Human malignancy evolves through the acquisition of genetic abnormalities. A signal transduction pathway that is frequently activated in cancer is the PI-3 kinase pathway. One major mechanism for activation of the pathway is mutation of the PTEN tumor suppressor. Another mechanism of activation is the amplification of the erb-B2/neu oncogene. PTEN mica develop a large number of different malignancies that activate the PI-3 kinase pathway. Treatment of these mica with CCI-779, an inhibitor of mTOR, is able to effectively curtail tumor progression, which is associated with down regulation of the hyperactivated p70 S6 kinase found in these tumors. The goal of this application is to determine the efficacy of treating tumors with inhibitors of the PI-3 kinase pathway. Tumors that develop due to the activation of the PI-3 kinase pathway are expected to respond to such pharmacological intervention. On the other hand, tumors that have no abnormality of the pathway are expected to be resistant to the same interventions. To test this goal we plan to use prostate neoplasia as a model for investigation, Prostatic tumors due to PTEN mutation, neu over expression, and large T antigen will be treated with either CCI-779 or PI-3 kinase inhibitors, The effect of therapy on tumor signaling, gene expression, and tumor progression will be examined. If the drugs work as expected PTEN and neu tumors will be sensitive to these medications, while large T antigen tumors will not be. Because this assumption is likely to be over simplisticwe will monitor the state of cell signaling and gene expression in all three models before and after therapy. This information in combination with accurate measurements of tumor progression with MRI imaging will allow us to identify potential mechanisms resulting in heterogeneous responses to therapy.
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