Combination strategies to target metabolic flexibility in cancer

Therapeutically interfering with metabolic pathways has great merit to curtail tumor growth because the demand for copious amounts of energy for growth-supporting biomass production is common to all cancer entities. A major impediment to a straight implementation of metabolic cancer therapy is the metabolic flexibility and plasticity of cancer cells (and their microenvironment) resulting in therapy resistance and evasion. Metabolic combination therapies, therefore, are promising as they are designed to target several energetic routes simultaneously and thereby diminish the availability of alternative substrates. Thus, dietary restrictions, specific nutrient limitations, and/or pharmacological interventions impinging on metabolic pathways can be combined to improve cancer treatment efficacy, to overcome therapy resistance, or even act as a preventive measure. Here, we review the most recent developments in metabolic combination therapies particularly highlighting in vivo reports of synergistic effects and available clinical data. We close with identifying the challenges of the field (metabolic tumor heterogeneity, immune cell interactions, inter-patient variabilities) and suggest a "metabo-typing" strategy to tailor evidence-based metabolic combination therapies to the energetic requirements of the tumors and the patient's nutritional habits and status.