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. Author manuscript; available in PMC: 2019 Mar 1.
Published in final edited form as: Semin Nephrol. 2018 Mar;38(2):175–182. doi: 10.1016/j.semnephrol.2018.01.006

Fig. 1. Targeting metabolic reprogramming in ccRCC (from Abu Aboud O, Weiss RH: Translating Metabolic Reprogramming into New Targets for Kidney Cancer, Kidney Cancer, in press, with permission).

Fig. 1

Glycolysis can be inhibited using inhibitors for hexokinase (HK), the hypoxia-inducible factor α (HIF-α) such as PT2385, Lactate dehydrogenase (LDH-A). Glycolysis can also be inhibited by activators of pyruvate dehydrogenase kinase-1 (PDK-1), which inhibits pyruvate dehydrogenase (PDH). Fatty acid oxidation can be inhibited using peroxisome proliferator-activated receptor (PPARα) antagonist (GW-6471). Also fatty acid synthesis can be inhibited using the fatty acid synthase (FASN) inhibitor TVB-2640. In ccRCC, upregulation of tryptophan metabolism results in increased production of the immunosuppressive metabolites kynuernine and quinolinate. This pathway can be inhibited using the indoleamine 2,3-dioxygenase (IDO) inhibitor epacadostat. Glutamine metabolism can be inhibited using the glutaminase (GLS) inhibitor CB-839. α–KG is α–ketoglutarate. Glutamine is also feeding glutathione (GSH) pathway. Inhibitors of glutathione peroxidase (GPX1) and inhibitors of NADPH such as KPT-9274 and FK866 will stop changing GSH to GSSG. This reaction is responsible for scavenging reactive oxygen species (ROS) in the cell. Arginine is synthesized from citrulline in two steps of the urea cycle using the enzymes argininosuccinate synthase-1 (ASS1), and argininosuccinate lyase (ASL). As ASS1 levels are markedly decreased in all grades of ccRCC, the tumour cells are dependent on extracellular sources of arginine for their survival. Extracellular arginine can be depleted using the pegylated form of arginine deaminase enzyme (ADI-PEG20). ASL inhibitors can also be used for targeted therapy of ccRCC.