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

前列腺癌的致命表型被称为雄激素非依赖性(Al)，因为它发生在 在男性雄激素水平很低或检测不到雄激素的情况下进行去势 小鼠模型中的水平。已有研究表明，多肽生长因子，如胰岛素样生长 通过IGF酪氨酸激酶受体(IGF-IR)传递信号的因子(IGF)驱动Al表型。 最近的数据清楚地表明雄激素受体(AR)在阿尔茨海默病模型中的表达增加。 疾病和人类组织中的AR在去势后主要保留在细胞核中。我们有 用全人IGF-IR单抗抑制雄激素中的IGF-IR信号 依赖(AD)和铝病降低核AR，修改AR转录程序，并 在去势后推迟铝病的出现。在这份提案中，我们将确定 胰岛素样生长因子/受体相互作用的机制及其对人体的抑制作用 肿瘤。假设：胰岛素样生长因子信号有助于雄激素的进展- 依赖[1]和雄激素不敏感[2]前列腺癌进展通过增强AR核 定位和AR信令。 目的1.确定在一个阶段使用人胰岛素样生长因子-IR单抗联合去势的效果 1B/11新辅助试验。这一目标将利用hmabs开发IGF-IR封锁的潜在用途 将去势作为前列腺癌的一种潜在治疗方式。为了实现这一目标，我们将 利用临床和组织终端。 目的2.目的2.前列腺癌中胰岛素样生长因子信号改变雄激素受体核转位 通过AR磷酸化的变化。在这个目标中，我们将[1]确定 AR的磷酸化与AR和[2]核进出口的改变有关 确定由IGF-IR信号改变的哪个AR磷酸化位点是导致 AR的核定位。[3]确定IGF-IR信号改变AR的机制 磷酸化。 目的3.确定AR磷酸化的变化对AR联合受体结合的影响。 调节因子和AR转录模式的变化。在初步数据中，我们注意到 抑制IGF-IR信号导致AR磷酸化改变导致AR改变 相关的辅助因素。最值得注意的是SMRT和BRCA1。为了实现这一目标，我们将 [1]，对相关的共同监管机构进行更完整的评估，[2]确定共同监管机构的影响 AR易位的因素，以及[3]决定相关辅助因素对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的目标的相关性在于，它将采取 我们收集的实验室数据表明，人对IGF-IR的抑制 单抗消除前列腺癌进展并将其应用于患者环境中 确定其在临床疾病中的潜在疗效。

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.