The Effect of Radiation on Androgen Receptor Expression and Activity in Prostate

放射治疗失败是局限性前列腺患者发病率和死亡率的主要原因 癌基于临床前研究，已经提出了几种辐射抗性的机制。 然而，只有有限的数据可从人类研究。最近，雄激素受体（AR） 已经显示出增加前列腺癌细胞对许多疗法的抵抗力。在初步研究中， 辐射诱导的AR蛋白表达和前列腺特异性抗原（PSA）分泌。这种反应是 依赖于p53，一种最近被认为调节AR表达的分子。重要的是，辐射- 介导的AR反式激活以配体非依赖性方式发生。因此，传统的雄激素 抑制（AS）可能不会在辐射期间最大限度地抑制AR。我们假设AR激活介导了 前列腺癌细胞辐射抗性。该项目的长期目标是： i）为了确定AR活性在人前列腺癌的辐射抗性中的作用， 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的新型药剂， iii）利用该平台发现新的组织和血清生物标志物，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.确定放射对临床前列腺癌中AR表达和功能的影响，以及 药理学AS对AR轴信号的影响。 2.确定放射介导的p53激活与临床中AR表达和功能的关系 前列腺癌 3.为了测试血清中PSA、雄激素和IGF-1的水平是否可以用作 放射对前列腺癌细胞的影响。 为了研究这些影响，将在放疗前后进行前列腺活检。的影响 辐射对p53-AR信号传导的影响以及AS阻止AR激活的能力将通过比较 p53和AR在辐射前和辐射后样品中的表达。将在辐射期间采集血清样本， 确定是否可以使用基于血清的PSA和其他标志物测定来预测局部组织反应。 相关性：这些研究将评估放射是否诱导临床前列腺中AR的表达和活性 癌症，如在临床前模型中观察到的。这些研究有望确定前列腺增生的新机制， 人类的癌症辐射抗性，确定AS在多大程度上能够克服抗性， 检查治疗期间的系列PSA检测是否可以作为放射治疗的实时临床标志物 响应能力。

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.