Mechanisms by Which the Type 1 Insulin-like Growth Factor Inhibition Enhances

前列腺癌的致死表型被称为雄激素非依赖性（Al），因为它发展为 在男性雄激素水平极低或检测不到雄激素的情况下进行去势后 小鼠模型中的水平。已经提出肽生长因子，例如胰岛素样生长因子， 通过IGF酪氨酸激酶受体（IGF-IR）的IGF因子（IGF）信号传导驱动Al表型。 最近的数据清楚地表明，雄激素受体（AR）的表达增加，在模型的Al 在人类组织中，AR在去势后主要保留在细胞核中。我们有 在雄激素受体中，用完全人IGF-IR单克隆抗体显示IGF-IR信号传导的抑制， 依赖性（AD）和Al疾病减少核AR，改变AR转录程序， 延缓去势后Al病的出现。在本提案中，我们将确定 IGF/AR相互作用的机制和抑制这些相互作用对人类的功效 肿瘤的假设：胰岛素样生长因子信号转导有助于雄激素的进展- 依赖性[1]和雄激素不敏感性[2]前列腺癌进展通过增强AR核 定位和AR信号。 目标1。确定在一个阶段中使用人IGF-IR单抗联合去势的效果 1b/ll新辅助试验。这一目标将利用hmabs阻断IGF-IR的潜在用途， 与去势作为前列腺癌的潜在治疗方式相关。为此，我们将 利用临床和组织终点。 目标二。目标2. IGF信号通路改变前列腺癌雄激素受体核转位 通过AR磷酸化的变化。在这个目标中，我们将[1]确定是否改变 AR的磷酸化与AR的核输入或输出的改变有关，[2] 确定哪个AR磷酸化位点被IGF-IR信号改变是导致 AR的核定位。[3].确定IGF-IR信号改变AR的机制 磷酸化 目标3。确定AR磷酸化的变化对AR共- 调节子和AR转录模式的变化。在初步数据中，我们注意到， 通过抑制IGF-IR信号传导改变AR磷酸化导致AR 相关的辅助因子。其中最值得注意的是SMRT和BRCA 1。为此，我们将 [1]，对相关的协同调节因子进行更全面的评估，[2]确定协同调节因子的影响， 影响AR易位的因素，[3]确定相关辅助因子对AR的影响 转录活性和AR转录程序。 这项研究与改善前列腺癌治疗目标的相关性在于， 我们收集的实验室数据表明，用人胰岛素样生长因子受体抑制剂抑制IGF-IR， 单克隆抗体消除前列腺癌进展，并将其应用于患者环境， 确定其在临床疾病中的潜在功效。

The lethal phenotype of prostate cancer is termed androgen-independent (Al), because it develops following castration in the presence of very low levels of androgen in men or undetectable androgen levels in mouse models. It has been suggested that peptide growth factors, e.g.insulin-like growth factors (IGF) signaling through the IGF tyrosine kinase receptor (IGF-IR), drive the Al phenotype. Recent data clearly demonstrates that androgen receptor (AR) expression is increased in models of Al disease and that in human tissue the AR remains primarily in the nucleus after castration. We have shown inhibition of IGF-IR signaling, with a fully human IGF-IR monoclonal antibody, in androgen- dependent (AD) and Al disease decreases nuclear AR, modifies the AR transcriptional program, and delays emergence of Al disease following castration. In this proposal we will determine the mechanisms of the IGF/AR interaction and efficacy of inhibition of these interactions on human tumors. Hypothesis: Insulin-like growth factor signaling contributes to progression of androgen- dependent [1] and androgen-insensitive [2] prostate cancer progression by enhancing AR nuclear localization and AR signaling. Aim 1. Determine effect of utilizing a human IGF-IR mab combined with castration in a phase 1b/ll neoadjuvant trial. This aim will exploit the potential use of IGF-IR blockade using hmabs in association with castration as a potential treatment modality for prostate cancer. In this aim we will utilize both clinical and tissue endpoints. Aim 2. Aim 2. IGF signaling alters androgen receptor nuclear translocation in prostate cancer through changes in AR phosphorylation. In this aim we will [1] determine if the change in phosphorylation of the AR is associated with an alteration in nuclear import or export of the AR and [2] determine which AR phosphorylation site altered by IGF-IR signaling is responsible for the change in nuclear localization of the AR. [3].Determine the mechanism by which IGF-IR signaling alters AR phosphorylation. Aim 3. Determine the effects of changes in AR phosphorylation on association of AR co- regulators and changes in AR transcription patterns. In the Preliminary Data, we note that alteration of AR phosphorylation by inhibition of IGF-IR signaling results in an alteration of AR associated co-factors. Most notably among the cofactprs were SMRT and BRCA1. In this aim we will [1], perform a more completed assessment of associated co-regulators, [2] determine effects of co- factors on AR translocation, and [3] determine effects of the associated co-factors on AR transcriptional activity and the AR transcriptional program. The relevance of this study to the goal of improving treatment for prostate cancer is that it will take the laboratory data we have assembled demonstrating that the inhibition of the IGF-IR with a human monoclonal antibody abrogates prostate cancer progression and apply it in a patient setting to determine its potential efficacy in clinical disease.