P-4: Mechanisms by Which the T1 Insulin-like Growth Factor Inhibition Enhances

P-4：T1 胰岛素样生长因子抑制增强的机制

• 批准号: 8130549
• 负责人: Stephen R. Plymate
• 金额: $ 29.15万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8130549
• 关键词: Affect; Androgen Receptor; Androgens; Antibodies; Apoptosis; BRCA1 gene; Castration; Cell Nucleus; Clinical; Complementary DNA; Data; Disease; Genetic Transcription; Goals; Growth Factor; Growth Factor Inhibition; Human; Laboratories; Localized Disease; Malignant neoplasm of prostate; Modality; Modeling; Monoclonal Antibodies; Neoadjuvant Therapy; Nuclear; Nuclear Import; Nuclear Translocation; Pathologic; Patients; Pattern; Peptides; Phase; Phenotype; Phosphorylation; Phosphorylation Inhibition; Phosphorylation Site; Pre-Clinical Model; Prostatectomy; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recurrent disease; Signal Transduction; Somatomedins; Tissues; cofactor; deprivation; high risk; human monoclonal antibodies; human tissue; improved; men; mouse model; programs; receptor expression; response; tumor; tumor growth; tumor progression

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.

前列腺癌的致死表型被称为雄激素非依赖性 (Al)，因为它的发展 在男性雄激素水平极低或雄激素检测不到的情况下进行去势 小鼠模型中的水平。有人建议肽生长因子，例如胰岛素样生长 因子 (IGF) 通过 IGF 酪氨酸激酶受体 (IGF-IR) 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) 表达在 Al 模型中增加 疾病，并且在人体组织中，去势后 AR 主要保留在细胞核中。我们有 显示出在雄激素中使用完全人 IGF-IR 单克隆抗体可抑制 IGF-IR 信号传导 依赖性 (AD) 和 Al 疾病会降低核 AR，修改 AR 转录程序，并且 延迟去势后阿尔病的出现。在本提案中，我们将确定 IGF/AR 相互作用的机制以及抑制这些相互作用对人类的功效 肿瘤。假设：胰岛素样生长因子信号传导有助于雄激素的进展 通过增强 AR 核依赖性 [1] 和雄激素不敏感 [2] 前列腺癌进展 定位和 AR 信号。 目标 1. 确定在一个阶段中使用人 IGF-IR mab 与去势相结合的效果 1b/ll 新辅助试验。这一目标将利用 hmabs 来开发 IGF-IR 阻断的潜在用途。 与阉割作为前列腺癌潜在治疗方式的关联。为了这个目标我们将 利用临床和组织终点。 目标 2. 目标 2. IGF 信号传导改变前列腺癌中的雄激素受体核转位 通过 AR 磷酸化的变化。为了这个目标，我们将 [1] 确定是否发生变化 AR 的磷酸化与 AR 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 信号改变导致了 AR的核定位。 [3].确定IGF-IR信号传导改变AR的机制 磷酸化。 目标 3. 确定 AR 磷酸化的变化对 AR co-关联的影响 调节因子和 AR 转录模式的变化。在初步数据中，我们注意到 通过抑制 IGF-IR 信号传导改变 AR 磷酸化会导致 AR 改变 相关的辅因子。其中最值得注意的是 SMRT 和 BRCA1。为了这个目标我们将 [1]，对相关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] 确定相关辅因子对 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，它将采取 我们收集的实验室数据表明，人类对 IGF-IR 的抑制作用 单克隆抗体可消除前列腺癌的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。