Maximal Targeted Inhibition of Androgen Signaling for Prostate Cancer Therapy

前列腺癌治疗中雄激素信号传导的最大靶向抑制

• 批准号: 7684771
• 负责人: PETER NELSON
• 金额: $ 21.51万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 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/7684771
• 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; End Point; Environment; Epithelium; Failure; Flutamide; Gene Expression; Growth; Histology; Hormones; Laboratories; Localized; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measurement; Measures; Mediating; Metastatic Prostate Cancer; Molecular; Neoadjuvant Therapy; Organ; Pathway interactions; Physiological; Plastics; Play; Principal Investigator; Proliferating; Prostate; Prostate Cancer therapy; Prostatic; Protein Biosynthesis; Receptor Inhibition; Receptor Signaling; Recurrence; Relapse; Research; Research Project Grants; Residual state; Role; Serum; Signal Transduction; Specific qualifier value; Staging; Stanolone; Testing; Testosterone; Therapeutic; Time; Tissues; base; cancer cell; clinical efficacy; concept; deprivation; design; disorder risk; neoplastic; neoplastic cell; novel; pre-clinical; prevent; programs; response; therapy design; tumor

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靶点。 已经设计了许多临床试验来干扰AR通路，但很少有实际的 通过证明最大靶点干扰来评估治疗的有效性。这项建议 目的是使用新辅助临床试验的形式，严格评估最大的有效性， 通过测量前列腺内雄激素水平来抑制雄激素，并以最大的 将DHT水平抑制为零。该方法的临床受益将通过以下方式进行评价： 肿瘤分级、分期、切缘、肿瘤细胞凋亡和雄激素调节基因的测定 表情其目标是： 目标1.确定达到特定（低）前列腺内雄激素水平的抗肿瘤疗效， 通过直接评估肿瘤活力、细胞凋亡、增殖抑制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的“去势”环境：（i）肾上腺雄激素的利用; (ii)主动雄激素转运;（iii）前列腺上皮肿瘤雄激素的cfenovo生物合成。 目标3.评价新靶向治疗的临床前疗效和活性机制 设计用于抑制睾丸、肾上腺和前列腺雄激素代谢和/或AR信号传导。 本研究项目的完成将：1）证明努力的有效性（或缺乏）， 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设计的其他方法提供背景。