Flavopiridol as a Potential Therapy in Multiple Myeloma

描述(申请人提供)：多发性骨髓瘤是一种浆细胞的克隆性恶性疾病，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提高存活率，然而，骨髓瘤患者的平均预期寿命只有3到5年。虽然没有单一的分子缺陷被确定为骨髓瘤的病因，但大量证据表明，白细胞介素6/JAK/STAT通路的激活是骨髓瘤的一个重要的潜在治疗靶点。我们最近在抗肿瘤临床试验中发现，小分子CDK抑制剂黄烷醇与DNA结合的解离常数与其他DNA导向的抗肿瘤药物相似，2)在体外三种模型体系中阻断STAT-3/DNA的相互作用，以及3)在体外转录水平和体内蛋白质水平下调STAT-3下游的抗凋亡蛋白(如Mcl-1)。初步证据还表明，在体外，黄烷醇对已不再依赖外源性IL-6刺激的骨髓瘤细胞具有特别的细胞毒作用。因此，我们假设，黄烷醇诱导的STAT-3/DNA相互作用的破坏在黄烷醇诱导的细胞毒性中可能是重要的，并且黄烷醇可能是多发性骨髓瘤的靶向治疗。我们现在建议以我们的初步研究为基础，并：1.在活体内检测黄皮醇对骨髓瘤细胞中选定细胞多肽水平的影响，并结合我们的CTEP批准的骨髓瘤黄皮醇第二阶段临床试验，评估体外黄皮醇敏感性和/或骨髓瘤细胞多肽水平预测患者反应的能力；2.利用Mye/OMA细胞系检验黄匹油醇对转录和转录因子/DNA相互作用的影响，并评估IL-6非依赖性和/或内源性上调的STAT-3信号可能与黄匹环素敏感性增加相关的假设，使用骨髓瘤细胞评估STAT-3信号通路在黄吡哆醇诱导的细胞毒性中的重要性，其特征是强制改变STAT-3信号通路的选定成分。建议的研究结果将提高对黄烷醇在骨髓瘤细胞中的作用和机制(S)的理解，从而可能有助于该药物的进一步临床开发。

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.