DEVELOPMENT OF SIGNAL TRANSDUCTION INHIBITORS FOR THE TREATMENT OF BREAST CANCER

这个项目的目标是确定乳腺癌的影响 用法尼基转移酶抑制剂抑制Ras加工的细胞 （FTI）。我们已经证明，FTIs通过p53依赖性和 独立的机制，并与紫杉烷类和抑制剂协同作用， EGF受体我们的目标是：确定关键的franesylated蛋白质 进一步阐明FTI诱导的机制 p21在含有野生型p53的细胞中的表达和核内复制， 缺乏p53功能的细胞凋亡;利用我们所掌握的知识， 累积以测试FTI治疗晚期乳腺癌的疗效 癌我们还确定安莎霉素抗生素与 热休克蛋白90，并导致几种特定类型的蛋白质降解 是癌细胞生长和存活所必需的。我们现在参与了 开发这项工作的临床应用，包括I期试验 格尔德霉素类似物选择性降解HER-1的先导化合物 激酶和雌激素受体已被鉴定， 表征了

The goal of this project is to determine the effects in breast cancer cells of inhibiting Ras-processing with a farnesyl transferase inhibitor (FTI). We have shown that FTIs arrest and kill cells by p53-dependent and independent mechanisms and synergize with both taxanes and inhibitors of EGF receptor. Our goals are: To identify the key franesylated protein targets of the drug; To further elucidate the mechanisms of FTI induction of p21 in cells containing wild type p53 and of endoreduplication and apoptosis in cells lacking p53 function; To use the knowledge we have accumulated to test the efficacy of FTI as treatment of advanced breast cancer. We have also determined that the ansamycin antibiotics bind to Hsp90 and cause degradation of several specific classes of protein required for cancer cell growth and survival. We are now involved in developing clinical applications of this work, including a phase I trial of a geldanamycin analog. Lead compounds that selectively degrade HER- kinases and estrogen receptor have been identified and are being characterized.