Adjuvant multimodal metabolic therapy of neuroblastoma

Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Pediatric patients with high-risk neuroblastoma still have poor outcomes, despite receiving multi-modal intensive therapy. Thus, there is an urgent need for new NB therapies. Targeting cellular metabolism is emerging as a promising strategy in cancer treatment. In particular, neuroblastoma tumors, like many other solid tumors, reduce their respiration and strongly depend on glucose for energy production, which renders them highly susceptible to glucose deprivation. Recent preclinical data of researchers at the Department of Pediatrics of the Paracelsus Medical University in Salzburg indicate that targeting this metabolic phenotype by a ketogenic diet, which has a high fat and low protein/carbohydrate content, slows neuroblastoma tumor growth and enhances the effectiveness of a classical chemotherapy. However, ketogenic diet alone is not very efficient at reducing blood glucose levels. Thus, some studies have used caloric restriction in combination with ketogenic diet to further reduce plasma glucose, but this therapeutic approach is not applicable in patients with low body mass index. As an alternative, we propose that combining ketogenic diet and specific metabolic inhibitors can be used as an adjuvant therapy in neuroblastoma. This approach should target not only glucose dependent bulk cancer cells, but also respiration-competent cancer stem cells. Several studies have demonstrated that the antidiabetic drug metformin, which inhibits the mitochondrial energy metabolism and antibiotics, which inhibit mitochondrial protein synthesis, can block tumor cell proliferation. Our first aim is to determine the effect of multi-level metabolic targeting on neuroblastoma proliferation in a murine xenograft model. Classical low-dose chemotherapy will be combined with KD and drugs targeting cancer metabolism, such as metformin (to inhibit gluconeogenesis and oxidative phosphorylation) and/or antibiotics like doxycycline (to reduce mitochondrial protein synthesis) and the effect on the proliferation of NB xenografts will be determined. Our second aim is to demonstrate that the proposed multi-modal therapy is also effective in an immunocompetent genetic neuroblastoma model. We will compare different treatment groups in terms of markers of proliferation and cell death. Because dietary intervention and application of drugs interacting with body/cellular metabolism will influence cellular and extracellular metabolites, our final aim is to determine the effect of the multi-modal therapy on the plasma and tumor metabolomes. Despite the fact that numerous approaches to target the tumor metabolism have been reported, none has tried to target different pathways of the tumor metabolism. The proposed preclinical studies targeting neuroblastoma metabolism will provide a strong foundation for multi-level metabolic targeting of other types of cancer as well as the initiation of clinical studies. The combination therapy aims at increasing the survival of the patients and at reducing therapy induced long-term toxicity by the possibility to reduce the duration of the therapy.