer prognosis, whereas a Western/unhealthy diet is associated with poorer overall mortality (RR 1.44, 95% CI 1.17-1.77). For low-fat diets, the findings are inconsistent. A positive effect of the Mediterranean Diet was found for all-cause mortality, but no beneficial effect from other diets such as low-carbohydrate, ketogenic or vegetarian/vegan diets was observed. Alcohol consumption was associated with an increased risk for breast cancer recurrence. No general recommendation for soy exists, but occasional intake seems to be acceptable, whereas the use of other supplements is not justified. Adherence to high-quality diets and a prudent/healthy dietary pattern seem to be beneficial for breast cancer prognosis. No clear evidence for a benefit from special diets, soy products, or other supplements was found.

Pub.: 12 Jun '18, Pinned: 12 Jul '18

Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health.

Abstract: Impaired mitochondrial function often results in excessive production of reactive oxygen species (ROS) and is involved in the etiology of many chronic diseases, including cardiovascular disease, diabetes, neurodegenerative disorders, and cancer. Moderate levels of mitochondrial ROS, however, can protect against chronic disease by inducing upregulation of mitochondrial capacity and endogenous antioxidant defense. This phenomenon, referred to as mitohormesis, is induced through increased reliance on mitochondrial respiration, which can occur through diet or exercise. Nutritional ketosis is a safe and physiological metabolic state induced through a ketogenic diet low in carbohydrate and moderate in protein. Such a diet increases reliance on mitochondrial respiration and may, therefore, induce mitohormesis. Furthermore, the ketone-hydroxybutyrate (BHB), which is elevated during nutritional ketosis to levels no greater than those resulting from fasting, acts as a signaling molecule in addition to its traditionally known role as an energy substrate. BHB signaling induces adaptations similar to mitohormesis, thereby expanding the potential benefit of nutritional ketosis beyond carbohydrate restriction. This review describes the evidence supporting enhancement of mitochondrial function and endogenous antioxidant defense in response to nutritional ketosis, as well as the potential mechanisms leading to these adaptations.

Pub.: 03 Apr '18, Pinned: 12 Jul '18

Investigating the Ketogenic Diet As Treatment for Primary Aggressive Brain Cancer: Challenges and Lessons Learned.

Abstract: Survival of glioblastoma multiforme (GBM) with the current recommended treatment is poor. Reported median survivals are approximately 8-15 months. Based on recent publications from animal models, combining cancer drugs, radiation, and diet-metabolic treatments may be a new route to better survivals. To investigate this possibility, we have begun a clinical trial that has enrolled 15 subjects using a ketogenic diet (KD) as an addition to current standard treatments that include surgery, radiation therapy, and chemotherapy. Of the 15 enrolled, 10 completed the protocol. This perspective describes the challenges and lessons learned during this clinical trial and discusses the critical elements that are essential for investigating treatment with a KD. We also reviewed and compared various types of KDs. We believe that the diet selected should be standardized within individual clinical trials, and more importantly, the patients' blood should be monitored for glucose and ketones twice daily so that the supervising dietitian can work with the patient and their caregivers to make appropriate changes in the diet. Compliance with the diet is best in highly motivated patients who have excellent home support from a family member or a friend who can help to overcome administrative, physical, and cognition deficiencies associated with the disease. Treatment of GBM using a KD represents a reasonable investigative approach. This perspective summarizes the challenges and lessons learned implementing and continuing KD therapy while the patients are concurrently being treated with radiation and chemotherapy.

Pub.: 15 Mar '18, Pinned: 12 Jul '18

Low ketolytic enzyme levels in tumors predict ketogenic diet responses in cancer cell lines in vitro and in vivo.

Abstract: The ketogenic diet (KD) is a high-fat, very-low-carbohydrate diet that triggers a fasting state by decreasing glucose and increasing ketone bodies, such as β-hydroxybutyrate (βHB). In experimental models and clinical trials, the KD has shown anti-tumor effects, possibly by reducing energy supplies to cells, which damages the tumor microenvironment and inhibits tumor growth. Here, we determined expression levels of genes encoding the ketolytic enzymes 3-hydroxybutyrate dehydrogenase 1 (BDH1) and succinyl-CoA: 3-oxoacid CoA transferase 1 (OXCT1) in 33 human cancer cell lines. We then selected two representative lines - HeLa and PANC-1 - for in vivo examination of KD sensitivity in tumors with high or low expression, respectively, of these two enzymes. In mice with HeLa xenografts, the KD increased tumor growth and mouse survival decreased, possibly because these tumors actively consumed ketone bodies as an energy source. Conversely, the KD significantly inhibited growth of PANC-1 xenograft tumors. βHB added to each cell culture significantly increased proliferation of HeLa cells, but not PANCI-1 cells. Downregulation of both BDH1 and OXCT1 rendered HeLa cells sensitive to the KD in vitro and in vivo. Tumors with low ketolytic enzyme expression may be unable to metabolize ketone bodies, thus predicting a better response to KD therapy.

