PS-341 in Hepatocellular Carcinoma: A Phase II Trial

PS-341 在肝细胞癌中的应用：II 期试验

• 批准号: 6690699
• 负责人: JORDAN D BERLIN
• 金额: $ 31.35万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-18 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6690699
• 关键词: I kappa B beta; antineoplastics; biomarker; clinical research; clinical trial phase II; cytokine; drug screening /evaluation; growth factor; hepatocellular carcinoma; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; nuclear factor kappa beta; patient oriented research; proteasome; protein localization

DESCRIPTION (provided by applicant): Hepatocellular carcinoma, a common malignancy worldwide, now with apparently increasing incidence in the United States, remains a deadly disease with few, if any, treatment options for unresectable disease. Activation of a key regulatory protein, nuclear factor kappaB (NF-kappaB) appears to be important in the development, growth and spread of hepatocellular carcinoma. PS-341, a proteasome 26S inhibitor, is being studied as an anticancer agent. By inhibiting proteasome 26S, PS 341 prevents the ubiquitination and degradation of IkappaBalpha, which remains bound to NF-?B, preventing activation of NF-?B. However, proteasome 26S interacts with several cellular proteins that play a role in malignancy, including p21, p27, p53, Bax and Bcl-2. NF-kappaB increases expression of chemokines/cytokines (e.g. MIP1-alpha, GROalpha, IL-8, and IL-1), and on growth factors such as vascular endothelial growth factor (VEGF). This proposal is designed first to learn the clinical effects (toxicity and efficacy) of PS-341 when administered in a phase II trial to patients with hepatocellular carcinoma. In addition, white blood cells and patient sera will be tested for effects of PS 341 on phosphorylation of IkappaBalpha, nuclear localization of NF-kappaB, apoptosis, and effects on chemokines and growth factors in serum. These will be correlated with clinical parameters (efficacy and toxicity) as well as effects in tumor tissue. Tumor tissue will be analyzed for PS 341 effects on phosphorylation of I(B(, nuclear localization of NF-kappaB, apoptosis, and other key regulatory proteins, p21, p27, p53, Bax, and Bcl-2. The goal of these laboratory evaluations is to determine first, if PS 341 appears to be affecting its anticipated target in tumor cells, and second, if any of the serum or WBC parameters appear to be potential markers of biologic activity worthy of further study on larger trials.

描述（由申请人提供）：肝细胞癌是世界范围内的一种常见恶性肿瘤，目前在美国的发病率明显增加，它仍然是一种致命的疾病，对于不可切除的疾病几乎没有治疗选择。关键调节蛋白核因子 kappaB (NF-kappaB) 的激活似乎在肝细胞癌的发生、生长和扩散中发挥着重要作用。 PS-341 是一种蛋白酶体 26S 抑制剂，目前正在研究作为抗癌剂。通过抑制蛋白酶体 26S，PS 341 防止 IkappaBalpha 泛素化和降解，IkappaBalpha 仍与 NF-κB 结合，从而防止 NF-κB 激活。然而，蛋白酶体 26S 与多种在恶性肿瘤中发挥作用的细胞蛋白相互作用，包括 p21、p27、p53、Bax 和 Bcl-2。 NF-kappaB 增加趋化因子/细胞因子（例如 MIP1-α、GROα、IL-8 和 IL-1）以及生长因子（例如血管内皮生长因子 (VEGF)）的表达。该提案首先旨在了解 PS-341 在 II 期试验中对肝细胞癌患者给药时的临床效果（毒性和功效）。此外，还将测试白细胞和患者血清中 PS 341 对 IkappaBalpha 磷酸化、NF-kappaB 核定位、细胞凋亡的影响以及对血清中趋化因子和生长因子的影响。这些将与临床参数（功效和毒性）以及对肿瘤组织的影响相关。将分析肿瘤组织的 PS 341 对 I(B( 磷酸化、NF-kappaB 核定位、细胞凋亡和其他关键调节蛋白、p21、p27、p53、Bax 和 Bcl-2) 的影响。这些实验室的目标评估的目的是首先确定 PS 341 是否似乎影响其在肿瘤细胞中的预期靶点，其次确定是否有任何血清或 WBC 参数似乎是值得进一步研究的生物活性的潜在标志物在更大的试验中。