DEVELOPMENT OF SIGNAL TRANSDUCTION INHIBITORS FOR THE TREATMENT OF BREAST CANCER

该项目的目标是确定对乳腺癌的影响。 法尼基转移酶抑制剂抑制RAS加工的细胞 (FTI)。我们已经证明，FTI通过依赖于P53和 独立的作用机制及与紫杉烷和抑制剂的协同作用 EGF受体。我们的目标是：确定关键的乳糖化蛋白质 药物的靶点；进一步阐明FTI的诱导机制 P21在含有野生型p53的细胞中的表达和内复制 缺乏P53功能的细胞中的细胞凋亡；利用我们已有的知识 累积检验FTI治疗晚期乳房的疗效 癌症。我们还确定了安沙霉素抗生素与 HSP90和引起几种特定类别蛋白质的降解 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 格尔达那霉素类似物。有选择性地降解她的先导化合物- 激酶和雌激素受体已经被识别出来，并正在 特色化的。

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.