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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107078-06
Application #
7426857
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Lees, Robert G
Project Start
2004-08-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2010-05-31
Support Year
6
Fiscal Year
2008
Total Cost
$382,942
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
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Kim, Donghwa; Shu, Shaokun; Coppola, Marc D et al. (2010) Regulation of proapoptotic mammalian ste20-like kinase MST2 by the IGF1-Akt pathway. PLoS One 5:e9616
Kim, Donghwa; Sun, Mei; He, Lili et al. (2010) A small molecule inhibits Akt through direct binding to Akt and preventing Akt membrane translocation. J Biol Chem 285:8383-94
Zhao, Jian-Jun; Lin, Jianhong; Lwin, Tint et al. (2010) microRNA expression profile and identification of miR-29 as a prognostic marker and pathogenetic factor by targeting CDK6 in mantle cell lymphoma. Blood 115:2630-9
Mohapatra, Subhra; Chu, Baoky; Zhao, Xiuhua et al. (2009) Apoptosis of metastatic prostate cancer cells by a combination of cyclin-dependent kinase and AKT inhibitors. Int J Biochem Cell Biol 41:595-602
Guo, Jian-Ping; Shu, Shao-Kun; He, Lili et al. (2009) Deregulation of IKBKE is associated with tumor progression, poor prognosis, and cisplatin resistance in ovarian cancer. Am J Pathol 175:324-33
Kayser-Bricker, Katherine J; Glenn, Matthew P; Lee, Sang Hoon et al. (2009) Non-peptidic substrate-mimetic inhibitors of Akt as potential anti-cancer agents. Bioorg Med Chem 17:1764-71
Zhao, Jian-Jun; Lin, Jianhong; Yang, Hua et al. (2008) MicroRNA-221/222 negatively regulates estrogen receptor alpha and is associated with tamoxifen resistance in breast cancer. J Biol Chem 283:31079-86
Cheng, George Z; Park, Sungman; Shu, Shaokun et al. (2008) Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery. Curr Cancer Drug Targets 8:2-6
Kong, William; Yang, Hua; He, Lili et al. (2008) MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol 28:6773-84

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