The alterations in tumor cell metabolism that result in a glycolytic phenotype have long been recognized, and are exploited as the basis of the FDG-PET scan. This aberrant metabolism is also thought to give tumor cells a growth advantage. Our recent work has identified the hypoxia-inducible gene pyruvate dehydroggenase kinase 1 (PDK1) as one factor that contributes to this metabolic shift by downregulating mitochondrial function. We propose to test the hypothesis that we can revert tumor cell metabolism to a more oxidative state by inhibition of PDK1 with the small molecule dichloroacetate (DCA). DCA has been shown to have anti- cancer effects in model tumors, and has been safely given to patients with metabolic disorders for over 30 years. We feel that this justifies a clinical trial in patients with advanced Head and Neck cancer whose treatment options have been exhausted. One innovative aspect of this trial will be the evaluation of the patients with functional PET imaging to determine if there is a change in the tumor metabolism in response to DCA. We will use standard FDG-PET to evaluate glucose uptake in the tumor and a novel hypoxic radiotracer EF5 to determine oxygen tension within the tumor. As DCA shifts metabolism to oxidative rather than glycolytic, FDG signal should decrease and EF5 signal should increase. Changes in tracer uptake will be correlated to molecular findings in vitro. We will obtain fine needle aspirate biopsies from the patient's pre and post DCA and determine the level of phosphorylation of the E1a subunit of the pyruvate dehydrogenase complex (the target of PDK1). We will also collect patient serum pre and post DCA and determine if there is any increase in the level of secreted gene products of hypoxia-responsive genes such as osteopontin or galectin-1. This trial will lay the groundwork for a phase 2 trial evaluating the clinical efficacy of DCA as an anti-cancer drug.
Novel anti-cancer treatments based on tumor cell metabolism represent an exciting new avenue of study. The proposed trial evaluates novel functional imaging modalities with a novel metabolic modulating anti-cancer agent. The combination of these technologies will give the most rigorous investigation of the potential for this class of drugs. )
|Papandreou, Ioanna; Goliasova, Tereza; Denko, Nicholas C (2011) Anticancer drugs that target metabolism: Is dichloroacetate the new paradigm? Int J Cancer 128:1001-8|