Recent advances in elucidating the molecular defects underlying prostate carcinogenesis provide a foundation for the molecular targeting of defective cellular pathways with novel agents that will prevent or delay progression of this disease. Our laboratory has developed small-molecule, orally bioavailable inhibitors of two clinically relevant targets of prostate cancer initiation and progression: Akt signaling and Bcl-xL/Bcl-2. Our mechanistic studies of the anticancer effects of celecoxib and troglitazone revealed that their apoptosis-inducing actions are independent of their well-known pharmacological activities (COX-2 inhibition and PPAR? activation). Subsequent structural optimization of celecoxib and troglitazone generated novel analogues devoid of COX-2 inhibitory and PPAR? activating effects, but possessing potent inhibitory effects on Akt signaling and Bcl-2/Bcl-xL functions, respectively. We hypothesize that Akt signaling and Bcl-2/Bcl-xL functions represent clinically relevant targets for prostate cancer prevention. Moreover, we postulate that the relationship between Akt and Bcl-2/Bcl-xL in modulating apoptosis can be exploited with the combination of Akt- and Bcl-2/Bcl-xL-targeted agents to induce mechanistic synergy in the prevention of prostate carcinogenesis. The proposed studies will address these hypotheses through the use of an established model of prostate carcinogenesis to achieve the following Specific Aims. 1) To demonstrate that the novel Akt signaling inhibitor OSU-03012 inhibits prostate carcinogenesis in the NMU and TRAMP models. 2) To perform structural optimization of troglitazone-derived Bcl-2/Bcl-xL binding inhibitors through contemporary medicinal chemistry techniques and to further characterize mechanisms. 3) To demonstrate the in vivo chemopreventive efficacy of troglitazone-derived Bcl-2/Bcl-xL inhibitors and to exploit the mechanistic synergy between Akt inhibition and Bcl-2/Bcl-xL inhibition in prostate carcinogenesis. These studies represent the first translation of our in vitro observations to an in vivo model of prostate cancer prevention. Endpoints of tumor incidence will be complemented by examination of biomarkers that will provide in vivo correlations for the activities and mechanisms established in our in vitro studies. We expect the proposed studies to yield data in support of our hypothesis and to serve as a critical step in developing new approaches to prostate cancer prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112250-05
Application #
7617624
Study Section
Special Emphasis Panel (ZRG1-ONC-B (02))
Program Officer
Perloff, Marjorie
Project Start
2005-06-01
Project End
2010-11-30
Budget Start
2009-05-01
Budget End
2010-11-30
Support Year
5
Fiscal Year
2009
Total Cost
$279,963
Indirect Cost
Name
Ohio State University
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Himmel, Lauren E; Lustberg, Maryam B; DeVries, A Courtney et al. (2016) Minocycline, a putative neuroprotectant, co-administered with doxorubicin-cyclophosphamide chemotherapy in a xenograft model of triple-negative breast cancer. Exp Toxicol Pathol 68:505-515
Chou, Chih-Chien; Chuang, Hsaio-Ching; Salunke, Santosh B et al. (2015) A novel HIF-1?-integrin-linked kinase regulatory loop that facilitates hypoxia-induced HIF-1? expression and epithelial-mesenchymal transition in cancer cells. Oncotarget 6:8271-85
Dokla, Eman M E; Fang, Chun-Sheng; Lai, Po-Ting et al. (2015) Development of Potent Adenosine Monophosphate Activated Protein Kinase (AMPK) Activators. ChemMedChem 10:1915-23
Berman-Booty, Lisa D; Thomas-Ahner, Jennifer M; Bolon, Brad et al. (2015) Extra-prostatic transgene-associated neoplastic lesions in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Toxicol Pathol 43:186-97
Girard, Emily; Ditzler, Sally; Lee, Donghoon et al. (2015) Efficacy of cabazitaxel in mouse models of pediatric brain tumors. Neuro Oncol 17:107-15
Chou, Chih-Chien; Salunke, Santosh B; Kulp, Samuel K et al. (2014) Prospects on strategies for therapeutically targeting oncogenic regulatory factors by small-molecule agents. J Cell Biochem 115:611-24
Lai, I-Lu; Chou, Chih-Chien; Lai, Po-Ting et al. (2014) Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells. Carcinogenesis 35:2203-13
Chuang, Hsiao-Ching; Chou, Chih-Chien; Kulp, Samuel K et al. (2014) AMPK as a potential anticancer target - friend or foe? Curr Pharm Des 20:2607-18
Chou, Chih-Chien; Lee, Kuen-Haur; Lai, I-Lu et al. (2014) AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res 74:4783-95
Ma, Yihui; McCarty, Samantha K; Kapuriya, Naval P et al. (2013) Development of p21 activated kinase-targeted multikinase inhibitors that inhibit thyroid cancer cell migration. J Clin Endocrinol Metab 98:E1314-22

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