Abstract A224: Noninvasive PD markers of a pyruvate dehydrogenase kinase inhibitor, dichloroacetate, in human colon carcinoma xenografts

Abstract

Abstract Pyruvate dehydrogenase (PDH) is the key mitochondrial enzyme that determines whether pyruvate formed during glycolysis from glucose will be metabolised to lactate or oxidised in the TCA cycle. Its regulator, pyruvate dehydrogenase kinase (PDK) negatively regulates PDH by phosphorylation. Dichloroacetate (DCA) is an inhibitor of PDK and treatment with DCA decreased proliferation and growth in cancer cells and solid tumors (1). The aim of this work was to develop a non-invasive and robust pharmacodynamic (PD) biomarker for tumor response following PDK inhibition. Human HT29 (colon) carcinoma xenografts were examined using in vivo1H- and 31P- magnetic resonance spectroscopy (MRS), before and after 3 days of DCA treatment (200mg/kg via po). Controls were treated with vehicle alone (water). Metabolic profiles of tumor extracts were measured by high resolution in vitro 1H- and 31P-MRS. Significant tumor growth inhibition (p<0.001) was observed in HT29 xenografts following 3 days of DCA treatment when compared with vehicle-treated controls. In vivo, significant decreases in ratios of phosphomonoester/total phosphorus signal (P=0.01) and total choline/water signal (P=0.05) were found in DCA-treated HT29 xenografts. The in vivo results were confirmed by significantly lower phosphocholine (PC) (P=0.02), glycerophosphocholine (P=0.01) and glycerophosphoethanolamine (P=0.05) levels, as found by 31P-MRS of tumor extracts from DCA treated animals when compared with controls. Increases in leucine (P=0.04), iso-leucine (P=0.02), valine (P=0.04) and succinate levels (P=0.03) and lower ATP (P=0.003), glucose (P=0.03) and creatine (P=0.05) levels were also found in DCA-treated HT29 tumor extracts when compared with controls. The drop in PC and other choline-related metabolites following DCA treatment is probably due to tumor stasis caused by the PDK inhibition, since DCA upregulates the mitochondrial membrane potential, induces apoptosis, decreases proliferation and inhibits tumor growth (1). These and the non-phospholipid changes in the metabolic profiles including lower ATP are consistent with previous findings where similar metabolic profiles were associated with antiangiogenic effects induced by LAQ824 (2). The phospholipid changes may have potential as surrogate non-invasive markers for determining tumor response following treatment with DCA or other PDK inhibitors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A224.