GROWTH FACTOR RECEPTOR DIRECTED THERAPY IN CANCER

生长因子受体定向治疗癌症

• 批准号: 2101602
• 负责人: Richard Joseph Pietras
• 金额: $ 10.43万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2101602
• 关键词: DNA repair; adduct; alkylating agents; athymic mouse; autocrine; biological response modifiers; breast neoplasms; cis platinum compound; combination cancer therapy; cytotoxicity; drug interactions; drug resistance; gene expression; genetic manipulation; growth factor receptors; ligands; monoclonal antibody; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; ovary neoplasms; paracrine; protooncogene; receptor expression; transfection

Growth factors and their cell surface receptors are crucial for cell growth regulation. One or more erb B proto-oncogenes encoding EGF, HER-2 and HER-3 receptors are amplified and/or overexpressed in about two- thirds of human breast cancers. Overexpression of HER-2 receptor in human breast and ovarian cancer correlates with poor outcome and may predict response to chemotherapy in the clinic. A growth-regulatory circuit involving HER-2/neu receptor and autocrine/paracrine activation by heregulin, a newly-purified ligand, is postulated to advance malignancy. Monoclonal antibodies that bind HER-2 receptors exert a cytostatic effect in suppressing growth of cells with HER-2 overexpression. New laboratory work suggests that activation of HER-2/neu receptors by antireceptor antibody enhances cellular sensitivity to drugs that -damage DNA- and, thereby, maximizes tumor cell killing. Models of human breast and ovarian cancers with and without overexpression of HER-2 receptors or heregulin have been established in our laboratory and will be used to study: * Anticancer effects of a new humanized monoclonal antibody to HER-2/neu receptor alone and in combination with chemotherapeutic drugs (cisplatin and alkylators) that damage cellular DNA. Preclinical data will be collected on efficacy and treatment schedules for a humanized antibody to HER-2 receptor designed for use in clinical trials. The postulated therapeutic advantage of combined therapy with antireceptor antibody and cytotoxic drugs will be tested, with aims to optimize in vivo conditions for maximal cytocidal effects. This data-is required to continue ongoing clinical trials with these agents. * Clinical significance of HER-2/neu receptor or heregulin gene expression in drug resistance. To test the role of HER-2 gene in genesis of chemotherapy resistance, parental cells with single-copy, low expression of HER-2 gene and molecularly-engineered daughter cells with multi-copy, high expression of HER-2 gene will be compared for relative drug sensitivity. Tumor cells engineered for overexpression of heregulin will also be used to test effects of autocrine/paracrine activation of HER-2 on drug sensitivity. * Modulation of DNA repair in synergistic antitumor effects of antireceptor antibody and cisplatin. Measure of the formation and repair of cisplatin-DNA adducts and unscheduled DNA synthesis will be done to test the hypothesis that DNA repair pathways are altered by growth factor receptor signaling pathways. Effects of ligand or receptor overexpression and of antireceptor antibody will be compared. This basic and translational research approach is aimed toward continuation and support of clinical trials of a novel treatment option in breast and ovarian cancer. New knowledge on biologic actions of heregulin and HER-2 receptors will be applied toward new strategies to target and exploit overexpressed growth factor receptors at the surfaces of malignant cells.

生长因子及其细胞表面受体对于细胞的生长至关重要 生长调节。编码 EGF、HER-2 的一种或多种 erb B 原癌基因 HER-3受体在大约两种情况下被扩增和/或过度表达 人类乳腺癌的三分之一。人类 HER-2 受体过度表达 乳腺癌和卵巢癌与不良预后相关，并可预测 对临床化疗的反应。生长调节回路 涉及 HER-2/neu 受体和自分泌/旁分泌激活 调蛋白（heregulin）是一种新纯化的配体，被认为可以促进恶性肿瘤的发生。 结合 HER-2 受体的单克隆抗体发挥细胞抑制作用 抑制 HER-2 过度表达的细胞生长。新实验室 研究表明，抗受体药物可激活 HER-2/neu 受体 抗体增强细胞对损伤 DNA 药物的敏感性， 从而最大限度地杀死肿瘤细胞。人体乳腺和卵巢模型 存在或不存在 HER-2 受体或调蛋白过度表达的癌症 我们的实验室已建立，将用于研究： * 新型人源化单克隆抗体 HER-2/neu 的抗癌作用 单独使用受体以及与化疗药物（顺铂）联合使用 和烷基化剂）会损害细胞 DNA。临床前数据将 收集人源化抗体的功效和治疗方案 设计用于临床试验的 HER-2 受体。假设的 与抗受体抗体联合治疗的治疗优势 将测试细胞毒性药物，旨在优化体内条件 以达到最大的杀细胞作用。该数据需要继续进行 使用这些药物进行临床试验。 * HER-2/neu受体或heregulin基因的临床意义 表达于耐药性。测试 HER-2 基因在发生中的作用 化疗耐药性，亲本细胞具有单拷贝，低 HER-2基因的表达和分子工程子细胞 HER-2基因的多拷贝、高表达将进行相对比较 药物敏感性。为过度表达调蛋白而设计的肿瘤细胞 还将用于测试自分泌/旁分泌激活的效果 HER-2 对药物敏感性。 * 调节 DNA 修复的协同抗肿瘤作用 抗受体抗体和顺铂。形成和修复的测量 顺铂-DNA 加合物和计划外的 DNA 合成将进行 检验生长因子改变 DNA 修复途径的假设 受体信号通路。配体或受体过度表达的影响 将比较抗受体抗体的和。 这种基础和转化研究方法旨在 继续和支持新治疗方案的临床试验 在乳腺癌和卵巢癌中。生物作用新知识 heregulin 和 HER-2 受体将应用于新策略 靶向并利用表面过度表达的生长因子受体 的恶性细胞。