PS-341 in Hepatocellular Carcinoma: A Phase II Trial

描述（由申请人提供）：肝细胞癌是一种世界范围内常见的恶性肿瘤，目前在美国的发病率明显上升，仍然是一种致命的疾病，对于不可切除的疾病，几乎没有治疗选择。关键调节蛋白核因子κ b （nf - κ b）的激活似乎在肝细胞癌的发生、生长和扩散中起重要作用。PS-341是一种蛋白酶体26S抑制剂，作为一种抗癌药物正在被研究。PS 341通过抑制蛋白酶体26S，阻止ikappabα的泛素化和降解，ikappabα仍然与NF-？B，阻止NF-?B的活化。然而，蛋白酶体26S与几种在恶性肿瘤中起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（如mip1 - α、groα、IL-8和IL-1）和生长因子（如血管内皮生长因子（VEGF））的表达。本提案旨在首先了解PS-341在肝细胞癌患者的II期临床试验中的临床效果（毒性和疗效）。此外，还将检测白细胞和患者血清中ps341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（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ps341对I(B)磷酸化、NF-kappaB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的首先是确定PS 341是否会影响其在肿瘤细胞中的预期靶标，其次是确定血清或白细胞参数是否有可能成为生物活性的潜在标记物，值得在更大规模的试验中进一步研究。

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.