Targeting the metabolic microenvironment of tumors

Abstract

The observation of aerobic glycolysis by tumor cells in 1924 by Otto Warburg, and subsequent innovation of imaging glucose uptake by tumors in patients with PET-CT, has incited a renewed interest in the altered metabolism of tumors. As tumors grow in situ, a fraction of it is further away from their blood supply, leading to decreased oxygen concentrations (hypoxia), which induces the hypoxia response pathways of HIF1α, mTOR, and UPR. In normal tissues, these responses mitigate hypoxic stress and induce neoangiogenesis. In tumors, these pathways are dysregulated and lead to decreased perfusion and exacerbation of hypoxia as a result of immature and chaotic blood vessels. Hypoxia selects for a glycolytic phenotype and resultant acidification of the tumor microenvironment, facilitated by upregulation of proton transporters. Acidification selects for enhanced metastatic potential and reduced drug efficacy through ion trapping. In this review, we provide a comprehensive summary of preclinical and clinical drugs under development for targeting aerobic glycolysis, acidosis, hypoxia and hypoxia response pathways. Hypoxia and acidosis can be manipulated, providing further therapeutic benefit for cancers that feature these common phenotypes.

Figure 1. Inhibitors of glucose metabolism

The figure depicts the glycolytic pathway from glucose entry into cells through production of pyruvate, which is converted either to lactate or to acetyl coA for entry into the TCA cycle. Movement of metabolic intermediates through the pathway is designated by arrows. Enzymes in the glycolytic pathway are placed next to the arrow leading from their substrate to their product. Inhibitors of glycolytic enzymes or glucose transporters appear in boxes.

Figure 2. Proteins that contribute to tumor acidosis and their inhibitors

The figure depicts proteins and transporters that contribute to extracellular acidosis in a tumor due to increased lactate production from increased glycolytic flux. Included are CAIX and CAXII, carbonic anhydrases that catalyze the interconversion between carbon dioxide and water to bicarbonate and protons; and V-ATPases and MCTs, which allow transport of H⁺ into the extracellular environment. Inhibitors of the proteins that contribute to tumor acidosis appear in boxes.