PHENYLBUTYRATE BIOACTIVITY ASSESSMENT IN PROSTATE CANCER

前列腺癌中苯丁酸生物活性评估

• 批准号: 2712891
• 负责人: Michael A Carducci
• 金额: $ 17.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2712891
• 关键词: bone imaging /visualization /scanning; butyrates; cell differentiation; clinical research; clinical trial phase I; drug administration rate /duration; drug resistance; drug screening /evaluation; enzyme activity; female; human subject; human therapy evaluation; interleukin 6; male; neoplasm /cancer chemotherapy; nuclear magnetic resonance spectroscopy; outcomes research; phenylcarboxylate; prostate neoplasms; prostate specific antigen; telomerase; vascular endothelial growth factors

DESCRIPTION: (Applicant's Description) Surrogate endpoints can be useful in phase I/II screening trials for identifying whether a new intervention is biologically active and for guiding decisions about whether the intervention is promising enough to justify a large definitive trial with clinically meaningful outcomes. Based on pre-clinical studies of biologic activity generated in the applicant's laboratory, sodium phenylbutyrate, an aromatic fatty acid, represents a potentially non-toxic, non-retinoid differentiating agent for use in the care of patients with prostate cancer and glioblastoma. To date, the role of differentiation therapy in the advanced, clinically progressing prostate cancer patient has not been defined or appropriately explored. Differentiation therapy lacks the allure of cytoreductive strategies and is likely to provide disease stabilization as a therapeutic endpoint. Given the projected, yet untested, endpoint of differentiation therapy using non-toxic agents, assessment of bioactivity is critical to the advancement and early clinical evaluation of agents such as phenylbutyrate. Two clinical trials evaluating continuous phenylbutyrate exposure, either through thrice daily oral administration (phase I), or by continuous intravenous infusion (phase II), provide the framework to develop, evaluate, and begin the process of validation of surrogate endpoints specific for prostate cancer in response to differentiation therapy. Specifically, the clinical trials will generate safety and toxicity data and efficacy data of phenylbutyrate in patients with prostate cancer. Using patient-derived samples, the laboratory aims to determine the patterns and the importance of cytokine alterations (IL-6, VEGF, ET-1), changes in prostate specific membrane antigen expression (PSMA, PSA), and the induction of cell cycle proteins associated with differentiation or growth arrest (p2lwaf1/cip, cyclin D1) in patients after phenylbutyrate treatment. Harvesting of large numbers of circulating, viable prostate cancer cells will provide the research material needed to assess in vivo inhibition of telomerase activity and effects of phenylbutyrate on cellular metabolism using NMR. These assays and quantitative bone scan imaging will be correlated with plasma phenylbutyrate levels, clinical response, and outcome in treated prostate cancer patients. This research application will provide new and clinically relevant information on differentiation therapy with phenylbutyrate and assessment of its bioactivity in patients with prostate cancer, as well as potentially identify useful surrogate endpoints of response and bioactivity.

描述：（申请人的描述） 替代终点可用于I/II期筛选试验， 确定新的干预措施是否具有生物活性， 指导决定干预是否有足够的希望， 证明一项具有临床意义结果的大型确定性试验是合理的。 基于 在申请人的临床前研究中产生的生物活性 实验室，苯丁酸钠，芳香族脂肪酸，代表一种 潜在无毒的非类视色素分化剂， 前列腺癌和胶质母细胞瘤患者的护理。 到目前为止，角色 分化治疗在先进的，临床进展前列腺 癌症患者尚未被定义或适当探索。 分化治疗缺乏细胞减灭策略的吸引力， 可能提供疾病稳定作为治疗终点。 给定 预测，但未经测试，分化治疗的终点， 无毒剂，生物活性的评估是至关重要的进展 以及对诸如苯丁酸盐的药剂的早期临床评价。 两 评价苯丁酸盐持续暴露的临床试验， 通过每日三次口服给药（I期），或通过连续 静脉输注（第二阶段），提供框架，以开发，评估， 并开始验证替代终点的过程， 前列腺癌对分化治疗的反应。 具体而言是 临床试验将产生安全性和毒性数据以及 苯丁酸在前列腺癌患者中的应用 使用患者来源的 样本，实验室旨在确定模式和重要性， 细胞因子改变（IL-6、VEGF、ET-1），前列腺特异性 膜抗原表达（PSMA、PSA）和细胞周期的诱导 与分化或生长停滞相关的蛋白质（p2 lwaf 1/cip， 细胞周期蛋白D1）。 收获大 大量的循环，活的前列腺癌细胞将提供 评估体内端粒酶活性抑制所需的研究材料 以及利用核磁共振技术研究苯丁酸盐对细胞代谢的影响。 这些 分析和定量骨扫描成像将与血浆 治疗前列腺患者的苯丁酸盐水平、临床应答和结局 癌症患者。 这项研究应用将提供新的和临床 关于苯丁酸盐的分化治疗的相关信息， 评估其在前列腺癌患者中的生物活性，以及 潜在地识别响应和生物活性的有用的替代终点。