Phase II Trial of PS341/Dox in Metastatic Breast Cancer

描述（由申请人提供）：NF-kB在乳腺癌的进展中起重要作用。在乳腺癌中已证实NF-kB水平升高，而周围组织水平正常。NF-kB是一种抗凋亡因子。它参与了血管生成、转移和防止细胞凋亡的基因激活。NF-kB通路的调控是通过IkB蛋白进行的。它通常存在于与IkB结合的细胞质中。激活导致IkB的泛素化和降解。NF-kB通路可以通过蛋白酶体抑制而改变。除NF-kB外，p21和p27在细胞周期中发挥重要作用。两者都促进细胞周期阻滞。这些基因的表达可在癌变过程中发生改变。与NF-kB类似，它们受蛋白酶体控制。蛋白酶体在细胞周期调控中起重要作用。它通常会降解以泛素化为标志的蛋白质。蛋白酶体的抑制导致泛素蛋白的积累，包括p21和p27。NF-kB活性随着蛋白酶体的抑制而降低。PS-341是蛋白酶体抑制剂。它已被证明在细胞培养和异种移植模型中具有临床活性。PS-341已被证明可以降低NF-kB活性并下调NF-k控制基因。PS-341也导致p21和p27的积累。I期试验表明，该药物单独或联合使用均具有抗肿瘤活性。PS-341和阿霉素的组合在异种移植模型中已被证明具有活性，而不改变任何一种药物的毒性。本申请旨在检验PS-341/多柔比星用于治疗转移性乳腺癌患者的临床疗效。它包括一个具有临床和生物学终点的II期试验。主要临床终点是总有效率。生物学终点旨在评估PS-341的生物学影响。评估5个终点：a) 20S蛋白酶体抑制；B)泛素蛋白偶联物的积累；C) p21和p27蛋白水平；d) UPA水平e) VEGF水平。

DESCRIPTION (provided by applicant): NF-kB plays an important role in the progression of breast cancer. Elevated levels of NF-kB have been demonstrated in breast cancer, with normal levels in the surrounding tissue. NF-kB is an anti-apoptotic factor. It is involved in the activation of genes responsible for angiogenesis, metastasis and preventing apoptosis. Regulation of the NF-kB pathway occurs through the protein IkB. It is normally found in the cytoplasm bound to IkB. Activation results in the ubiquination and degradation of IkB. The NF-kB pathway can be altered through proteasome inhibition. In addition to NF-kB, p21 and p27 play important roles in the cell cycle. Both promote cell cycle arrest. The expression of these genes can be altered in carcinogenesis. Similar to NF-kB, they are controlled by proteasome. The proteasome serves an important role in cell cycle regulation. It normally degrades proteins marked by ubiquination. Inhibition of proteasome results in the accumulation of ubiquinated proteins, including p21 and p27. NF-kB activity decreases with proteasome inhibition. PS-341 is a proteasome inhibitor. It has been shown to have clinical activity in cell cultures and xenograft models. PS-341 has been shown to decrease NF-kB activity and downregulate NF-k controlled genes. PS-341 also results in the accumulation of p21 and p27. Phase I trials have shown the agent to have antitumor activity, both alone and in combination. The combination of PS-341 and doxorubicin has been demonstrated to have activity in a xenograft model, without altering toxicity of either agent. This application proposes to examine the clinical efficacy of PS-341/doxrubicin when used at treatment for patients with metastatic breast cancer. It consists of a phase II trial with clinical and biologic endpoints. The primary clinical endpoint is overall response rate. The biologic endpoints seek to assess the biologic affect of PS-341. Five endpoints will be assessed: a) 20S proteasome inhibition; b) accumulation of ubiquinated protein conjugates; c) p21 and p27 protein levels; d) UPA levels and e) VEGF levels.