Diet low in sugar improves cancer therapy
In our cells, sugars, fats and proteins are channeled into in various metabolic pathways in strictly regulated proportions in order to produce building blocks for growth on the one hand and energy on the other. If a cell mutates into a cancer cell, the metabolic balance will shift. “Tumor cells switch to the use of sugar, especially the sugar molecule glucose,” says Barbara Kofler, head of the research laboratory at the University Hospital for Pediatrics and Adolescent Medicine in Salzburg. Her research focuses on solid tumors in children, i.e. solid clusters of cancer cells that are initially localized. “Solid tumors absorb up to ten times more glucose than healthy tissue. In terms of therapy it therefore makes obvious sense to remove the sugar from the system,” says Kofler. This is an approach her team investigated in the project “Multimodal metabolic therapy in neuroblastoma”, which was funded by the Austrian Science Fund FWF. The researchers were able to demonstrate that a diet low in sugar increases the effectiveness of chemotherapy. If the results are confirmed in clinical applications, it would mean that the duration and dosage of chemotherapy and, consequently, its side effects could be reduced.
Only 50 percent success rate so far
Tumors develop when cells mutate and divide in an uncontrolled manner. Neuroblastomas develop from embryonic cells and will occur, for example, in the adrenal medulla or in the nerve pathways on both sides of the spine. They account for around 6 percent of solid tumors in children and are one of the most common cancers in this age group. “Despite numerous studies, only one out of two children will survive more than five years in certain high-risk groups of neuroblastomas,” notes Kofler. “Current treatment is often a combination of surgery, chemotherapy, bone marrow transplants, radiation and immunotherapy, all of which have severe side effects and a long-term deleterious effect on the surviving children.” For this reason, Kofler is looking for factors that will improve the effectiveness of standard therapies.
Tumor cells live on sugar
The metabolism of tumor cells offers a point of attack in this context. Not only do tumor cells have an increased demand for sugar, they are also marked by a shift away from oxygen-dependent glucose degradation through cellular respiration and towards oxygen-independent glucose fermentation (anaerobic glycolysis). While the shift has been known for a long time under the name of “Warburg effect”, the reasons for it are still being debated by scientists. “One result of this fermentation is lactate, which acidifies the cell environment, thereby allowing tumor cells to migrate and form metastases. Secondly, the process generates building blocks that the tumor cells can use to form new cells,” explains Kofler. Although the exact mechanism behind this metabolic flexibility has not yet been identified, it can still be harnessed for therapeutic purposes.
How to starve tumor cells
In case of a low-sugar diet, it is important to provide alternative sources of energy. “Whereas tumor cells are not very good at metabolizing ketone bodies, the by-products of fat breakdown, this is not a problem for almost all other human cells,” explains Kofler. This is why a ketogenic diet suggests itself – a low-carb diet in which up to 90 percent of the energy comes from fats, 8 percent from proteins and only 2 percent from carbohydrates (sugar). “In oncology, ketogenic diets have been researched in glioblastoma, for example, where we have also seen first promising clinical data from patients,” notes Kofler, but adds that there is not an abundance of studies. “As far as I know, our research group is the only one working in the field of neuroblastoma,” she says.
Several fronts against the tumor
Alongside the ketogenic diet, Kofler's team added a second aspect to the metabolic therapy. Although tumor cells largely switch to anaerobic glycolysis, there is still a low degree of cellular respiration. “We wanted to provide a two-pronged attack: on the one hand with the ketogenic diet and on the other with a well-known antidiabetic drug called metformin,” explains Kofler. Metformin blocks a component of cellular respiration, which forces the tumor to shift even more towards anaerobic glycolysis. “It is important to note that we would not offer either the ketogenic diet or metformin as sole therapies against cancer, but only as adjuvant measures,” Kofler says with emphasis. In the study, the team therefore compared the effect of various combinations of low-dose chemotherapy, ketogenic diet and metformin on mice in which human neuroblastoma cells had been transplanted.
Personal details
Barbara Kofler has been heading the laboratory at the University Hospital for Pediatrics and Adolescent Medicine in Salzburg for almost 30 years. In 2009. she was appointed Professor of Receptor Biochemistry and Tumor Metabolism at Paracelsus Medical University.
The Austrian Science Fund FWF awarded EUR 387,716 in funding to the project “Multimodal metabolic therapy in neuroblastoma”.
Metabolic therapy increases survival
It was shown that the triple therapy results in more test animals surviving over a longer period of time. At the end of the experiment, 65 or 100 percent of the animals (depending on the neuroblastoma cell line) were still alive, while 0 or 10 percent survived with chemotherapy alone. It should be noted that the dual combination of a ketogenic diet and chemotherapy also improved the therapeutic outcome. While the improvement was not as strong, it was still significant (40 to 50 percent survival). “Mice and humans cannot be directly compared, of course. But considering the fact that the five-year survival of high-risk patients with neuroblastoma has only increased by a few percentage points in the past ten years despite multicenter international studies, our results are still groundbreaking,” says Kofler in respect of the study findings.
From animal model to clinical application
Kofler's team is currently continuing to work on test animals in order to clarify the underlying mechanism. “That we starve the tumor is not the only responsible factor. We assume that there is a reprogramming process in the body which reduces factors that would be important for tumor growth,” explains Kofler. Ultimately, the aim is to extend the research to the clinical area. “Parents of affected children in particular are looking for options,” Kofler says. “The ketogenic diet is a therapeutic measure, however, and should definitely be supervised by a doctor and dietician.” The chemist knows from her own experience that it is possible to avoid carbohydrates in everyday life. “I initially wanted to try the ketogenic diet for two months to see how the patients feel,” she says, “but I've now been on it for five years.”
