Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio

Abstract

To meet the anabolic demands of the proliferative potential of tumor cells, malignant cells tend to rewire their metabolic pathways. Although different types of malignant cells share this phenomenon, there is a large intracellular variability how these metabolic patterns are altered. Fortunately, differences in metabolic patterns between normal tissue and malignant cells can be exploited to increase the therapeutic ratio. Modulation of cellular metabolism to improve treatment outcome is an emerging field proposing a variety of promising strategies in primary tumor and metastatic lesion treatment. These strategies, capable of either sensitizing or protecting tissues, target either tumor or normal tissue and are often focused on modulating of tissue oxygenation, hypoxia-inducible factor (HIF) stabilization, glucose metabolism, mitochondrial function and the redox balance. Several compounds or therapies are still in under (pre-)clinical development, while others are already used in clinical practice. Here, we describe different strategies from bench to bedside to optimize the therapeutic ratio through modulation of the cellular metabolism. This review gives an overview of the current state on development and the mechanism of action of modulators affecting cellular metabolism with the aim to improve the radiotherapy response on tumors or to protect the normal tissue and therefore contribute to an improved therapeutic ratio.

Keywords: cancer; drug repurposing; metabolism; oncology; radiation; radiotherapy.

Figure 1

Schematic representation of different interventions to improve the therapeutic ratio. Interventions can either improve the radiosensitivity of the primary tumor or metastatic lesion or protect the healthy tissue. Influencing the differential stress response between tumor and normal healthy tissue can contribute to an enhanced therapeutic ratio. Different pathways and proteins can be influenced in relationship to enhancement of the therapeutic ratio, such as mitochondrial and glucose metabolism, ROS scavenging and redox signaling, hypoxia response, DNA repair capacity and inflammation.