Cancer therapies are stressful and only have a limited life-prolonging effect. A Salzburg research team has now been able to increase the effectiveness of chemotherapy by combining it with a low-sugar diet and a diabetes medication. Neuroblastomas, the second most common solid tumor in children, were examined.
In the body’s cells, sugar, fats and proteins flow into various metabolic pathways in strictly regulated ratios. This creates building blocks for growth on the one hand and energy on the other. If a cell mutates into a cancer cell, the metabolic balance shifts. “Tumor cells switch to using sugar, especially the sugar molecule glucose,” says Barbara Kofler, head of the research laboratory at the University Clinic for Pediatrics and Adolescents in Salzburg. In her research, she focuses on solid tumors in children, i.e. solid and initially localized associations of cancer cells. “Solid tumors absorb up to 10 times more glucose than healthy tissue. Therapeutically, it is therefore obvious to remove the sugar from the system,” says the chemist. Her team examined the approach in the “Multimodal metabolic therapy for neuroblastoma” project, which was funded by the FWF Science Fund. The researchers showed that a low-sugar diet increases the effectiveness of chemotherapy. If the results are confirmed in the clinic, the duration and dose of chemotherapy and thus its side effects could be reduced.
So far only 50 percent success rate
Tumors arise when cells mutate and divide uncontrollably. Neuroblastomas develop from embryonic cells and occur, for example, in the adrenal medulla or in the nerve tracts on both sides of the spine. They account for approximately 6 percent of solid tumors in children and are one of the most common cancers in this age group. “Despite numerous studies, in certain high-risk groups of neuroblastoma, only every second child survives longer than 5 years,” says Kofler. “Current therapy is often a combination of surgery, chemotherapy, bone marrow transplantation, radiation and immunotherapy, all of which have severe side effects and long-term impact on surviving children.” The researcher is therefore looking for factors that can increase the effectiveness of classic therapies.
Tumor cells live on sugar
One such target is the metabolism of tumor cells. In addition to the increased sugar requirement, it is characterized by a shift away from oxygen-dependent glucose breakdown in the form of cellular respiration and towards oxygen-independent fermentation of sugar (anaerobic glycolysis). This adjustment has long been known as the “Warburg effect”, although the reasons are still being debated in science. “On the one hand, fermentation produces lactate, which acidifies the cell environment. This allows tumor cells to migrate and form metastases. On the other hand, building blocks are generated with which the tumor cells can form new cells again,” explains Kofler. The exact mechanism behind this metabolic flexibility is not yet clear – but it can be used therapeutically.
How to starve tumor cells
When following a low-sugar diet, it is important to provide alternative energy sources. “Tumor cells cannot metabolize the by-products of fat breakdown, the ketone bodies, well. In contrast, this is not a problem for almost all other human cells,” explains Kofler. A ketogenic diet is therefore a good option – a low-carb diet in which up to 90 percent of energy comes from fats, 8 percent from proteins and only 2 percent from carbohydrates (sugar). “In oncology, ketogenic diets have been researched on glioblastoma, for example, where we also know the first promising clinical data from patients,” says Kofler. Overall, the number of studies is manageable. “To my knowledge, our research group is the only one working in the field of neuroblastoma,” she says.
Several fronts against the tumor
In addition to the ketogenic diet, Kofler’s team added a second facet to metabolic therapy. Although tumor cells largely switch to anaerobic glycolysis, cellular respiration is still only slightly active. “We wanted to attack the tumor from two sides: on the one hand with the ketogenic diet and on the other hand with a well-known anti-diabetic drug called metformin,” explains Kofler. Metformin blocks a component of cellular respiration, which pushes the tumor toward anaerobic glycolysis. “It is important to emphasize that we would neither offer the ketogenic diet nor metformin as individual therapies against cancer, but only as complementary measures,” emphasizes Kofler. In the study, the team therefore compared the effect of the various possible combinations of low-dose chemotherapy, ketogenic diet and metformin on mice to which human neuroblastoma cells were transplanted.
Metabolic therapy increases survival
It was shown that with triple therapy, more laboratory animals survive 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 also be noted that the dual combination of a ketogenic diet and chemotherapy had a weaker, but also significantly improved outcome with a survival rate of 40 to 50 percent. “Of course, mice and humans cannot be compared directly. But if you consider that the five-year survival of high-risk patients with neuroblastoma has only increased by a few percentage points over the past ten years, despite multicenter international studies, then our results are groundbreaking,” says Kofler, classifying the study data.
From animal models to clinical applications
Kofler’s team is currently continuing to work on laboratory animals to clarify the underlying mechanism. “The fact that we are starving the tumor is not solely responsible. We assume that reprogramming occurs in the body and factors that are important for tumor growth are reduced,” explains Kofler. Ultimately, the goal is to expand research into the clinical area. “The parents of affected children in particular are looking for options,” says Kofler. “However, the ketogenic diet is a therapeutic measure and should definitely be accompanied by medical and dietary advice.” 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 find out how the patients fared,” she says. “I’ve been doing them for five years now.”
To person
Barbara Kofler has been head of the laboratory at the University Clinic for Pediatrics and Adolescent Medicine at the University Hospital of Salzburg for almost 30 years. Since 2009 she has been working as a professor of receptor biochemistry and tumor metabolism at the Paracelsus Medical University.
The FWF funded the project “Multimodal metabolic therapy for neuroblastoma” with around 388,000 euros.
Kontakt: Ingrid Ladner Österreichischer Wissenschaftsfonds FWF Redaktion scilog Telefon: +43 676 83487 8117 E-mail: [email protected] Website: https://scilog.fwf.ac.at/