Flavopiridol as a Potential Therapy in Multiple Myeloma

描述（由申请人提供）：多发性骨髓瘤是一种浆细胞克隆恶性肿瘤，每年在美国导致超过11,000人死亡。包括自体干细胞移植在内的治疗方法可以改善生存，然而，骨髓瘤患者的平均预期寿命只有大约3到5年。虽然没有单一的分子缺陷被确定为该疾病的病理特征，但大量证据表明，白介素-6/JAK/STAT通路的激活是骨髓瘤重要的潜在治疗靶点。我们最近在抗肿瘤临床试验中发现黄吡醇，一种小分子CDK抑制剂，1)以类似于其他DNA定向抗肿瘤药物的解离常数与DNA结合，2)在体外三种模型系统中破坏STAT-3/DNA相互作用，3)在体外转录水平和体内蛋白水平下调STAT-3下游的抗凋亡蛋白（如Mcl-1）。初步证据还表明，黄吡醇可能在体外对失去外源性IL-6刺激依赖性的骨髓瘤细胞具有特别的细胞毒性。因此，我们假设黄嘌呤诱导的STAT-3/DNA相互作用的破坏可能在黄嘌呤诱导的细胞毒性中很重要，黄嘌呤可能代表多发性骨髓瘤的靶向治疗。我们现在建议在初步研究的基础上：检查黄吡醇对骨髓瘤细胞中选定细胞多肽水平的影响，并评估体外黄吡醇敏感性和/或基线骨髓瘤细胞多肽水平的能力，以预测患者对ctep批准的黄吡醇骨髓瘤2期临床试验的反应。2 .研究黄酮吡醇对转录和转录因子/DNA相互作用的影响，并利用mye/oma细胞系评估IL-6独立性和/或内源性上调STAT-3信号可能与黄酮吡醇敏感性增加有关的假设。利用骨髓瘤细胞，评估STAT-3信号在黄嘌呤诱导的细胞毒性中的重要性，骨髓瘤细胞的特征是STAT-3信号级联的选定组分被强制改变。拟议的研究结果将提高对黄吡醇在骨髓瘤细胞中的作用和作用机制的理解，从而有可能为该药物的进一步临床开发做出贡献。

DESCRIPTION (provided by applicant): 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.