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

Sloan-Kettering Inst Can Research, New York NY

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Abstract

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.