The PTEN/PISK/AKtpathway is a critical regulator of prostate carcinogenesis. Loss of the lipid phosphatase activity of PTEN and constitutive activation of phosphoinositide-3 kinase and Akt occur in high-grade and metastatic prostate cancers at high frequency. In the initial grant period we modeled the consequences of Akt activation in the murine prostate by developing a transgenicline (AKT1-Tg) where expressionof myristoylated, and hence activated human AKT1 is spatially restricted to the ventral prostate. These mice develop a highly penetrant prostatic intraepithelial neoplasia phenotype {Majumder, 2003 #1171}. We showed 1) that the phenotype is completely mTOR dependent {Majumder, 2004 #1170} 2) that the Hif1 D pathway is activated downstream of mTOR in this model and can acts as pharmacodynamic marker of mTOR activity;3) that phosphorylation of eiF4G is a robust tissue marker of mTOR activity in mice and in humans {Majumder, 2004 #1170} (Tabernero et. al., in prep.);4) that p27 acts as a phenotype checkpoint limiting progression to invasive cancer (Majumder et. al.,submitted), and 5) have confirmed the discovery of TMPRSS2:ERG translocation, and shown that this frequently co-occurs with PTEN deletion and that the endogenous TMPRSS2 transcript is regulated by mTOR signaling. Based on these data and other data illustrated in the preliminary data section we propose:
Specific Aim 1 : To validate pharmacodynamic signatures of mTOR activity in murine prostate models of PI3K pathway activation. To validate refined signatures of mTOR activity in clinical samples obtained in a clinical trial of RAD001 in prostate cancer patients.
Specific Aim 2 : To identifying a """"""""response"""""""" signature in the AKT1-Tg model mouse. To cross-validate the response signature in murine models of PTEN loss and/or PI3K activation. To initiated validation studies in human plasma and prostate cancer samples.
Specific Aim 3 : To determine whether PI3K/AKT/mTOR pathway activation and TMPRSS2:ERG cooperate to induce transformation of the murine prostate.
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