PHENYLBUTYRATE BIOACTIVITY ASSESSMENT IN PROSTATE CANCER

描述：(申请人描述) 替代终点在I/II期筛查试验中非常有用 确定一种新的干预措施是否在生物学上是活跃的 关于干预是否有足够前景的指导性决定 证明一项具有临床意义的结果的大型决定性试验是合理的。基座 关于申请者体内产生的生物活性的临床前研究 实验室里，苯丁酸钠，一种芳香脂肪酸，代表着一种 潜在无毒、非维甲酸的分化剂，用于 前列腺癌和胶质母细胞瘤患者的护理。到目前为止，角色 辨证治疗在进展期晚期前列腺癌中的应用 癌症患者还没有被定义，也没有得到适当的探索。 分化治疗缺乏细胞减少策略的诱惑力， 可能提供疾病稳定作为治疗终点。vt.给出 预期的，但未经测试的，分化治疗的终点 无毒药物，生物活性的评估是进步的关键 以及苯丁酸酯等药物的早期临床评估。二 评估持续苯丁酸酯暴露的临床试验 每日三次口服(第一阶段)，或连续服用 静脉输液(第二阶段)，提供开发、评估、 并开始验证特定于 前列腺癌对分化治疗的反应。具体地说， 临床试验将产生安全性和毒性数据以及疗效数据 前列腺癌患者的苯丁酸酯。使用患者派生的 样本，实验室的目的是确定模式和重要性 细胞因子变化(IL-6、VEGF、ET-1)、前列腺特异性 膜抗原表达(PSMA、PSA)与细胞周期的诱导 与分化或生长停滞相关的蛋白质(p2lwaf1/CIP， 在苯丁酸盐治疗后的患者中，细胞周期蛋白D1)。收割大型 循环中的、有活力的前列腺癌细胞的数量将为 评估体内端粒酶活性抑制所需的研究材料 用核磁共振技术研究了苯丁酸酯对细胞代谢的影响。这些 化验和定量骨扫描成像将与血浆相关 治疗前列腺癌患者的苯丁酸酯水平、临床反应和预后 癌症患者。这一研究应用将为临床提供新的 关于丁酸苯酯和丁酸苯酯辨证治疗的相关信息 前列腺癌患者对其生物活性的评价 潜在地确定有用的反应和生物活性的替代终点。

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.