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Nicholas Denko
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- Assistant Professor, Radiation Oncology - Radiation Biology
- Member, Cancer Center
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Several clinical studies have observed that tumor hypoxia is an independent prognostic indicator of patient outcome. Many hypotheses have been proposed to explain these observations. Hypoxia can be shown in vitro to be a regulator of metabolism, stimulator of apoptosis, modifier of sensitivity to chemotherapy/radiation, and even an accelerator of local invasion and distant metastasis. However, the molecular mechanism(s) responsible for many these effects have not been identified.
It is the current emphasis of the lab to identify changes in gene expression in response to hypoxia. These induced/repressed genes may then offer insight into the specific hypoxia-dependent changes that are responsible for the clinical correlations. We have used microarray technology to scan the genome for hypoxia-responsive genes at the 36,000 gene level. To date, we estimate that 1.6% of the genome is transcriptionally responsive to hypoxia and it is within this family of genes that we can identify functional classes. We are currently investigating in more detail both unknown genes (ESTs) and genes with presumed function. The analysis is twofold, at the functional protein level, and at the level of transcriptional regulation.
One of the genes we identified as regulated by tumor hypoxia is pyruvate dehydrogenase kinase 1 (PDK1). PDK1 is an important metabolic controller because it can phosphorylate and inhibit pyruvate dehydrogenase (PDH). PDH controls the flow of carbohydrates into the mitochondria. Induction of PDK1 by hypoxia reduces mitochondrial function and reduces oxygen consumption.
We are currently determining the effects on tumor growth and metabolism of a small molecule inhibitor of PDK, dichloroacetate. DCA effectively blocks this "adaptive" response and increases oxygen consumption in tumors. The increased oxygen consumption decreases tumor oxygen concentrations. Low oxygen within the tumor leads to increased tumor sensitivity to a...
Publications
- Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy. Proc Natl Acad Sci U S A. 2007; (22): 9445-50
- HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006; (3): 187-97
- Oxygen consumption can regulate the growth of tumors, a new perspective on the warburg effect. PLoS One. 2009; (9): e7033
- FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell. 2009; (5): 527-39
- Pharmacologically Increased Tumor Hypoxia Can Be Measured by 18F-Fluoroazomycin Arabinoside Positron Emission Tomography and Enhances Tumor Response to Hypoxic Cytotoxin PR-104. Clin Cancer Res. 2009
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