The concept of targeting cancer therapeutics towards specific mutations or abnormalities in tumor cells not found in normal tissues has the potential advantages of high selectivity for the tumor and correspondingly low secondary toxicities. At least 20% of all human malignancies display activating mutations in the p21 Ras genes, and perhaps another 60% display other activating mutations (or over-activity) of p21 Ras signaling pathways. We have discovered that over-activity of p21 Ras signaling sensitizes cells to apoptosis induced by a number of conditions, including suppression of PKC activity, which are not toxic to cells with normal levels of p21 Ras activity. This property, designated """"""""Ras-mediated apoptosis"""""""", can be exploited as a targeted cancer therapeutic. We have characterized Ras-mediated apoptosis molecularly, demonstrated its selectivity in vitro and in vivo, and propose to develop this strategy as a targeted therapeutic for cancer. In this application, we propose to use in vitro and in vivo studies to select the optimal inducer of Ras-mediated apoptosis, for eventual advancement into formal preclinical studies. We will also determine if other mutations, which result in activation of p21Ras-signaling pathways without point-mutations in p21 Ras itself, similarly confer sensitivity to Ras-meditated apoptosis. This would substantially broaden the potential application of Ras-mediated apoptosis as a therapeutic modality. We will elucidate the molecular mechanisms leading to Ras-mediated apoptosis. Finally, we will employ, and continuously refine, a new molecular strategy (a pharmacophore model) in the search for more active and more specific inducers of Ras-mediated apoptosis.
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