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(申请人提供)：肝细胞癌是一种全球常见的恶性肿瘤，目前在美国的发病率明显上升，仍然是一种致命的疾病，对于无法切除的疾病几乎没有治疗选择。核转录因子kappaB(NFkappaB)的激活在肝细胞癌的发生、发展和扩散过程中起重要作用。PS-341是一种蛋白酶体26S抑制剂，正在作为抗癌剂进行研究。PS 341通过抑制蛋白酶体26S，阻止IkappaBalpha的泛素化和降解，IkappaBalpha仍然与核因子-βB结合，防止核因子-βB的激活。然而，蛋白酶体26S与几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。核因子-kappaB增加趋化因子/细胞因子(如MIP1-α、GROAlpha、IL-8和IL-1)和生长因子(如血管内皮生长因子(VEGF))的表达。这项建议首先是为了了解PS-341在II期试验中对肝细胞癌患者的临床效果(毒性和有效性)。此外，还将测试PS 341对IkappaBalpha的磷酸化、NF-kappaB的核定位、细胞凋亡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(疗效和毒性)以及对肿瘤组织的影响相关。将分析PS 341对肿瘤组织I(B)的磷酸化、核因子-kappaB的核定位、细胞凋亡以及其他关键调控蛋白p21、p27、p53、Bax和Bcl-2的影响。这些实验室评估的目标是首先确定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参数似乎是值得在更大规模试验中进一步研究的潜在生物学活性标志。