This Project should be perceived as a completely new project. It is built on the premise that standard cytotoxictherapy 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 approachof 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 Rochecompound that inhibits MDM2. Even though each of these agents inhibits a different target, we haveobserved 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 thisapproach in drug development greatly expands our strategy to identify new agents in the treatment of softtissue sarcomas. It also clearly extends our therapeutic spectrum beyond flavopiridol to other agentscurrently in clinical development. The laboratory studies outlined have provided the foundation for threeclinical trials with the inclusion of defined correlative studies in the treatment of STS.
The specific aims ofthis project are: 1. To conduct the phase I clinical trial of doxorubicin and flavopiridol in STS with assessmentof correlative markers of response. 2. To conduct a multi-center phase II clinical trial of sorafenib in patientswith STS. 3. To conduct a multi-center phase II clinical trial of 17-AAG in patients with STS. 4. To identifyand 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 therapeuticapproaches that will have a profound impact on the successful treatment of patients with this rare but oftenfatal disease.
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