Disruption of AKT Pathway for Cancer Intervention

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DESCRIPTION (provided by applicant): AKT is a major pathway to induce cell survival, growth and transformation. Three isoforms, AKT1, AKT2 and AKT3, have been identified from the AKT family. Frequent alterations of AKT, especially AKT2, have been detected in human malignancies. Ectopic expression of AKT induces chemo-resistance, whereas, dominant negative AKT sensitizes cells to chemotherapeutic drug-induced apoptosis. By screening the NCI diversity set that was derived from 140,000 compounds, we have recently obtained more than 30 compounds that significantly inhibited growth in AKT2-transformed, but not in pcDNA3-transfected NIH 3T3 cells. Further analyses show that two of them directly inhibited constitutively active AKT2 kinase activity, and another two directly decreased AKT phosphorylation. All four (4) compounds significantly inhibit growth in three (3) human cancer cell lines where the AKT pathway is altered. Based on these findings, we hypothesize that AKT is a critical therapeutic target for cancer intervention and that specific inhibitor(s) of AKT signaling will reduce tumorigenicity in tumors with elevated AKT activity. Since inhibition of AKT induces apoptosis in a range of mammalian cells, AKT inhibitor(s) could be effective, in combination with other anticancer drugs, for the treatment of tumors with other gene alterations. As accumulated studies show clearly biological/physiological function differences between three (3) isoforms of AKT, identification of inhibitor(s) for each isoform of AKT will enhance therapeutic efficacy and reduce side effects. The rationale for the proposed research is that AKT is frequently altered in human malignancy and that inhibition of AKT induces apoptosis and cell growth arrest. Therefore, development of specific AKT inhibitor(s) has great potential to improve cancer treatment and provide additional means to characterize the AKT signal transduction pathway. The objective of this project is to develop specific AKT inhibitors and evaluate their abilities to reverse malignant transformation of human tumors by disruption of the AKT pathway without gross toxicity. The specific aims are: (1) Validate AKT1, AKT2, and AKT3 as therapeutic targets in human cancer and identify lead compounds as potential disruptors of AKT by high-throughput screening of compounds from synthetic AKT substrate mimics and the NCI diversity set. (2) Determine the specificity of lead compounds in the inhibition of AKT pathway. (3) Examine the abilities of promising AKT inhibitor(s) to disrupt AKT signaling in intact cells and inhibit cell transformation by wild type and constitutively active AKT 1, AKT2 and AKT3. (4) Evaluate anti-tumor efficacy of active compounds in cell culture and animal models of human cancers where the PI3K/PTEN/AKT pathway is altered.