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

该项目应被视为一个全新的项目。它建立在标准细胞毒性 在软组织肉瘤（STS）患者的治疗进展中， 未来取决于新靶向药物的鉴定。使用基于实验室的方法 通过靶点验证的药物发现，我们相信我们已经朝着这个目标取得了相当大的进展。 我们目前已经确定的药物包括flavopiridol，细胞周期蛋白依赖性激酶抑制剂，索拉非尼 （BAY-43 9006），Raf-kinase B的抑制剂，17-AAG，HSP 90的抑制剂，和Nutlin，Roche 抑制MDM 2的化合物。尽管每种药物抑制不同的目标， 观察到存在细胞周期停滞的普遍效应。有鉴于此，该项目已更名为 “软组织肉瘤治疗中细胞周期活性剂的实验室和临床开发” 以反映这些新的靶向剂对细胞周期调节的共同潜在作用。我们相信这 在药物开发的方法大大扩展了我们的战略，以确定新的药物在治疗软 组织肉瘤它也清楚地将我们的治疗范围从flavopiridol扩展到其他药物 目前在临床开发中。概述的实验室研究为以下三个方面提供了基础： 临床试验，包括STS治疗中定义的相关研究。的具体目标 本项目是：1.进行多柔比星和flavopiridol在STS中的I期临床试验， 相关的反应标记。2.开展索拉非尼多中心II期临床试验 在STS。3.在STS患者中进行17-AAG的多中心II期临床试验。4.以识别 并在实验室中验证治疗STS的新靶点，包括CDK 4/CDK 2，Raf-kinase B， HSP 90、MDM 2和E2 F1。我们相信这种方法将导致新的治疗方法的发展。 这种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的影响。 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.