GROWTH FACTOR RECEPTOR DIRECTED THERAPY IN CANCER

生长因子受体定向治疗癌症

• 批准号: 2654120
• 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/2654120
• 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; heregulin; 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细胞增殖和分化至关重要。 生长调节一个或多个编码EGF、HER-2的erB B原癌基因 和HER-3受体在约两个- 三分之一的人类乳腺癌HER-2受体在人乳腺癌细胞中的过表达 乳腺癌和卵巢癌与预后不良相关， 在临床上对化疗的反应。生长调节回路 涉及HER-2/neu受体和自分泌/旁分泌激活， 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过表达细胞的生长。新实验室 研究表明，HER-2/neu受体被抗受体抗体激活， 抗体增强了细胞对药物的敏感性-破坏DNA-并且， 从而使肿瘤细胞杀伤最大化。人乳腺和卵巢模型 HER-2受体或heregulin过表达或不过表达的癌症 已在我们的实验室建立，并将用于研究： * 人源化HER-2/neu单克隆抗体的抗肿瘤作用 受体单独和与化疗药物（顺铂）组合 和烷化剂），其破坏细胞DNA。临床前数据将 根据人源化抗体的功效和治疗时间表收集 用于临床试验的HER-2受体。假定的 抗受体抗体联合治疗的治疗优势， 将测试细胞毒性药物，目的是优化体内条件 以达到最大的杀细胞效果。此数据-需要继续进行 这些药物的临床试验 * HER-2/neu受体和heregulin基因检测的临床意义 耐药性的表达。探讨HER-2基因在乳腺癌发生中的作用 化疗耐药，单拷贝，低水平的亲本细胞 HER-2基因表达和分子工程子代细胞， HER-2基因的多拷贝、高表达将被比较用于相对的 药物敏感性用于过表达调蛋白的肿瘤细胞 也将用于测试自分泌/旁分泌激活的影响， HER-2对药物敏感性的影响 * DNA修复在药物协同抗肿瘤作用中的调节作用 抗受体抗体和顺铂。形成与修复措施 顺铂-DNA加合物和非程序性DNA合成将进行， 测试DNA修复途径被生长因子改变的假设 受体信号通路配体或受体过表达的影响 和抗受体抗体进行比较。 这种基础和转化的研究方法旨在 继续和支持新治疗方案的临床试验 乳腺癌和卵巢癌生物学作用的新认识 heregulin和HER-2受体将被应用于新的策略， 靶向并利用表面上过表达的生长因子受体 恶性细胞。