Pub.: 08 Feb '18, Pinned: 11 Jul '18

A ketogenic diet supplemented with medium-chain triglycerides enhances the anti-tumor and anti-angiogenic efficacy of chemotherapy on neuroblastoma xenografts in a CD1-nu mouse model.

Abstract: Neuroblastoma (NB) is a pediatric malignancy characterized by a marked reduction in aerobic energy metabolism. Recent preclinical data indicate that targeting this metabolic phenotype by a ketogenic diet (KD), especially in combination with calorie restriction, slows tumor growth and enhances metronomic cyclophosphamide (CP) therapy of NB xenografts. Because calorie restriction would be contraindicated in most cancer patients, the aim of the present study was to optimize the KD such that the tumors are sensitized to CP without the need of calorie restriction. In a NB xenograft model, metronomic CP was combined with KDs of different triglyceride compositions and fed to CD1-nu mice ad libitum. Metronomic CP in combination with a KD containing 8-carbon medium-chain triglycerides exerted a robust anti-tumor effect, suppressing growth and causing a significant reduction of tumor blood-vessel density and intratumoral hemorrhage, accompanied by activation of AMP-activated protein kinase in NB cells. Furthermore, the KDs caused a significant reduction in the serum levels of essential amino acids, but increased those of serine, glutamine and glycine. Our data suggest that targeting energy metabolism by a modified KD may be considered as part of a multimodal treatment regimen to improve the efficacy of classic anti-NB therapy.

Pub.: 17 Oct '17, Pinned: 11 Jul '18

Rationale, Feasibility and Acceptability of Ketogenic Diet for Cancer Treatment.

Abstract: Ketogenic diet has been used for more than 80 years as a successful dietary regimen for epilepsy. Recently, dietary modulation by carbohydrate depletion via ketogenic diet has been suggested as an important therapeutic strategy to selectively kill cancer cells and as adjuvant therapy for cancer treatment. However, some researchers insist ketogenic diet to be highly undesirable as ketogenic diet may trigger and/or exacerbate cachexia development and usually result in significant weight loss. This review revisits the meaning of physiological ketosis in the light of this evidence and considers possibility of the use of ketogenic diet for oncology patients. Article search was performed from 1985 through 2017 and finally 10 articles were analyzed. The review focused on the results of human trials for cancer patients and checked the feasibility of using ketogenic diet for cancer patients as adjuvant therapy. The main outcomes showed improvement of body weight changes, anthropometric changes, serum blood profiles, and reduction in novel marker for tumor progression, TKTL1, and increase of ketone body. Lactate concentration was reduced, and no significant changes were reported in the measurements of quality of life. Ketogenic diet may be efficacious in certain cancer subtypes whose outcomes appear to correlate with metabolic status, but the results are not yet supportive and inconsistent. Therefore, it warrants further studies.

Pub.: 12 Oct '17, Pinned: 11 Jul '18

Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer.

Abstract: Triple-negative breast cancer (TNBC) is more aggressive and metastatic than other breast cancer types. Cytotoxic chemotherapy is presently the predominant systemic therapy for TNBC patients. This case report highlights the influence of metabolically supported chemotherapy (MSCT), ketogenic diet (KD), hyperthermia (HT), and hyperbaric oxygen therapy (HBOT) in an overweight 29-year-old woman with stage IV (T4N3M1) triple-negative invasive ductal carcinoma of the breast. The patient presented with an observable mass in her left breast detected during a physical examination in December 2015. Magnetic resonance imaging revealed a Breast Imaging Reporting and Data System Category 5 tumor and multiple lymphadenomegaly in the left axilla. A Tru-Cut biopsy led to the diagnosis of a triple-negative nuclear grade 2 invasive ductal carcinoma. The patient was admitted to ChemoThermia Oncology Center, Istanbul, Turkey in October 2016, and a whole body (18F)-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET-CT) scan revealed a 77 mm x 55 mm primary tumor in her left breast, multiple left pectoral and axillary lymph nodes, multiple widespread liver masses, and an upper left nodular abdominal lesion. The patient received a treatment protocol consisting of MSCT, KD, HT, and HBOT. A follow-up whole body 18F-FDG PET-CT scan in February 2017 showed a complete therapeutic response with no evidence of abnormal FDG uptake. The patient continued to receive this treatment protocol and in April 2017 underwent a mastectomy, which revealed a complete pathological response consistent with the response indicated by her PET-CT imaging. This single case study presents evidence of a complete clinical, radiological, and pathological response following a six-month treatment period using a combination of MSCT and a novel metabolic therapy in a patient with stage IV TNBC.

Pub.: 20 Sep '17, Pinned: 11 Jul '18

Tumor Cells Growth and Survival Time with the Ketogenic Diet in Animal Models: A Systematic Review.

