PROJECT 2: Cell surface receptors comprise an important class of membrane molecules that form communication links between the extracellular milieu and the cell's interior. In addition, a number of cell surface receptors have been shown to play a significant role in imparting specific phenotypes to transformed cells, for example growth factor independence and metastatic behavior. Non-invasive imaging of receptor activity dynamically in live cells and mouse models would significantly enhance our understanding of the role of these receptors in the etiology of cancer and the response of tumors to therapeutic agents directed against these receptors. For the purpose of this proposal we will focus on three distinct receptors. The epidermal growth factor receptor (EGFR) is often over-expressed and activated in tumors in a ligand independent manner, while the hepatocyte growth factor receptor (Met) is activated in an autocrine manner in that tumor cells express the ligand (HGF) and the receptor (Met) simultaneously thus constitutively activating intracellular signaling cascades. The CXCR7 receptor is activated in a paracrine manner in that specific organs such as bone marrow, lung and liver express SDF, the ligand which through CXCR7 activation results in the spread and growth of metastasis to these sites. In Project 2, we propose to develop molecular imaging strategies to image activity of three receptors that contribute significantly to the transformed phenotype. The proposal is organized in three aims, one for each of the above three receptors. In each of the aims we will develop two independent approaches to image the receptor and the one with the best signal to noise and specificity will be used in further in-vitro validation studies to demonstrate that the reporter faithfully reports on the appropriate molecular events. Lastly, in each of the aims, the appropriate receptor will be used to investigate the efficacy of novel therapies directed against each receptor in a live mouse model and the efficacy of the therapy will be correlated with molecular imaging as a non-invasive surrogate for receptor activity. Public Health: The studies proposed here will result in the development of imaging based mouse models that will facilitate the development and testing of anti-cancer therapies directed against key receptor molecules.
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