Laboratory & Clinical Develpmt of Cell Cycle Active Agents in the Treatmt of STS

这个项目应该被视为一个全新的项目。它是建立在标准细胞毒性的前提下 软组织肉瘤(STS)患者的治疗进展一直不成功。 而未来取决于新靶向制剂的确定。使用基于实验室的方法 在药物发现和靶向验证方面，我们相信我们在这方面已经取得了相当大的进展。 到目前为止，我们已确认的药物包括细胞周期蛋白依赖性激酶抑制剂索拉非尼，即黄烷醇。 (Bay-43 9006)，Raf-Kinase B的抑制剂，17-AAG，HSP90的抑制剂，以及Nutlin，罗氏 抑制MDM2的化合物。尽管每种药物都抑制不同的靶点，但我们有 观察到存在细胞周期停滞的普遍效应。有鉴于此，该项目已更名 软组织肉瘤治疗中细胞周期活性物质的实验室与临床研究进展 以反映这些新的靶向制剂对细胞周期调节的共同潜在影响。我们相信这一点 药物开发的方法极大地扩展了我们寻找治疗软组织疾病的新药物的战略 组织肉瘤。它还清楚地将我们的治疗范围从黄烷醇扩展到其他药物。 目前正在进行临床开发。概述的实验室研究为以下三个方面奠定了基础 STS治疗的临床试验，包括明确的相关研究。的具体目标 本项目为：1.进行阿霉素和黄吡哆醇治疗STS的I期临床试验及评价 反应的相关标记物。2.索拉非尼的多中心II期临床试验 性传播疾病。3.对STS患者进行17-AAG的多中心II期临床试验。4.识别 并在实验室验证治疗STS的新靶点，包括CDK4/CDK2，Raf-Kinase B， HSP90、MDM2和E2F1。我们相信这种方法将导致新的治疗方法的发展 这些方法将对这种罕见但经常发生的患者的成功治疗产生深远影响 致命的疾病。

This Project should be perceived as a completely new project. It is built on the premise that standard cytotoxic therapy has been unsuccessful in the advancement of treatment for patients with soft tissue sarcoma (STS) and that the future depends on the identification of new targeted agents. Using a laboratory based approach of drug discovery with target validation, we believe we have made considerable progress toward this end. The drugs we have thus far identified include flavopiridol, the cyclin dependent kinase inhibitor, sorafenib (BAY-43 9006), an inhibitor of Raf-kinase B, 17-AAG, the inhibitor of HSP90, and Nutlin, the Roche compound that inhibits MDM2. Even though each of these agents inhibits a different target, we have observed that there is a generalized effect of cell cycle arrest. In view of this, the Project has been renamed "Laboratory and Clinical Development of Cell Cycle Active Agents in the Treatment of Soft Tissue Sarcomas" to reflect a common underlying effect of cell cycle modulation by these new targeted agents. We believe this approach in drug development greatly expands our strategy to identify new agents in the treatment of soft tissue sarcomas. It also clearly extends our therapeutic spectrum beyond flavopiridol to other agents currently in clinical development. The laboratory studies outlined have provided the foundation for three clinical trials with the inclusion of defined correlative studies in the treatment of STS. The specific aims of this project are: 1. To conduct the phase I clinical trial of doxorubicin and flavopiridol in STS with assessment of correlative markers of response. 2. To conduct a multi-center phase II clinical trial of sorafenib in patients with STS. 3. To conduct a multi-center phase II clinical trial of 17-AAG in patients with STS. 4. To identify and validate in the laboratory new targets for the treatment of STS, including CDK4/CDK2, Raf-kinase B, HSP90, MDM2 and E2F1. We believe this approach will lead to the development of new therapeutic approaches that will have a profound impact on the successful treatment of patients with this rare but often fatal disease.