Abstract
Molecular profiling studies of tumor tissue from patients with clear cell renal cell cancer (ccRCC) have revealed extensive metabolic reprogramming in this disease. Associations were found between metabolic reprogramming, histopathologic Fuhrman grade, and overall survival of patients. Large-scale genomics, proteomics, and metabolomic analyses have been performed to identify the molecular players in this process. Genes involved in glycolysis, the pentose phosphate pathway, glutamine metabolism, and lipogenesis were found to be upregulated in renal cell cancer (RCC) specimens as compared to normal tissue. Preclinical research indicates that mutations in VHL, FBP1, and the PI3K-AKT-mTOR pathway drives aerobic glycolysis through transcriptional activation of the hypoxia-inducible factors (HIF). Mechanistic studies revealed glutamine as an important source for de novo fatty acid synthesis through reductive carboxylation. Amplification of MYC drives reductive carboxylation. In this review, we present a detailed overview of the metabolic changes in RCC in conjunction with potential novel therapeutics. We discuss preclinical studies that have investigated targeted agents that interfere with various aspects of tumor cell metabolism and emphasize their impact specifically on glycolysis, lipogenesis, and tumor growth. Furthermore, we describe a number of phase 1 and 2 clinical trials that have been conducted with these agents.
Highlights
Renal cell cancer (RCC) is an aggressive type of cancer that arises from the proximal renal tubular epithelium of the kidneys
The altered pattern in glucose metabolism in tumors has first been described by the German physiologist Otto Warburg as aerobic glycolysis [6]
No significant differences in isocitrate dehydrogenase (IDH1/2) protein levels were observed between RCC and normal kidney tissues
Summary
Renal cell cancer (RCC) is an aggressive type of cancer that arises from the proximal renal tubular epithelium of the kidneys. The altered pattern in glucose metabolism in tumors has first been described by the German physiologist Otto Warburg as aerobic glycolysis [6]. This phenomenon, nowadays frequently referred to as “the Warburg effect,” has been found in an important subset of the patients with RCC and was associated with a poor prognostic outcome. We will provide a detailed overview of the genetic changes van der Mijn et al Cancer & Metabolism (2016) 4:14 that cause the Warburg effect, in conjunction with therapeutic agents that may interfere with this process. Genetic defects in cancer cells lead to increased import of these amino acids from the extracellular space. The frequency of genetic changes is of importance for the selection of potential therapeutic targets. The frequency of the metabolic reprogramming may render RCC a suitable disease for the investigation of potential novel therapeutic agents that target tumor metabolism
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