NEW THARAPY FOR HER 2/NEU POSITIVE BREAST CANCER

HER-2/neu的扩增或过表达发生在20-30 %的人类乳腺癌，并且表达增加与 患者预后差。迫切需要新的药物， 治疗这种疾病。几条证据表明，考克斯-2是重要的 在致癌作用中。考克斯-2缺乏可预防肠道和皮肤肿瘤 在实验动物中形成。申请人已经发现， 考克斯-2在HER-2/neu阳性的人乳腺癌中升高。这就提出了一个 选择性考克斯-2抑制剂预防neu诱导的乳腺癌的可能性 肿瘤发生，如最近显示的结肠癌和皮肤癌。这样做的目的之一 因此，建议是确定药理学抑制或 考克斯-2的基因切除抑制了 MMTV/neu转基因小鼠中乳腺肿瘤的转移。也有越来越多 临床前证据表明，核受体PPAR γ的配体可能是 有效预防或治疗乳腺癌。申请人已经表明 PPAR γ配体抑制HER-2/neu转化乳腺癌细胞的生长 抑制HER-2/neu介导的考克斯-2基因的激活 表情第二个目标是确定曲格列酮，一种PPRP， γ配体，预防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 γ配体引起G1期细胞周期阻滞的机制 并抑制HER-2/neu介导的考克斯- 2诱导。的结果予以 研究将为做出合理决定提供依据， 选择性考克斯-2抑制剂或过氧化物酶体增殖物激活受体γ配体应在妇女中进行评估 HER-2/neu过度表达的乳腺癌

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.