The Role of AKT in Prostate Cancer

PTEN/Pisk/AKt通路是前列腺癌发生的关键调控因子。脂磷酸酶的丧失 PTEN活性和肌醇磷脂-3激酶和Akt的结构性激活在高级别和 转移性前列腺癌高发。在最初的资助期，我们模拟了 AKT在小鼠前列腺中的激活作用 肉豆蔻酰化，因此激活的人AKT1在空间上局限于前列腺腹侧。这些老鼠 形成一种高度穿透性的前列腺上皮内瘤变表型(Maumder，2003#1171)。我们 结果表明：1)表型完全依赖于HIF1 D 在该模型中，通路在mTOR下游被激活，并可作为 MTOR活性；3)eiF4G磷酸化是小鼠和小鼠体内mTOR活性的一个强有力的组织标志物 人类(Majumder，2004#1170)(Tabernero et.4)p27作为一个表型检查点 限制浸润性癌症的进展(Majumder et.Al.，提交)和5)已确认发现 TMPRSS2：ERG易位，并表明这种情况经常与PTEN缺失同时发生，并且 内源性TMPRSS2转录本受mTOR信号调控。 根据这些数据和初步数据部分说明的其他数据，我们建议： 具体目标1：验证mTOR活性在PI3K小鼠前列腺模型中的药效学特征 途径被激活。验证临床样本中mTOR活性的改进特征 RAD001在前列腺癌患者中的试验。 具体目标2：识别AKT1-TG模型小鼠的“反应”特征。要交叉验证 PTEN缺失和/或PI3K激活小鼠模型的反应特征。在以下项目中启动验证研究 人体血浆和前列腺癌样本。 特异性目标3：确定PI3K/AKT/mTOR通路激活与TMPRSS2：ERG是否协同 来诱导小鼠前列腺的转化。

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.