When we talk about metabolism in this context it’s important to remember that we’re talking about the metabolic activity inside cancer cells, not the rate at which the body processes energy from food.
Cancer is caused by the uncontrolled growth of cells. To meet their expanding needs, cancer cells have a unique metabolism; that is, they convert and use energy differently to normal, healthy cells. The difference in cancer cell metabolism was first noticed in 1924 by Otto Warburg, who won a Nobel Prize in 1931 for his discovery of the nature and mode of action of the respiratory enzyme. Normal cells undergo a process called oxidative phosphorylation, which turns glucose into carbon dioxide to produce energy. Much of this process happens in the powerhouses of the cell called the mitochondria. The Warburg Effect describes the way that cancer cells produce energy differently. Warburg showed that unlike healthy cells, cancer cells metabolise most of their glucose through biochemical pathways that do not require oxygen, regardless of whether oxygen is available. This change results in the production of lactate. The reason why cancer cells switch to a relatively less efficient energy metabolism is still being debated. But this change in the way cells use energy seems to be important to the ability of cancers to grow rapidly.
Metabolic therapy is based on the idea that the metabolic differences between normal cells and cancer cells could be exploited as a means of targeting treatment only to cancer cells. Targeted therapies have become an important focus in medical oncology more generally, with fields such as precision medicine, targeted immunotherapies and even radiosurgery attracting a lot of attention. The idea behind targeted therapies is that cancer cells can be killed specifically with minimal damage to normal cells, significantly reducing side effects associated with more traditional treatments like chemotherapy and radiotherapy.
Some people in the metabolic therapy sphere would go so far as to suggest that cancer should be thought of as a metabolic disease, rather than a genetic one. A major advocate of this theory is Dr Thomas Seyfried from Boston College, who wrote Cancer as a Metabolic Disease. A somewhat controversial figure, he is nonetheless well-published in the field. Seyfried believes that certain diets - like a ketogenic diet - can affect cancer development and act as a treatment.
Ketogenic diets are sometimes called low-carb diets because they significantly reduce the amount of carbohydrates ingested. This reduction in carbohydrates in turn reduces the amount of glucose in the body and means that chemicals called ketones are used instead. Although normal cells use glucose as a primary fuel source, they are somewhat like hybrid engines and can easily switch to using ketones for energy when glucose is in short supply. As cancer cells process energy differently, they often struggle to make this switch.
Dominic D’Agostino, who has worked with Seyfried, explored ketogenic diets as a possible treatment for cancer when he began studying the reason why navy seals experience seizures when they dive using rebreathers. Navy seals require stealth and oxygen rebreathers allow them to dive without bubbles. D’Agostino and his team found that the high oxygen and high pressure environment under the sea overstimulates the neurons in the brain, causing a decrease in brain energy metabolism. This overstimulation and change in metabolism causes the potential for a seizure at any time without warning. These oxygen seizures were found to be similar to epileptic seizures in patients whose seizures are drug resistant. Ketogenic diets have been shown control the seizures of drug-resistant epileptic patients. Both adults and children have been shown to benefit greatly to tailored ketogenic diets and have been administered through paediatric and adult clinics at Johns Hopkins since the early 1920s.
The ketogenic diet’s effectiveness for various neurological disorders including epilepsy may have led to the idea that it could be used effectively to treat brain cancer. As part of his research, D’Agostino also found that cancer cells’ tolerance of oxygen at high pressures was significantly lower than normal cells. They performed experiments to test the efficacy of a ketogenic diet in combination with high pressures of oxygen by placing metastatic mouse models who had been on a ketogenic diet in an oxygen-rich hyperbaric chamber. They found that this combination treatment showed a reduction in the growth of the cancers in the mouse, however there have not been any clinical trials run for this treatment to date.
It sounds too good to be true that a simple diet change could improve cancer survival, but it’s not necessarily as simple as saying ‘a low sugar diet can treat cancer’, in and of itself. Seyfried notes that metabolic therapy as a broad-based cancer treatment strategy would need to be personalised to individual patients’ unique physiology. This diet is currently being explored in clinical trials as a way of sensitising cancer cells to other types of treatment, such a radiotherapy.
The ERGO pilot study in Germany examined the feasibility of a ketogenic diet in recurrent glioblastoma, following evidence that limiting carbohydrates inhibits glioma growth in preclinical models. The study concluded that while a ketogenic diet is feasible and safe, it probably has no significant clinical activity when used in isolation against recurrent glioma. The team concluded that further clinical trials are necessary to see whether calorie restriction or the combination with other therapies, such as radiotherapy, could make it more effective. The ERGO2 trial is currently being conducted at the Dr. Senckenberg Institute of Neurooncology in Frankfurt to examine a calorie-restricted, ketogenic diet during reirradiation of patients with recurrent glioblastoma.
In a 2013 Berlin study, researchers found that resting cancer cells can be destroyed by targeting their energy metabolism. Not all cancer cells are killed off by chemotherapy, with some entering a resting state known as senescence. While in this state they are inactive and do not divide, but they still pose a risk of cancer recurrence. The researchers have found that senescent cells show a major increase in energy metabolism and crave sugar. By inhibiting sugar metabolism in these cells, they were able to kill them off. This points to a potential new therapeutic approach, using a cancer-specific metabolic state as a target.
Elsewhere, Michigan State University is investigating the effects of a ketogenic diet on brain cancer. A pilot study, which is currently underway, is looking at whether a diet which restricts blood sugar in this way can decrease tumour size or prevent it from growing in the first place in glioblastoma patients, as well as examining potential side effects.
There are currently two phase II studies being undertaken which are testing ketogenic diets in combination treatments for people with glioblastoma. One run by St Joseph’s Hospital and Medical Center in Phoenix, USA is looking to see if reducing blood sugar and increasing ketones can increase survival and enhance effects of standard radiation and chemotherapy for patients with glioblastoma. The second study is being run by Mid-Atlantic Epilepsy and Sleep Center, LLC testing the safety, efficacy and tolerability of 4:1 ketogenic diet in combination with standard radiation and chemotherapy treatment in patients with glioblastoma.
Taking a different approach to utilising cancer cells' metabolism, a team at Memorial Sloan Kettering Cancer Center have recently published a study in Science Translational Medicine into using glutamine to facilitate a new imaging technique. Because cancer cells are hungry for glutamine, they tagged a tracer with glutamine and noted a high uptake by the glial cells but a low update by healthy brain cells. This meant that when the tracer was then viewed through the positron emission tomography or PET scan the delineation of the tumours could be better visualised.
To date, there isn’t definitive empirical evidence that metabolic therapy can be used to treat brain cancer. Nonetheless, it is an increasingly popular field of research and is gaining interest as understanding of cancer cells’ metabolism grows. If a breakthrough could be made in this area for brain cancer, it could potentially be extended to other types of cancer.
Clemency Norris & Sofia Casbolt
If you are undergoing treatment for brain cancer it is important to speak to your doctor before making changes to your diet.