P-2: The Effect of Rad on Androgen Receptor Expression and Activity in Prostate

放射治疗失败是局限性前列腺癌患者发病率和死亡率的主要来源 癌症。基于临床前的研究，已经提出了几种辐射抵抗的机制。 然而，从人体研究中获得的数据有限。最近，雄激素受体(AR)已经 已被证明增加了前列腺癌细胞对多种治疗方法的耐药性。在初步研究中， 辐射诱导AR蛋白表达和前列腺特异性抗原(PSA)分泌。这一反应是 依赖于P53，这是最近被发现调节AR表达的分子。重要的是，辐射- 介导的AR反式激活是以非配体依赖的方式发生的。因此，传统的雄激素 在辐射过程中，抑制(AS)可能不能最大限度地抑制AR。我们假设AR的激活在 前列腺癌细胞耐受辐射。这个项目的长期目标是： I)确定AR活性在人前列腺癌辐射抵抗中的作用， Ii)开发一个平台，用于在接受放射治疗的患者中测试针对AR的新型药物， 三)利用这一平台发现新的组织和血清生物标记物，这将有助于改善 人前列腺癌的辐射敏感性。为了实现这些目标，我们建议重点关注三个方面 具体目标： 1.探讨放射治疗对前列腺癌患者AR表达和功能的影响 药理AS对AR轴信号转导的影响。 2.确定辐射介导的P53激活与AR表达和功能的临床相关性 前列腺癌。 3.检测血清中PSA、雄激素和IGF-1水平是否可以作为高血压的替代标志物。 辐射对前列腺癌细胞的影响。 为了研究这些影响，将在放射治疗之前和之后进行前列腺活检。的影响 对P53-AR信号的辐射和AS阻止AR激活的能力将通过比较确定 照射前后标本中P53和AR的表达。在辐射期间将采集血清样本以 确定是否可以使用基于血清的PSA和其他标记物分析来预测局部组织反应。 相关性：这些研究将评估辐射是否诱导临床前列腺癌AR的表达和活性 癌症，在临床前模型中观察到的。这些研究有望确定前列腺癌的一种新机制。 人类对癌症辐射的抵抗力，决定了AS在多大程度上能够克服抵抗力，以及 检查治疗期间的PSA系列检测是否可以作为放射治疗的实时临床标志 响应性。

Radiation-treatment failure is a major source of morbidity and mortality for men with localized prostate cancer. Based on pre-clinical studies, several mechanisms for radiation resistance have been proposed. However, only limited data are available from human studies. Recently, the androgen receptor (AR) has been shown to increase prostate cancer cell resistance to a host of therapies. In preliminary studies, radiation induced AR protein expression and prostate-specific antigen (PSA) secretion. This response was dependent on p53, a molecule recently recognized to modulate AR expression. Importantly, radiation- mediated AR transactivation occurred in a ligand-independent fashion. Thus, conventional androgen suppression (AS) may not maximally inhibit AR during radiation. We hypothesize that AR activation mediates prostate cancer cell radiation-resistance. The long-range GOALS of this project are: i) To determine the role of AR activity in the radiation resistance of human prostate cancer, ii) To develop a platform for testing novel agents against the AR in patients undergoing radiation therapy, iii) To employ this platform to discover novel tissue and serum biomarkers that will be useful in improving radiation sensitivity of human prostate cancer. To accomplish these goals we propose to focus on three SPECIFIC AIMS: 1. Determine the effect of radiation on AR expression and function in clinical prostate cancer, and the effect of pharmacologic AS on AR-axis signaling. 2. Determine the association of radiation-mediated p53 activation with AR expression and function in clinical prostate cancer. 3. To test whether levels of PSA, androgens and IGF-1 in serum can be used as surrogate markers of the effect of radiation on prostate cancer cells. To study these effects, prostate biopsies will be performed prior to and following radiation. The effect of radiation on p53-AR signaling and the ability of AS to prevent AR activation will be determined by comparing p53 and AR expression in pre- and post-radiation samples. Serum samples will be taken during radiation to determine if local tissue responses can be predicted using serum-based assays for PSA and other markers. Relevence: These studies will assess if radiation induces AR expression and activity in clinical prostate cancer, as observed in pre-clinical models. These studies promise to identify a novel mechanism of prostate cancer radiation-resistance in humans, determine to what extent AS is able to overcome resistance, and examine whether serial PSA testing during therapy could be a real-time clinical marker for radiation responsiveness.