Abstract: Recently, interest in targeted cancer therapies via metabolic pathways has been renewed with the discovery that many tumors become dependent on glucose uptake during anaerobic glycolysis. Also the inability of ketone bodies metabolization due to various deficiencies in mitochondrial enzymes is the major metabolic changes discovered in malignant cells. Therefore, administration of a ketogenic diet (KD) which is based on high in fat and low in carbohydrates might inhibit tumor growth and provide a rationale for therapeutic strategies. So, we conducted this systematic review to assess the effects of KD on the tumor cells growth and survival time in animal studies. All databases were searched from inception to November 2015. We systematically searched the PubMed, Scopus, Google Scholars, Science Direct and Cochrane Library according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. To assess the quality of included studies we used SYRCLE's RoB tool. 268 articles were obtained from databases by primary search. Only 13 studies were eligible according to inclusion criteria. From included studies, 9 articles indicate that KD had a beneficial effect on tumor growth and survival time. Tumor types were included pancreatic, prostate, gastric, colon, brain, neuroblastoma and lung cancers. In conclusions, although studies in this field are rare and inconsistence, recent findings have demonstrated that KD can potentially inhibit the malignant cell growth and increase the survival time. Because of differences physiology between animals and humans, future studies in cancer patients treated with a KD are needed.

Pub.: 07 Jun '17, Pinned: 11 Jul '18

Consuming a Ketogenic Diet while Receiving Radiation and Chemotherapy for Locally Advanced Lung Cancer and Pancreatic Cancer: The University of Iowa Experience of Two Phase 1 Clinical Trials.

Abstract: Ketogenic diets are low in carbohydrates and high in fat, which forces cells to rely more heavily upon mitochondrial oxidation of fatty acids for energy. Relative to normal cells, cancer cells are believed to exist under a condition of chronic mitochondrial oxidative stress that is compensated for by increases in glucose metabolism to generate reducing equivalents. In this study we tested the hypothesis that a ketogenic diet concurrent with radiation and chemotherapy would be clinically tolerable in locally advanced non-small cell lung cancer (NSCLC) and pancreatic cancer and could potentially exploit cancer cell oxidative metabolism to improve therapeutic outcomes. Mice bearing MIA PaCa-2 pancreatic cancer xenografts were fed either a ketogenic diet or standard rodent chow, treated with conventionally fractionated radiation (2 Gy/fraction), and tumor growth rates were assessed daily. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modfied proteins as a marker of oxidative stress. Based on this and another previously published preclinical study, phase 1 clinical trials in locally advanced NSCLC and pancreatic cancer were initiated, combining standard radiation and chemotherapy with a ketogenic diet for six weeks (NSCLC) or five weeks (pancreatic cancer). The xenograft experiments demonstrated prolonged survival and increased 4HNE-modfied proteins in animals consuming a ketogenic diet combined with radiation compared to radiation alone. In the phase 1 clinical trial, over a period of three years, seven NSCLC patients enrolled in the study. Of these, four were unable to comply with the diet and withdrew, two completed the study and one was withdrawn due to a dose-limiting toxicity. Over the same time period, two pancreatic cancer patients enrolled in the trial. Of these, one completed the study and the other was withdrawn due to a dose-limiting toxicity. The preclinical experiments demonstrate that a ketogenic diet increases radiation sensitivity in a pancreatic cancer xenograft model. However, patients with locally advanced NSCLC and pancreatic cancer receiving concurrent radiotherapy and chemotherapy had suboptimal compliance to the oral ketogenic diet and thus, poor tolerance.

Pub.: 25 Apr '17, Pinned: 11 Jul '18

A Nutritional Perspective of Ketogenic Diet in Cancer: A Narrative Review.

Abstract: The predominant use of glucose anaerobically by cancer cells (Warburg effect) may be the most important characteristic the majority of these cells have in common and, therefore, a potential metabolic pathway to be targeted during cancer treatment. Because this effect relates to fuel oxidation, dietary manipulation has been hypothesized as an important strategy during cancer treatment. As such, the concept of a ketogenic diet (KD) in cancer emerged as a metabolic therapy (ie, targeting cancer cell metabolism) rather than a dietary approach. The therapeutic mechanisms of action of this high-fat, moderate-to-low protein, and very-low-carbohydrate diet may potentially influence cancer treatment and prognosis. Considering the lack of a dietetics-focused narrative review on this topic, we compiled the evidence related to the use of this diet in humans with diverse cancer types and stages, also focusing on the nutrition and health perspective. The use of KD in cancer shows potentially promising, but inconsistent, results. The limited number of studies and differences in study design and characteristics contribute to overall poor quality evidence, limiting the ability to draw evidence-based conclusions. However, the potential positive influences a KD may have on cancer treatment justify the need for well-designed clinical trials to better elucidate the mechanisms by which this dietary approach affects nutritional status, cancer prognosis, and overall health. The role of registered dietitian nutritionists is demonstrated to be crucial in planning and implementing KD protocols in oncology research settings, while also ensuring patients' adherence and optimal nutritional status.

Pub.: 04 Apr '17, Pinned: 11 Jul '18