Molecular Mechanisms of Insulin Signaling in the Malignant Cell Transformation

在血糖升高或糖尿病的状态下，癌症发病率的增加表明代谢变化对癌症的发展有影响。胰岛素/IGF1轴或相关通路的异常调节可能会导致新陈代谢的变化以及与癌症相关的过程，如增殖和凋亡。阐明这些潜在的因果关系将有助于癌症治疗和癌症预防，这是几年来科学工作的目标。在初步实验中，我们已经表明，使用胰岛素/IGF1受体抑制剂OSI-906的药理抑制可以防止细胞的恶性转化。本研究的目的是通过研究合适的啮齿动物致癌模型，在时空分子水平上阐明潜在的保护机制，并将这些机制应用于更多的转化影响。预期的结果将使人们能够深入了解肿瘤发展过程中胰岛素/IFG1信号的分子机制，以及通过使用下游PI3K/Akt信号通路的抑制剂来治疗现有肿瘤的方法。该项目可能有助于解释胰岛素信号在不同组织中的癌症发展过程中的作用。通过药物或饮食干预来调节这些信号事件可能会促进现有癌症治疗的疗效。由于大多数癌症治疗方法在健康组织中也存在基因毒性缺陷，因此同时调节胰岛素/IGF1信号可能具有保护作用似乎是可行的。这一提议的初步结果将阐明能量代谢改变与恶性转化中的分子事件之间的分子联系，直接影响癌症预防和癌症治疗。

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.