P-5: Maximal Targeted Inhibition of Androgen Signaling for Prostate Ca Therapy

P-5：前列腺钙治疗中雄激素信号传导的最大靶向抑制

基本信息

批准号：
8330641
负责人：
PETER NELSON
金额：
$ 19.96万
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 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8330641
关键词：
Ablation Adjuvant Adrenal Glands Affinity Agonist Anabolism Androgen Antagonists Androgen Metabolism Androgen Receptor Androgen Suppression Androgens Apoptosis Bicalutamide Biochemical Biological Assay Castration Cell Proliferation Cell physiology Chemicals Clinical Clinical Research Clinical Trials Complement Development Disease Disease Resistance Effectiveness Environment Epithelium Failure Flutamide Gene Expression Growth Histology Hormones Laboratories Malignant neoplasm of prostate Mass Spectrum Analysis Measurement Measures Mediating Metastatic Prostate Cancer Molecular Neoadjuvant Therapy Organ Pacific Northwest Pathway interactions Physiological Plastics Play Principal Investigator Proliferating Prostate Prostatic Protein Biosynthesis Receptor Inhibition Receptor Signaling Recurrence Relapse Research Research Project Grants Residual state Role Serum Signal Transduction Staging Stanolone Testing Testosterone Therapeutic Time Tissues base cancer cell clinical efficacy deprivation design effectiveness measure high risk neoplastic neoplastic cell novel pre-clinical prevent programs response therapy design treatment strategy tumor

项目摘要

Clinical and laboratory evidence continues to demonstrate that androgens and the androgen receptor (AR) are the best available targets for treating/preventing both early and advanced prostate cancer. Numerous clinical trials have been designed to interfere with the AR pathway, but few have actually assessed the effectiveness of the therapy by demonstrating maximal target interference. This proposal aims to use a neoadjuvant clinical trial format to rigorously evaluate the effectiveness of maximal androgen suppression through measurements of intraprostatic androgen levels, and to target a maximal suppression of DHT levels to zero. The clinical benefit of this approach will be evaluated through measurements of tumor grade, stage, margin, tumor cell apoptosis and androgen-regulated gene expression. The aims are: Aim 1. To determine the anti-tumor efficacy of achieving specific (low) intraprostatic androgen levels and inhibition of AR-signaling through direct assessments of tumor viability, apoptosis, proliferation, and androgen-regulated gene expression. Aim 2. To evaluate and compare alternative mechanisms capable of maintaining androgen-activity in a 'castrate' environment in both primary and metastatic prostate cancer: (i) utilization of adrenal androgens; (ii) active androgen transport; (iii) cfenovo biosynthesis of androgens by neoplastic prostate epithelium. Aim 3. To evaluate the pre-clinical efficacy and mechanism(s) of activity of new targeted therapies designed to inhibit testicular, adrenal, and prostatic androgen metabolism and/or AR signaling. The completion of this research project will: 1) demonstrate the efficacy (or lack thereof) of efforts to ablate tissue androgens; 2) measure tumor responses to specific androgen levels and AR inhibition; and 3) provide a context for additional approaches designed to target the AR.

临床和实验室证据继续证明雄激素和雄激素受体 (AR) 是治疗/预防早期和晚期前列腺癌的最佳可用靶点。许多临床试验旨在干扰 AR 通路，但实际上很少有试验通过展示最大目标干扰来评估治疗的有效性。这个提议旨在使用新辅助临床试验形式来严格评估最大剂量的有效性通过测量前列腺内雄激素水平来抑制雄激素，并以最大目标为目标将 DHT 水平抑制为零。该方法的临床效益将通过以下方式进行评估肿瘤分级、分期、边缘、肿瘤细胞凋亡和雄激素调节基因的测量表达。目标是：目标 1. 确定达到特定（低）前列腺内雄激素水平的抗肿瘤功效和通过直接评估肿瘤活力、细胞凋亡、增殖和抑制 AR 信号传导雄激素调节的基因表达。目标 2. 评估和比较能够维持雄激素活性的替代机制原发性和转移性前列腺癌中的“阉割”环境：（i）肾上腺雄激素的利用； (ii) 主动雄激素运输； (iii)肿瘤性前列腺上皮雄激素的cfenovo生物合成。目标 3. 评估新靶向疗法的临床前疗效和活性机制旨在抑制睾丸、肾上腺和前列腺雄激素代谢和/或 AR 信号传导。该研究项目的完成将：1）证明努力的有效性（或缺乏有效性）消融组织雄激素； 2) 测量肿瘤对特定雄激素水平和 AR 抑制的反应；和 3) 为针对 AR 的其他方法提供背景。