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

辐射对前列腺雄激素受体表达和活性的影响

基本信息

批准号：
7902178
负责人：
MARK GARZOTTO
金额：
$ 27.71万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7902178
关键词：
Acute Androgen Receptor Androgen Suppression Androgens Apoptosis Biological Markers Biopsy Cell Cycle Arrest Cell physiology Clinical Clinical Markers Clinical Trials Conduct Clinical Trials DNA Data Evaluation Event Excision Repair Freezing Glare Goals Gonadotropin-Releasing Hormone Analog Harvest Homeostasis Human Induction of Apoptosis Insulin-Like Growth Factor I Knowledge Laboratories Ligands Link Maintenance Malignant Epithelial Cell Malignant neoplasm of prostate Mediating Morbidity - disease rate Outcome Pacific Northwest Patients Phase III Clinical Trials Pre-Clinical Model Principal Investigator Prostate Prostate carcinoma Prostate specific antigen measurement Prostate-Specific Antigen Prostatic Protein p53 Radiation Radiation Tolerance Radiation therapy Receptor Activation Receptor Inhibition Receptor Signaling Receptor Up-Regulation Reproduction spores Resistance Role Sampling Serum Signal Transduction Source Surrogate Markers TP53 gene Testing Therapeutic Intervention Time Tissues Transactivation Treatment Failure Treatment outcome Tumor Suppressor Genes Work base cancer cell high risk improved men mortality neoplastic cell novel preclinical study prevent programs protein expression radiation effect radiation resistance receptor receptor expression research study response selective androgen receptor modulator senescence tumor

项目摘要

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.

放疗失败是前列腺局限性患者发病和死亡的主要原因