The physiological or pathophysiological state of cells and organs is reflected in their energy metabolism. For example, deviations in glucose metabolism is almost always observed in tumors. The energy metabolism of cancer cells differs strikingly from normal tissue with glycolysis and subsequent lactate production being much more prominent in cancer cells, even under aerobic conditions. Increasingly, therapeutic strategies for cancer treatment are designed to target metabolic deviations, making levels of energy metabolites such glucose or lactate potential correlates of drug efficacy. The goal of this proposal is to develop a lab-on-chip platform for in vitro monitoring of the effects of drug candidates on energy metabolism of cancer cells. The proposed platform will intimately integrate small groups of glioma (brain cancer) cells with miniature glucose biosensors in a microfabricated device, where the cellular microenvironment can be precisely defined and easily modulated. This platform will be used to: 1) establish tumor-mimicking microenvironment conditions (e.g. hypoxic, acidic, nutrient-limiting) in glioma cell cultures; 2) challenge the cells with pharmacological inhibitors of kinase signal transduction pathways central in energy metabolism; and 3) monitor local extracellular glucose levels. Thus the cell culture/biosensor platform will connect tumor microenvironment, energy metabolism and anti-cancer drug efficacy, and will help to delineate conditions making cancer cells more susceptible to therapy. The proposed technology will be a valuable tool for the development of therapeutic anti-cancer agents, and will help illuminate molecular aspects of metabolic adaptation of cancer cells. ? ? ?
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