The Role of AKT in Prostate Cancer

PTEN/PISK/Akt通路是前列腺癌发生的关键调节因子。脂质磷酸酶丧失 PTEN的活性以及磷酸肌醇-3激酶和Akt的组成性激活发生在高级别和高水平的细胞中， 高频率的转移性前列腺癌。在最初的赠款期间，我们模拟了 通过开发转基因株（AKT 1-Tg）在鼠前列腺中激活Akt， 豆蔻酰化的，因此活化的人AKT 1在空间上局限于腹侧前列腺。这些小鼠 形成高度渗透性前列腺上皮内瘤形成表型{Majumder，2003 #1171}。我们 表明1）表型完全依赖于mTOR {Majumder，2004 #1170} 2）Hif 1 D 在该模型中，mTOR的下游激活了mTOR通路，并且可以作为 mTOR活性; 3）eIF 4G磷酸化是小鼠和哺乳动物中mTOR活性的稳健组织标记物， 人类{Majumder，2004 #1170}（Tabernero et.例如，in prep.）; 4)p27作为一个表型检查点 限制进展为侵袭性癌症（Majumder et.例如，（5）已确认发现 TMPRSS 2：ERG易位，并显示这经常与PTEN缺失共同发生，并且TMPRSS 2：ERG易位的表达与PTEN缺失的表达相关。 内源性TMPRSS 2转录物受mTOR信号传导调节。 根据这些数据和初步数据部分中说明的其他数据，我们建议： 具体目的1：验证PI 3 K的鼠前列腺模型中mTOR活性的药效学特征 通路激活为了验证在临床试验中获得的临床样品中mTOR活性的精确特征， RAD 001在前列腺癌患者中的试验。 具体目标2：鉴定AKT 1-Tg模型小鼠中的“应答”特征。为了交叉验证 在PTEN缺失和/或PI 3 K活化的鼠模型中的应答信号。启动验证研究， 人血浆和前列腺癌样品。 具体目标3：确定PI 3 K/AKT/mTOR通路激活和TMPRSS 2：ERG是否协同作用 以诱导鼠前列腺的转化。

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.