GROWTH FACTOR RECEPTOR DIRECTED THERAPY IN CANCER

生长因子受体定向治疗癌症

• 批准号: 2330846
• 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/2330846
• 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至关重要 生长调节。一个或多个编码EGF的ERB B原始癌基因 和HER-3受体在大约两个 - 人类乳腺癌的三分之一。人类中HER-2受体的过表达 乳腺癌和卵巢癌与预后不良相关，可能预测 对诊所化疗的反应。生长调节电路 涉及HER-2/NEU受体和自分泌/旁分泌激活 据推测，刚纯化的配体是一种新纯化的配体，以提高恶性肿瘤。 结合HER-2受体的单克隆抗体发挥细胞抑制作用 在抑制HER-2过表达的细胞生长中。新实验室 工作表明抗受体激活HER-2/NEU受体 抗体增强了对损伤DNA-和， 从而使肿瘤细胞杀死最大化。人类乳房和卵巢的模型 癌症患有和没有过度表达HER-2受体或此处的癌症 已在我们的实验室中建立，将用于研究： *新的人源化单克隆抗体抗HER-2/NEU的抗癌作用 单独并与化学治疗药物（顺铂）结合使用（顺铂） 和烷基机）损害细胞DNA。临床前数据将是 根据人源化抗体的功效和治疗时间表收集 用于用于临床试验的HER-2受体。假定 与抗受体抗体联合治疗的治疗优势和 将测试细胞毒性药物，目的是优化体内条件 对于最大的胞质作用。此数据 - 需要继续进行 与这些药物进行的临床试验。 * HER-2/NEU受体或此处基因基因的临床意义 耐药性的表达。测试HER-2基因在创世纪中的作用 化学疗法耐药性，单拷贝的亲本细胞，低 HER-2基因和分子工程的子细胞的表达 将比较多复制，高表达HER-2基因的相对 药物敏感性。肿瘤细胞设计用于过表达的肿瘤细胞 还将用于测试自分泌/旁分泌激活的效果 HER-2关于药物敏感性。 *调节DNA修复在协同抗肿瘤作用中的调节 抗受体抗体和顺铂。构造和修复的度量 顺铂DNA加合物和计划外的DNA合成将进行 测试了DNA修复途径通过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 将比较抗受体抗体。 这种基本和转化的研究方法旨在 持续和支持新型治疗选择的临床试验 在乳腺癌和卵巢癌中。关于生物行动的新知识 这里策略蛋白和HER-2受体将用于新的策略 靶标和利用表面上过表达的生长因子受体 恶性细胞。