PS-341 in Hepatocellular Carcinoma: A Phase II Trial

描述（由申请人提供）：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增加，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。核因子-κ B（NF-κ B）是一种重要的调节蛋白，其激活在肝细胞癌的发生、生长和扩散中起重要作用。PS-341是一种蛋白酶体26 S抑制剂，正在研究作为抗癌剂。通过抑制蛋白酶体26 S，PS 341防止泛素化和降解的IkappaB α，这仍然结合到NF-？B，阻止NF-？B。然而，蛋白酶体26 S与在恶性肿瘤中起作用的几种细胞蛋白相互作用，包括p21、p27、p53、Bax和Bcl-2。NF-κ B增加趋化因子/细胞因子（例如MIP 1-α、GRO α、IL-8和IL-1）的表达，并增加生长因子如血管内皮生长因子（VEGF）的表达。本提案首先旨在了解PS-341在II期试验中对肝细胞癌患者给药的临床效果（毒性和疗效）。此外，将检测白色血细胞和患者血清中PS 341对I κ B α磷酸化、NF-κ B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（疗效和毒性）以及对肿瘤组织的影响相关。将分析肿瘤组织中PS 341对I β B β磷酸化、NF-κ B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。这些实验室评价的目的是首先确定PS 341是否影响其在肿瘤细胞中的预期靶点，其次确定任何血清或WBC参数是否是值得在大型试验中进一步研究的生物活性的潜在标志物。

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.