The Role of Ubiquitin-Proteasome Pathway in Myeloma Bone Disease

泛素-蛋白酶体途径在骨髓瘤骨病中的作用

• 批准号: 7028458
• 负责人: BABATUNDE OLUKAYODE OYAJOBI
• 金额: $ 17.71万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028458
• 关键词: RNA interference; bone density; bone disorder; bone morphogenetic proteins; cell differentiation; cytotoxicity; genetically modified animals; host neoplasm interaction; laboratory mouse; longitudinal animal study; melphalan; molecular oncology; morphometry; multiple myeloma; neoplastic growth; organ culture; osteoblasts; paraplegia; pathologic bone resorption; positron emission tomography; protease inhibitor; proteasome; single photon emission computed tomography; ubiquitin

Multiple myeloma continues to be associated with high morbidity and mortality rates due mostly to complications resulting from its effects on the skeleton. These complications reflect, in part, an impairment of osteoblast function and failure of bone formation. Currently available treatment modalities do not increase the already low bone mass in myeloma patients, and there is a compelling need for new treatment paradigms that enhance new bone formation to reverse the bone deficit. Although the mechanism underlying this inadequate osteoblast response in myeloma remains unknown, Dickkopf 1 (DKK1) has recently been implicated. Inhibition of the ubiquitin-proteasome (Ub-prot) pathway with small molecule inhibitors such as Velcade is having a significant impact on clinical management of myeloma patients with relapsed, refractory disease. We have recently made the exciting discovery that, in addition to their profound anti-tumor effects, proteasome inhibitors, including Velcade, also enhance bone formation in vitro and in rodents and data emerging from on-going clinical trials of Velcade in myeloma patients support these findings. We also find that Velcade is a potent inhibitor of DKK1 expression. Our hypothesis is that proteasome inhibition in myeloma affects both 'seed' (tumor) and 'soil', (bone microenvironment), and thereby has outstanding beneficial effects in the treatment of myeloma patients. This hypothesis is based on the fact that Velcade works through inhibition of the proteasome to block myeloma cell growth and also to restore osteoblast function by inhibiting DKK1 expression. Specifically, we propose that (i) both seed and soil are exquisitely sensitive to inhibition of the Ub-prot pathway; (ii) the precise mechanism in either case may be different but the E3 Ub ligase beta-TrCP appears to be centrally involved; (iii) Velcade has the potential to reduce tumor burden and concomitantly reverse bone disease, unlike other known chemotherapeutic approaches. Using the murine 5TGM1 model of myeloma bone disease as well as novel transgenic mouse models, coupled with novel state-of-the-art small animal imaging modalities that allow us to longitudinally track dynamics of tumor burden (microPET) and bone cell activity (microSPECT/CT), the proposed studies seek to elucidate the mechanisms mediating the beneficial effects of inhibiting the Ub-prot pathway in myeloma. The Specific Aims are to (I) Determine the effects of proteasome inhibition on Dkk1 and related bone disease of myeloma (ii) Determine the role of Dkk1 in bone formation in myeloma bone disease and the relationship to proteasome inhibition; (iii) Define the relationship between proteasome inhibition and beta-TrCP in cells within the tumor microenvironment (tumor cells and bone cells) in myeloma bone disease. The proposed studies will further our understanding of the mechanisms mediating the impact of proteasome inhibitors on tumor cells and the skeleton and suggest new molecular targets which potentially would serve as the basis for development of targeted therapeutics to treat myeloma bone disease.

多发性骨髓瘤仍然与高发病率和死亡率相关，主要原因是并发症 这是由于其对骨骼的影响而产生的。这些并发症部分反映了成骨细胞功能受损和 骨形成失败。目前可用的治疗方式不会增加已经很低的骨量 骨髓瘤患者迫切需要新的治疗模式来增强新骨形成 逆转骨质流失。尽管骨髓瘤中成骨细胞反应不足的机制仍然存在 未知，Dickkopf 1 (DKK1) 最近受到牵连。抑制泛素蛋白酶体 (Ub-prot) 通路 使用 Velcade 等小分子抑制剂对骨髓瘤的临床治疗产生重大影响 患有复发、难治性疾病的患者。我们最近有了令人兴奋的发现，除了他们 蛋白酶体抑制剂（包括 Velcade）具有深远的抗肿瘤作用，还可以在体外和体内增强骨形成 啮齿类动物和正在进行的万珂在骨髓瘤患者中的临床试验数据支持了这些发现。我们也 发现 Velcade 是 DKK1 表达的有效抑制剂。我们的假设是骨髓瘤中的蛋白酶体抑制 影响“种子”（肿瘤）和“土壤”（骨微环境），因此对人体有显着的有益作用 治疗骨髓瘤患者。该假设基于以下事实：万珂通过抑制 蛋白酶体可阻断骨髓瘤细胞生长，并通过抑制 DKK1 表达来恢复成骨细胞功能。 具体来说，我们提出 (i) 种子和土壤对 Ub-prot 途径的抑制都非常敏感； (二) 两种情况下的精确机制可能不同，但 E3 Ub 连接酶 beta-TrCP 似乎是主要参与的； (三) 与其他已知的药物不同，Velcade 具有减少肿瘤负荷并同时逆转骨病的潜力 化疗方法。使用骨髓瘤骨病的小鼠 5TGM1 模型以及新型转基因 小鼠模型，加上新颖的最先进的小动物成像模式，使我们能够纵向跟踪 肿瘤负荷（microPET）和骨细胞活性（microSPECT/CT）的动态，拟议的研究试图阐明 介导抑制骨髓瘤中 Ub-prot 途径的有益作用的机制。具体目标是 （一）确定蛋白酶体抑制对Dkk1及骨髓瘤相关骨病的影响（二）确定作用 Dkk1 在骨髓瘤骨病骨形成中的作用及其与蛋白酶体抑制的关系； (iii) 定义 肿瘤微环境（肿瘤细胞和肿瘤细胞）内的细胞中蛋白酶体抑制与β-TrCP之间的关系 骨细胞）在骨髓瘤骨病中。拟议的研究将进一步加深我们对机制的理解 介导蛋白酶体抑制剂对肿瘤细胞和骨骼的影响，并提出新的分子靶点，这些靶点可能成为开发治疗骨髓瘤骨病的靶向疗法的基础。