MECHANISM OF ACTION OF HERCEPTIN R IN BREAST CANCER

描述：（申请人的摘要）HER-2 neu原癌基因产物是 在20%到30%的乳腺癌中过度表达， 临床结果更差。转移性乳腺癌患者的临床证据 乳腺癌表明，一种新的重组体干扰HER-2， DNA衍生的人源化单克隆抗体rhumMabHer-2（赫赛汀）可导致 临床反应。为了进一步开发赫赛汀的临床应用， 重要的是要确定其在早期疾病中的疗效， 还是有可能的虽然细胞的作用机制并不完全 据了解，这种靶向生物治疗针对的是一种分子决定因素， 乳腺癌的治疗代表了一个有希望的原型， 抗癌治疗。申请人希望更好地了解 对赫赛汀的细胞反应将提供关于最佳临床应用的见解 这种受体靶向的策略，以及细胞的机制， 对HER-2阻断的抗性。对该机制的理解也可以 导致小分子靶向的关键部分的发展， 对治疗效果很重要的途径。该项目有两个具体的 目标。首先是证明赫赛汀的临床疗效， 多西他赛作为新辅助治疗。二是明确机制 细胞对赫赛汀的反应对于具体目标1，申请人 建议在局部患者中进行新辅助治疗临床试验， 每周给予赫赛汀治疗的晚期HER-2过表达乳腺癌 最初作为前三周的单一药物，随后是联合用药 赫赛汀每周一次和多西他赛每周三次，持续12周， 手术最后的手术标本将进行组织学检查 完全响应，并且该响应的速率将作为验证的 长期疗效替代标志物。组织学完整性增加 与历史对照相比，该方案的缓解将提供 令人鼓舞的证据表明，赫赛汀具有更大的治愈潜力， 多西他赛，尤其是在辅助治疗中。对于特定目标2，顺序 将对入选患者进行原发性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，赫赛汀首次给药后24小时， 在第8、15和22天给予后续剂量的赫赛汀。这些核心活检和 然后对手术中获得的肿瘤标本进行效果评估， 通过免疫组织化学分析在以下区域检测赫赛汀： 增殖和细胞周期调节分子（Ki 67、p27、细胞周期蛋白D1）， 凋亡及其调控（TUNEL法，p53，bcl-2，bax）， 抗体依赖性细胞介导的细胞毒性（淋巴细胞浸润，NK 细胞、巨噬细胞）、血管生成（VEGF和微血管密度）、HER-2水平 和它的磷酸化状态，以及乳腺细胞分化成 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).