Multiple myeloma is a clonal malignancy of plasma cells that results in over 11,000 deaths in the United States annually. Therapies, including autologous stem cell transplantation, can improve survival, however, average life expectancy among patients with myeloma is only about 3 to 5 years. Although no single molecular defect has been identified as pathognomonic of the disease, considerable evidence implicates activation of the interleukin-6/JAK/STAT pathway as an important potential therapeutic target in myeloma. We have recently found that flavopiridol, a small molecule CDK inhibitor in antineoplastic clinical trials, 1) binds to DNA with a dissociation constant similar to that of other DNA-directed antineoplastic agents, 2) disrupts STAT-3/DNA interactions in vitro in three model systems, and 3) down regulates antiapoptotic proteins (e.g. Mcl-1) downstream of STAT-3 at the transcriptional level in vitro and at the protein level in vivo. Preliminary evidence also suggests that flavopiridol may be especially cytotoxic in vitro to myeloma cells that have lost dependence upon exogenous IL-6 stimulation. We therefore hypothesize that flavopiridol-induced disruption of STAT-3/DNA interactions may be important in flavopiridol-induced cytotoxicity and that flavopiridol may represent a target-directed therapy in multiple myeloma. We now propose to build on our preliminary studies and: 1. Examine the effects of flavopiridol on levels of selected cellular polypeptides in myeloma cells in vivo, and evaluate the ability of ex vivo flavopiridol sensitivity, and/or baseline myeloma cell polypeptide levels, to predict patient response in conjunction with our CTEP-approved Phase 2 clinical trial of flavopiridol in myeloma, 2. Examine the effects of flavopiridol on transcription and on transcription factor/DNA interactions, and evaluate the hypothesis that IL-6 independence and/or endogenously up regulated STAT-3 signaling may be associated with increased flavopiridol sensitivity using mye/oma cell lines, and 3. Evaluate the importance of STAT-3 signaling on flavopiridol-induced cytotoxicity using myeloma cells characterized by forced alterations of selected components of the STAT-3 signaling cascade. Results of proposed studies will improve understanding of the effects and mechanism(s) of action of flavopiridol in myeloma cells, thereby potentially contributing to the further clinical development of the drug.
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