Challenges in targeting cancer metabolism for cancer therapy.

Abstract

A tumour is clonogenic in origin, dividing and accumulating accidental mutations over time to become a complex, heterogeneous mix of cells. By the time it is diagnosed, a typical tumour mass contains 30–80 somatic mutations [[1]]. This heterogeneity makes it difficult to eliminate all cancerous cells simultaneously by targeting mutated gene products [[2]], and we believe that even a single cancer cell left behind after surgery and/or chemotherapy might cause a recurrence of cancer [[3],[4],[5]]. We thought, therefore, that a simpler approach would be to target highly elevated levels of glycolysis common to most cancer types—the effect known as the ‘Warburg effect’. However, it turns out that targeting glycolysis and metabolic pathways in cancer might be just as complicated as targeting somatic mutations, if not more so. In 1956, Otto Warburg characterized cancer cells as having higher glycolysis rates than normal healthy cells [[6]]. At the time, it was thought that cancer cells in the dense interior of the tumour survive the highly hypoxic conditions by generating energy through anaerobic respiration. However, advances in imaging technology have shown the existence of highly glycolytic cancer cells in oxygen‐rich environments. In fact, in most cancer cells, glucose is used to synthesize lipids, amino acids and nucleotides for rapid cell division. In some cases, too much glucose is diverted from the tricarboxylic acid cycle, and the cycle must be supplied with glutamate from glutamine imported from an extracellular source, suggesting that complex metabolic changes take place in cancer cells. For example, Bishop and colleagues, have compared liver tumours induced by tissue‐specific overexpression of either MYC or MET. MYC‐induced mouse liver tumours significantly increase both glucose and glutamine catabolism, whereas MET‐induced liver tumours use glucose …