Metabolic targets for cancer therapy

Key Points During the past decade, the metabolic alterations that intimately accompany oncogenesis and tumour progression have been intensively investigated, generating great expectations on the development of novel antineoplastic agents that would selectively target the metabolism of malignant cells. With the notable exception of oncometabolites, the metabolism of cancer cells resembles very much that of any rapidly proliferating cell, exhibiting a prominent shift towards anabolic reactions and an increased dependency on intermediates and pathways that — directly or indirectly — sustain such an accelerated biosynthetic activity. At least in some settings, systemic metabolism exerts a prominent influence on carcinogenesis and tumour progression. This is best exemplified by the increased risk of developing cancer that accompanies metabolic syndromes such as diabetes and obesity as well as by the antineoplastic effects of several drugs that are currently used for the treatment of these conditions. The extensive metabolic rewiring of malignant cells is not yet another hallmark of cancer but instead a process that intervenes along with — and hence cannot be discriminated from — oncogenesis. In line with this notion, multiple oncogenes (for example, MYC ) and oncosuppressor genes (for example, the tumour suppressor p53 gene TP53 ) have been shown to regulate bioenergetic and anabolic metabolic circuitries. The accumulation of metabolic intermediates such as fumarate, succinate and 2-hydroxyglutarate suffices to drive oncogenesis, at least in some settings. The existence of such oncometabolites reinforces the notion that the metabolic rearrangements of malignant cells are not a mere epiphenomenon of oncogenesis but one of its crucial components. A huge amount of preclinical data and accumulating clinical experience indicate that several metabolic circuitries can be efficiently targeted to achieve antineoplastic effects in vivo . Thus, in spite of an essential similarity between the metabolism of cancer cells and that of any highly proliferating cell, a therapeutic window exists for this promising approach to treat cancer. Cellular metabolism is substantially altered during oncogenesis and tumour progression, and targeting these metabolic changes is being actively pursued in the development of selective antineoplastic agents. Here, Kroemer and colleagues discuss the intimate relationship between metabolism and malignancy, focusing on therapeutic strategies and em