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Experimental Therapeutics Programme

CNIO - Lilly Cell Signalling Therapies Section

Head of Section:  Susana Velasco
Research highlights

The observation of an altered metabolic state in cancer cells dates back to the early 20th century when Otto Warburg observed that cancer cells preferentially utilise glycolysis over oxidative phosphorylation for growth, even in the presence of normal oxygen levels (Warburg 1956), a phenomenon known as the ‘Warburg effect’. Warburg argued that, ‘this altered metabolic state was the underlying cause for cancer’. The molecular mechanisms driving an altered tumour metabolism have only recently begun to be understood as a result of large-scale genomic sequencing as well as advances in metabolomic profiling technologies. Recent studies have shown that many oncogenes, including MYC and RAS, impart an altered metabolic phenotype in cancer cells through the regulation of genes involved in central metabolic pathways such as glycolysis, fatty acid metabolism, oxidative phosphorylation, nucleotide synthesis and the one carbon pool (reviewed by Gilmour & Velasco, 2017).

Cellular metabolism is a fine tuned process; tumours rely heavily on specific metabolic pathways to obtain their energy while using other pathways to grow in order to give tumour cells a growth advantage. This situation may leave tumour cells in a frail position under certain treatments or circumstances, while normal cells may be able to compensate and survive. Furthermore, the high requirements of nutrients and other soluble factors, and the release of metabolites with immunosuppressive properties, together with the hypoxic conditions found in tumours creates a ‘non-friendly ’ microenvironment for an anti-tumour immune surveillance, while facilitating the growth of other tumourpromoting cells such as stromal and myeloid cells (FIGURE). Thus, the mechanistic understanding of cancer metabolism has led to renewed interest in developing therapeutics that target key enzymes involved in this process. Checkpoint-blockade immunotherapy has been one of the most exciting advances made in cancer treatment in recent years. Metabolic interplay in the local microenvironment can mediate T cell differentiation and function. ‘Checkpoint-blockade’ antibodies can also influence cellular metabolism. Finally, recent clinical trials have shown that combination immunotherapy based on immune checkpoints blockade and other oncology therapies, provides even higher response rates than either approach alone.