Drugging cancer metabolism: Expectations vs. reality

Abstract

As compared to their normal counterparts, neoplastic cells exhibit a variety of metabolic changes that reflect not only genetic and epigenetic defects underlying malignant transformation, but also the nutritional and immunobiological conditions of the tumor microenvironment. Such alterations, including the so-called Warburg effect (an increase in glucose uptake largely feeding anabolic and antioxidant metabolism), have attracted considerable attention as potential targets for the development of novel anticancer therapeutics. However, very few drugs specifically conceived to target bioenergetic cancer metabolism are currently approved by regulatory agencies for use in humans. This reflects the elevated degree of heterogeneity and redundancy in the metabolic circuitries exploited by neoplastic cells from different tumors (even of the same type), as well as the resemblance of such metabolic pathways to those employed by highly proliferating normal cells. Here, we summarize the major metabolic alterations that accompany oncogenesis, the potential of targeting bioenergetic metabolism for cancer therapy, and the obstacles that still prevent the clinical translation of such a promising therapeutic paradigm.

Keywords: Glutamine; Krebs cycle; Oxidative phosphorylation; Pentose phosphate pathway; Reductive carboxylation; Serine.