Molecular Mechanisms of Insulin Signaling in the Malignant Cell Transformation

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Increased cancer incidence in states of elevated blood glucose or diabetes mellitus suggest an influence of metabolic changes onto cancer development. Dysregulations of the insulin/IGF1-axis or related pathways may cause changes in metabolism as well as cancer-related processes like proliferation and apoptosis. The elucidation of these potentially causal relations would give benefits for cancer therapies and cancer prevention and is aim of scientific works since several years.In preliminary experiments we have shown that pharmacological inhibition using the insulin/IGF1-receptor inhibitor OSI-906 prevents the malignant transformation of cells. This inhibitor-mediated protective mechanism is highly effective and may help to elucidate the causal relations between changed energy metabolism an malignant transformation of cells.The aims of the current proposal are to apply these cell-based results onto the in vivo-situation by studying appropriate rodent carcinogenicity models to elucidate the underlying protective mechanisms on a spatiotemporal molecular level, and to subsequently apply these mechanisms to additional transforming influences.The anticipated results will enable insights into molecular mechanisms of the insulin/IFG1 signaling during tumor developmental processes as well as therapeutic approaches on existing tumors by use of inhibitors of the downstream PI3K/Akt signaling pathways. This project may help to interpret the action of insulin signaling during cancer development in different tissues. Modulation of these signaling events via pharmacological or dietary interventions may promote efficacy of pre-existing cancer therapies. Due to the fact that most cancer therapeutic treatments exert genotoxic defects also in healthy tissues it seems feasible that concomitant modulation of insulin/IGF1 signaling may in addition have protective effects.Anticipated results from this proposal will elucidate molecular links between altered energy metabolism and molecular events in malignant transformation directly impacting both cancer prevention as well as cancer therapy.