MECHANISM OF ACTION OF HERCEPTIN R IN BREAST CANCER

描述：(申请人摘要)HER-2 neu原癌基因产物是 在20%到30%的乳腺癌中过度表达，并与 临床结果更差。转移性肿瘤患者的临床证据 乳腺癌显示一种新的重组人对HER-2的干扰 DNA来源的人源化单抗rhumMabHer-2(Herceptin)可以导致 临床反应。为了进一步发展赫赛汀的临床应用，它将 重要的是要确定它在早期疾病中的有效性，在那里治愈是 还是有可能的。尽管细胞的作用机制还不完全 理解，这种有针对性的生物疗法针对的是一种分子决定因素 乳腺癌的研究代表了一个有希望的原型，可以提高乳腺癌的疗效 抗癌治疗。申请人希望更好地了解 赫赛汀的细胞反应将为临床最佳使用提供洞察力 这一受体靶向的策略，以及关于细胞内 抵抗她-2封锁。对这一机制的理解也可以 导致靶向关键部分的小分子的发展 这条途径对治疗效果很重要。这个项目有两个具体的 目标。第一个是证明赫赛汀的临床疗效。 多西紫杉醇作为新的辅助治疗。二是明确机制 细胞对赫赛汀的反应。对于特定的目标1，申请人 建议在局部癌症患者中进行一项新辅助临床试验 晚期HER-2过表达乳腺癌每周服用赫赛汀 最初作为单一药物，前三周，然后联合 在初选前每周服用赫赛汀和每周三次的多西紫杉醇 做手术。最后的手术标本将进行组织学检查。 完全响应，此响应率将作为已验证的 长期疗效的替代标记物。组织学完成度的增加 与既往的对照相比，这种疗法的缓解将提供 令人鼓舞的证据表明，赫赛汀和安慰剂有更大的治愈潜力 多西紫杉醇，特别是在佐剂环境中。对于特定目标2，按顺序 入选的患者将接受原发乳腺肿瘤的核心活检 在这项临床研究中。这些患者将在以下时间进行活检 诊断，在第一剂赫赛汀后24小时，就在 在第8天、第15天和第22天连续服用赫赛汀。这些核心活组织检查和 然后将评估手术中获得的肿瘤标本的效果。 Herceptin在以下区域的免疫组织化学分析： 增殖和细胞周期调控分子(Ki67、p27、细胞周期蛋白D1)， 细胞凋亡及其调控(TUNEL法、P53、bcl2、bax)，成分 抗体依赖细胞介导的细胞毒作用(淋巴细胞浸润性，NK 细胞、巨噬细胞)、血管生成(血管内皮生长因子和微血管密度)、HER-2水平 和它的磷酸化状态，以及乳腺细胞分化为 产奶表型(酪蛋白和乳脂的表达)。

DESCRIPTION: (Applicant's Abstract) The HER-2 neu proto-oncogene product is over-expressed in 20 percent to 30 percent of breast cancers and is associated with a worse clinical outcome. Clinical evidence in patients with metastatic breast cancer demonstrates that interference with HER-2 by a new recombinant DNA-derived humanized monoclonal antibody, rhumMabHer-2 (Herceptin) can lead to clinical responses. To further develop the clinical use of Herceptin, it would be important to define its efficacy in earlier stage disease, where cure is still possible. Although the cellular mechanisms of action are not fully understood, this targeted biologic therapy directed at a molecular determinant of breast cancer represents a promising prototype for improving the efficacy of anti-cancer treatment. The applicant expects that greater understanding of the cellular response to Herceptin will provide insight on the optimal clinical use of this receptor-targeted strategy, and on the mechanisms of cellular resistance to HER-2 blockade. The understanding of the mechanism could also lead to the development of small molecules targeting the critical portion of the pathway important for therapeutic effect. This project has two specific aims. The first is to demonstrate the clinical efficacy of Herceptin when given with docetaxel as neoadjuvant therapy. The second is to define the mechanisms of the cellular response to Herceptin. For Specific Aim 1, the applicant proposes to perform a neoadjuvant clinical trial in patients with locally advanced HER-2 over-expressing breast cancers with weekly Herceptin given initially as a single agent for the first three weeks, followed by combination of weekly Herceptin and three-weekly docetaxel for 12 weeks before primary surgery. The final surgical specimen would be examined for histological complete response, and the rate of this response would serve as a validated surrogate marker of long-term efficacy. An increase in histological complete remission with this regimen when compared to historical controls would provide encouraging evidence of the greater potential of cure with Herceptin and docetaxel, especially in the adjuvant setting. For Specific Aim 2, sequential core biopsies of the primary breast tumors will be taken in patients enrolled in this clinical study. These patients will have biopsies taken at time of diagnosis, 24 hours after the first dose of Herceptin, and just prior to subsequent doses of Herceptin on days 8, 15, and 22. These core biopsies and the tumor specimens obtained at surgery will then be assessed for the effects of Herceptin by immunohistochemical analysis in the following areas: proliferation and cell cycle regulatory molecules (Ki67, p27, cyclin D1), apoptosis and its regulation (TUNEL assay, p53, bcl-2, bax), components of antibody-dependent cell mediated cytotoxicity (lymphocytic infiltrate, NK cells, macrophages), angiogenesis (VEGF and microvessel density), HER-2 levels and its phosphorylation status, and breast cell differentiation into a milk-producing phenotype (expression of casein and milk lipids).