Molecular Targeting of the P13K/Akt Pathway to Prevent the Development Hormone Resistant Prostate Cancer
Annual rept. 15 Jan 2006-14 Jan 2006
ARIZONA UNIV TUCSON
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Recently the Pl3KIAkt pathway has been found to be a significant factor in the development and progression of prostate cancer. It is our belief that the Pl3KAkt pathway is the critical pathway that is maintaining survival by blocking apoptosis in the absence of hormonal stimulation. We will use molecular targeting to inhibit the phosphorylation of Akt. Celecoxib is a FDA approved COX-2 inhibitor however unique to celecoxib is its ability to inhibit the phosphorylation of Akt. This effectively turns off the Pl3kIAkt pathway leading to apoptosis. Celecoxib has been shown to induce apoptosis in a number of different malignancies. Unfortunately the 1050 of celecoxib is less than usually clinically obtainable. Therefore in an attempt to improve upon the Akt activity and decrease the 1050 concentration to clinically obtainable levels Chin et al. synthesized multiple 2nd and 3rd generation compounds. These newer compounds have significantly lower 1050 and thus therapeutic levels can be obtained clinically. We will use celecoxib and these newer compounds to evaluate the effects of combined Pl3KAkt inhibition and androgen ablation.
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