Repositioning Bazedoxifene as a novel IL-6/GP130 inhibitor for sarcoma therapy

 描述(申请人提供)：横纹肌肉瘤是最常见的儿童软组织肉瘤。对于30-40%治疗失败或出现转移性疾病的患者，目前还没有有效的治疗方法，而且这一结果15年来没有任何改善。因此，横纹肌肉瘤需要新的治疗策略。已有研究表明，IL-6信号转导通路在癌细胞的生存和发展中起着重要作用。IL-6与IL-6受体结合形成二元复合体，然后招募gp130形成IL-6/IL-6 R/gp130杂三聚体，在下游触发信号级联反应。在目前的研究中，我们提出了在横纹肌肉瘤和人类横纹肌肉瘤细胞系的原发肿瘤中IL-6水平升高的证据。因此，IL-6信号通路为横纹肌肉瘤的治疗提供了一个新的靶点。然而，到目前为止，还没有靶向IL-6/gp130信号的小分子可用于临床试验中的癌症治疗。为了加快IL-6/gp130的药物开发，我们利用了一种多配体同时对接和药物重新定位相结合的药物发现方法来靶向gp130。使用这一新方法，我们已经鉴定了FDA批准的药物bazedoxifene[辉瑞公司销售的用于预防和治疗绝经后骨质疏松症的药物Duavee(Bazedoxifene With Codited Esturens)]，该药物具有抑制IL-6和gp130蛋白-蛋白质相互作用的新功能。本研究的目的是进一步鉴定巴多昔芬在体外对横纹肌肉瘤细胞的生物活性，并在小鼠体内检测其对IL-6/gp130信号转导的抑制活性。我们的长期目标是通过对横纹肌肉瘤患者的临床评估来翻译巴多昔芬，最终目标是改善横纹肌肉瘤的临床结果，延长我国人民的健康生活质量。研究的具体目标如下：目的1.研究巴多昔芬对横纹肌肉瘤细胞的抑制作用及其靶向抑制机制。目的：2.在小鼠横纹肌肉瘤模型中评价巴多昔芬抑制IL-6/gp130途径的生物学活性。

 DESCRIPTION (provided by applicant): Rhabdomyosarcoma is the most common childhood soft tissue sarcomas. No effective therapy exists for the 30-40% of patients that fail therapy or present with metastatic disease and no improvements in this outcome have occurred for over 15 years. Hence, there is a need for new therapeutic strategies for the rhabdomyosarcoma. It has been shown that IL-6 signaling plays an important role in cancer cell survival and progression. IL-6 binds to IL-6 R to form a binary complex, then recruits GP130 to form the IL-6/IL-6 R/GP130 heterotrimer and triggers a signaling cascade downstream. In the current study, we have presented evidence that IL-6 levels are elevated in primary tumors of rhabdomyosarcoma and human rhabdomyosarcoma cell lines. Therefore, IL-6 signaling presents a viable new target for rhabdomyosarcoma therapy. To date, however, no small molecules that target IL-6/GP130 signaling are available for cancer therapy in clinical trials. To speed up the IL-6/GP130 drug development, we have utilized a novel drug discovery approach combining Multiple Ligand Simultaneous Docking and drug repositioning to target GP130. Using this novel method, we have identified a FDA-approved drug Bazedoxifene [marketed as DUAVEE (Bazedoxifene with conjugated estrogens) by Pfizer for the prevention and treatment of postmenopausal osteoporosis] with a novel function to inhibit IL-6 and GP130 protein-protein interactions. The objective of this proposal is to further characterize the biologic activity of Bazedoxifene in rhabdomyosarcoma cells in vitro and test their inhibitory activity against IL-6/GP130 signaling in mice. Our long-term objective is to translate Bazedoxifene through clinical evaluation in patients with rhabdomyosarcoma with the ultimate goal of improving the clinical outcome for rhabdomyosarcoma and extending the quality of healthy life for people in this country. The following specific aims will be studied: Aim 1. Characterize the inhibitory effects and mechanisms of target inhibition of the Bazedoxifene in rhabdomyosarcoma cells. Aim 2. Evaluate the biologic activity of IL-6/GP130 pathway inhibition by Bazedoxifene on rhabdomyosarcoma cells in mouse tumor model in vivo.