Anticancer drugs that target metabolism: is dichloroacetate the new paradigm?

Recent findings in the fields of oncogenic regulation of metabolism, mitochondrial function and macromolecular synthesis have brought tumor metabolism and the Warburg effect back into the scientific limelight. A number of metabolic pathways that seem to be important for tumor growth are being touted as novel targets for anticancer drug development. One of the candidates in this class of drugs being investigated is dichloroacetate (DCA), a molecule used for over 25 years in the treatment of children with inborn errors in mitochondrial function. This pyruvate mimetic compound stimulates mitochondrial function by inhibiting the family of regulatory pyruvate dehydrogenase kinases (PDK1-4). The stimulation of mitochondrial function, at the expense of glycolysis, reverses the Warburg effect and is thought to block the growth advantage of highly glycolytic tumors. Interestingly, some of the recent in vitro findings have shown very modest antitumor cell activity of DCA when cells are treated in a dish. However, several studies have reported antitumor activity in model tumors. This apparent paradox raises the question, how do we evaluate cancer drugs designed to target tumor metabolism? Traditional approaches in cancer drug development have used in vitro assays as a first pass to evaluate potential lead compounds. The fact that DCA has better in vivo activity than in vitro activity suggests that there are unique aspects of solid tumor growth and metabolism that are difficult to recapitulate in vitro and may be important in determining the effectiveness of this class of drugs.