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Computational Model Predicts the Effects of Targeting Cellular Metabolism in Pancreatic Cancer.

Reprogramming of energy metabolism is a hallmark of cancer that enables the cancer cells to meet the increased energetic requirements due to uncontrolled proliferation. One prominent example is pancreatic ductal adenocarcinoma, an aggressive form of cancer with an overall 5-year survival rate of 5%. The reprogramming mechanism in pancreatic cancer involves deregulated uptake of glucose and glutamine and other opportunistic modes of satisfying energetic demands in a hypoxic and nutrient-poor environment. In the current study, we apply systems biology approaches to enable a better understanding of the dynamics of the distinct metabolic alterations in KRAS-mediated pancreatic cancer, with the goal of impeding early cell proliferation by identifying the optimal metabolic enzymes to target. We have constructed a kinetic model of metabolism represented as a set of ordinary differential equations that describe time evolution of the metabolite concentrations in glycolysis, glutaminolysis, tricarboxylic acid cycle and the pentose phosphate pathway. The model is comprised of 46 metabolites and 53 reactions. The mathematical model is fit to published enzyme knockdown experimental data. We then applied the model to perform in silico enzyme modulations and evaluate the effects on cell proliferation. Our work identifies potential combinations of enzyme knockdown, metabolite inhibition, and extracellular conditions that impede cell proliferation. Excitingly, the model predicts novel targets that can be tested experimentally. Therefore, the model is a tool to predict the effects of inhibiting specific metabolic reactions within pancreatic cancer cells, which is difficult to measure experimentally, as well as test further hypotheses toward targeted therapies.

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