Molecular Imaging of Akt Kinase Activity In Vivo
Hicks, Michael J.
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Understanding the processes that regulate cell death and cell survival is essential for the development of therapeutic strategies for the treatment of cancer. In this regard, targeting and inhibiting the activity of particular enzymes involved in cancer signaling pathways, or pathways that promote cell survival and proliferation, has particular significance. Akt is one specific enzyme kinase that has been shown to be a key mediator of abnormal cell survival and resistance to cancer therapy. When active, Akt is able to send signals to other cellular components and prevent the cell from undergoing otherwise fated self-destruction. Presently, researchers are designing drugs that inhibit this cancer-inducing Akt kinase activity and that, therefore, encourage cell death. A difficulty still remains however—determining Akt activity in vivo after treatment with an Akt inhibitor. To help facilitate this effort, we offer a novel technique to assess the therapeutic utility of inhibitors of this serine/threonine protein kinase. We have designed an Akt reporter that can be detected via non-invasive fluorescence imaging. To date, the reporter has not been shown to respond to Akt activity in vivo, however. It is posited that, due to an overexpression of Akt reporter, the Akt inhibition assay produced cellular fluorescence independent of Akt phosphorylation. A reduced expression of the Akt reporter may lead to phosphorylation-dependent fluorescence. If so, we propose that this reporter will allow accurate observation of Akt activity in cells following the administration of a specific Akt-inhibiting anti-cancer drug and therefore will provide insight into a drug’s therapeutic potential. Future work with this reporter will allow it to be imaged in living mice and with more sensitive imaging modalities such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT).