Metabolic modulation of cancer: a new frontier with great translational potential.

Metabolic oncology is an exciting new field in cancer research, offering a new window to cancer's molecular plasticity and promise for the development of effective, cancer-selective therapies and novel biomarkers. It is based on the realization that cancer's unique metabolism (known since Warburg's report in 1923) with suppression of mitochondrial glucose oxidation and upregulation of cytoplasmic glycolysis is not a secondary but a primary event, offering many growth advantages to cancer cells. Many mechanisms have been revealed, including growth factors, oncogenes, and mutations, all contributing to a suppression of mitochondria, similar to what takes place in hypoxia. This suppression leads to inhibition of mitochondria-driven apoptosis, promotes proliferation, and enhances angiogenesis and metastatic potential. A number of molecular tools and small molecules targeting metabolic enzymes, including pyruvate kinase, pyruvate dehydrogenase kinase, isocitrate dehydrogenase, and lactate dehydrogenase, have been developed, inhibiting cancer growth in vitro and in vivo in several cancer types. Several have already entered early-phase trials, a great translational success considering the young age of the field (less than 10 years). Here we review the mechanisms and effects of these metabolic modulators and the rationale for further development. This rapidly accumulating knowledge allows some optimism that this may prove to be a paradigm shift in the way we understand and treat cancer.