Program Director/Principal Investigator (Last, First, Middle): Simons, Andrean L. PROJECT SUMMARY (Seeinstructions): Activation of the PI3K/Akt pathway is observed frequently in human head and neck cancer (HNSCC) and its activation has been found to induce a dose-dependent stimulation of glycolysis in cancer cells, which correlates with a more aggressive malignancy in vivo. Increased glucose metabolism in cancer cells (compared to normal cells) is believed to function as a compensatory mechanism protecting from intracellular hydroperoxides formed as byproducts of altered mitochondrial respiration via the formation of pyruvate and NADPH. Furthermore, increased glucose metabolism (measured by FDG-PET) has been associated with increased sensitivity to glucose deprivation using the glycolytic inhibitor 2-deoxy-D-glucose (2DG). The current proposal tests the hypotheses: Inhibition of Akt/EGFR signaling will significantly enhance 2DG-induced radio-/chemo-sensitization via metabolic oxidative stress in human head and neck cancer cells in vitro and in vivo. A corollary hypothesis that will also be tested is that the extent to which human head and neck cancer cells in vivo take up FDG as determined by PET imaging will predict sensitivity to combined modality cancer therapies based on inhibition of Akt/EGFR signaling combined with 2DG.
Aims 1 and 2 will determine if 2DG-induced radio-sensitization can be enhanced by inhibitors of the PI3K/Akt pathway [i.e., LY294002, perifosine, wortmannin] and/or chemotherapeutic agents believed to inhibit the activation of EGFR [i.e., erlotinib and cetuximab] in human head and neck cancer cells via metabolic oxidative stress in vitro and in vivo.
Aim 3 will determine if the extent of 2DG+Akt/EGFR inhibitor-induced radio-sensitization and oxidative stress can be predicted by glucose uptake as determined by FDG-PET. The long term goal of this work is to provide a biochemical rationale for the use of glycolytic inhibitors, using 2DG, PI3K/Akt pathway inhibitors and/or EGFR inhibitors, to develop combined modality therapies to treat HNSCC based on tumor specific sensitivity to glucose deprivation and metabolic oxidative stress.
(Seeinstructions): Activation of Akt signaling is commonly observed in human head and neck cancers and induces stimulation of glycolysis. If head and neck cancer cells utilize glucose metabolism to compensate for increased metabolic production of hydroperoxides, then inhibition of glycolysis (with 2-deoxyglucose, 2DG) combined with Akt inhibitors should enhance sensitivity of cancer cells to radiation by inducing oxidative stress. This project tests the hypothesis that inhibitors of Akt/EGFR signaling can enhance 2DG-induced radio-sensitization via metabolic oxidative stress in HNSCC. The results could provide a new paradigm for designing combination therapies for improving head and neck cancer therapy.
|Simons, Andrean L; Lu, Ping; Gibson-Corley, Katherine N et al. (2013) The Justy mutant mouse strain produces a spontaneous murine model of salivary gland cancer with myoepithelial and basal cell differentiation. Lab Invest 93:711-9|
|Sobhakumari, Arya; Schickling, Brandon M; Love-Homan, Laurie et al. (2013) NOX4 mediates cytoprotective autophagy induced by the EGFR inhibitor erlotinib in head and neck cancer cells. Toxicol Appl Pharmacol 272:736-45|
|Fletcher, Elise V M; Love-Homan, Laurie; Sobhakumari, Arya et al. (2013) EGFR inhibition induces proinflammatory cytokines via NOX4 in HNSCC. Mol Cancer Res 11:1574-84|
|Kang, M A; So, E-Y; Simons, A L et al. (2012) DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway. Cell Death Dis 3:e249|
|Orcutt, Kevin P; Parsons, Arlene D; Sibenaller, Zita A et al. (2011) Erlotinib-mediated inhibition of EGFR signaling induces metabolic oxidative stress through NOX4. Cancer Res 71:3932-40|
|Simons, Andrean L; Mattson, David M; Dornfeld, Ken et al. (2009) Glucose deprivation-induced metabolic oxidative stress and cancer therapy. J Cancer Res Ther 5 Suppl 1:S2-6|
|Simons, Andrean L; Parsons, Arlene D; Foster, Katherine A et al. (2009) Inhibition of glutathione and thioredoxin metabolism enhances sensitivity to perifosine in head and neck cancer cells. J Oncol 2009:519563|