In most of cancers, anti-angiogenic therapies are approved as a single-agent drug or in combination with cytotoxic chemotherapy. However, several works suggest that both in clinical and preclinical models, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis.
Previous studies demonstrate that anti-angiogenic therapies perturb tumor metabolism toward anaerobic glycolysis and suggest that glycolysis inhibitors, such as 3PO or MCT4/MCT1 inhibitors, could be a new approach to overcome resistance after anti-angiogenic therapies, even if recent data are not so clear.
Furthermore, these results underline the importance to investigate better the metabolic changes, focusing on the intra-tumoral heterogeneity. Here, we demonstrate that ex vivo cultures derived from Bevacizumab treated tumors have marked metabolic heterogeneity, compared with control tumors. Starting from these evidences, we isolate and characterize clones with different glycolytic profiles. In particular, we speculated that highly glycolytic cells could be more glucose addicted and hence they less tolerate culture under glucose starvation. In order to identify different glycolytic subpopulations, that we call glucose deprivation resistant (GDR) or glucose deprivation sensitive (GDS) clones, we perform a glucose deprivation assay at different time points. Results demonstrate that GDR and GDS clones have transcriptomic and metabolomic differences. Therefore, investigation of the metabolic heterogeneity at clonal level could be a strategy to understand better the development of resistance to anti-angiogenic therapy and to find more efficient molecular targets.