NEW THARAPY FOR HER 2/NEU POSITIVE BREAST CANCER

针对 2/NEU 阳性乳腺癌的新疗法

• 批准号: 6254704
• 负责人: ANDREW Jess DANNENBERG
• 金额: $ 28.65万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-15 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6254704
• 关键词: antineoplastics; apoptosis; athymic mouse; breast neoplasms; chemoprevention; cyclin dependent kinase; cyclins; enzyme induction /repression; epidermal growth factor; genetically modified animals; growth factor receptors; guanine nucleotide binding protein; metastasis; monoclonal antibody; mouse mammary tumor virus; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; nonhuman therapy evaluation; peroxisome proliferator activated receptor; prostaglandin E; prostaglandin endoperoxide synthase; troglitazone; viral carcinogenesis

Amplification or overexpression of HER-2/neu occurs in 20-30 percent of human breast cancers, and increased expression has been associated with poor prognosis in the patients. New medications are urgently needed to treat this disease. Several lines of evidence suggest that COX-2 is important in carcinogenesis. COX-2 deficiency protects against intestinal and skin tumor formation in experimental animals. The applicant has discovered that levels of COX-2 are elevated in HER-2/neu-positive human breast cancer. This raises the possibility that selective COX-2 inhibitors will prevent neu-induced mammary tumorigenesis, as was recently shown for colon and skin cancer. One aim of this proposal, therefore, is to determine whether pharmacological inhibition or genetic ablation of COX-2 suppresses the formation of or inhibits the metastasis of mammary tumors in MMTV/neu transgenic mice. There is also growing preclinical evidence that ligands of the nuclear receptor PPAR gamma may be effective in preventing or treating breast cancer. The applicant has shown that PPAR gamma ligands inhibit the growth of HER-2/neu-transformed mammary epithelial cells and suppressed HER-2/neu-mediated activation of COX-2 gene expression. A second aim will be to determine whether troglitazone, a PPRP gamma ligand, prevents mammary tumorigenesis in MMTV/neu transgenic mice or enhances the antitumor activity of Herceptin. Finally, the applicant will elucidate the mechanisms by which PPAR gamma ligands cause G1 cell cycle arrest and inhibit HER-2/neu-mediated induction of COX- 2. The results of these studies will provide the basis for making a rational decision about whether selective COX-2 inhibitors or PPAR gamma ligands should be evaluated in women with HER-2/neu-overexpressing breast cancer.

HER-2/NEU的扩增或过表达发生在20-30 人类乳腺癌的百分比和表达的增加与 患者预后不良。迫切需要新药 治疗这种疾病。几条证据表明COX-2很重要 在癌变中。 COX-2缺乏可预防肠道和皮肤肿瘤 实验动物的形成。申请人发现 COX-2在HER-2/NEU阳性人类乳腺癌中升高。这提高了 选择性COX-2抑制剂可能会防止NEU诱导的乳腺 肿瘤发生，如最近显示的结肠癌和皮肤癌。一个目的 因此，建议是确定药理学抑制或 COX-2的遗传消融抑制了形成或抑制 MMTV/NEU转基因小鼠中乳腺肿瘤的转移。也在增长 临床前证明核受体PPAR伽玛的配体可能是 有效预防或治疗乳腺癌。申请人表明 PPAR伽马配体抑制HER-2/NEU转化的乳腺的生长 上皮细胞并抑制HER-2/NEU介导的Cox-2基因的激活 表达。第二个目标是确定troglitazone是否是PPRP 伽马配体，可防止MMTV/NEU转基因小鼠中的乳腺肿瘤发生或 增强赫赛汀的抗肿瘤活性。最后，申请人将 阐明PPAR伽马配体引起G1细胞周期停滞的机制 并抑制HER-2/NEU介导的Cox-2的诱导。 研究将为做出理性决定提供基础 选择性COX-2抑制剂或PPARγ配体应在女性中评估 与HER-2/过表达乳腺癌。