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目标。 已经设计了许多临床试验来干扰AR途径，但实际上很少有 通过证明最大目标干扰来评估治疗的有效性。这个建议 旨在使用新辅助临床试验格式严格评估最大的有效性 雄激素通过测量雄激素抑制雄激素，并靶向最大值 抑制DHT水平为零。这种方法的临床益处将通过 测量肿瘤等级，阶段，边缘，肿瘤细胞凋亡和雄激素调节的基因 表达。目的是： 目标1。确定达到特定（低）胸部内雄激素水平的抗肿瘤功效 通过直接评估肿瘤生存力，凋亡，增殖和抑制AR信号的抑制作用 雄激素调节的基因表达。 目标2。评估和比较能够维持雄激活的替代机制 原发性和转移性前列腺癌中的“ castrate”环境：（i）肾上腺雄激素的利用； （ii）主动雄激素转运； （iii）肿瘤前列腺上皮对雄激素的Cfenovo生物合成。 目标3。评估新靶向疗法的活动的临床前功效和机制 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（或缺乏）努力（或缺乏）努力 灌溉组织雄激素； 2）测量对特定雄激素水平和AR抑制作用的肿瘤反应；和 3）提供旨在针对AR的其他方法的背景。