NEK2 Over-expression Causes Drug Resistance in Myeloma

NEK2 过度表达导致骨髓瘤耐药

• 批准号: 8616967
• 负责人: FENGHUANG ZHAN
• 金额: $ 30.39万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616967
• 关键词: NEK2; Over; expression; Causes; Drug

DESCRIPTION (provided by applicant): The long-term objective of this work is to determine the functional role of NEK2 in promoting cancer progression and to use this knowledge to develop novel therapies. The variability in survival of multiple myeloma patients ranges from only a few months to >10 years. We have previously shown that NEK2- expression is increased in multiple cancers including myeloma; higher levels of NEK2-expression induce cell rapid growth and resistance to multiple chemotherapeutics. This project builds upon our finding that when a specific gene (NEK2) that regulates the cell cycle is overexpressed, patients experience a clinically aggressive form and rapid death of myeloma and other cancers. We have made several striking discoveries supporting the hypothesis that NEK2 over-expression disrupts the normal cycle of tumor cell proliferation, resulting in poor survival for myeloma patients. Our goal to test the hypothesis will be accomplished by execution of three specific aims using both in vitro and in vivo models. Aim1: To examine the role of NEK2 in the development and progression of myeloma. We propose to evaluate whether myeloma cells with high-NEK2 expression are characterized with drug resistance in a large cohort of patients with myeloma at different stages; we will also test the growth and drug-resistance of primary myeloma cells with NEK2 high- or NEK2 low-expression in vitro and in vivo; we will introduce NEK2 into normal fibroblast cells and murine cancer-derived myeloma cell line that have low endogenous NEK2 expression, we will then analyze the effects of this alteration on cell transformation, cellular growth, and response to chemotherapeutic agents. Aim 2: to determine NEK2-mediated signaling pathways in cancer cell proliferation and survival. To achieve this goal, we will determine whether some cell growth related signaling pathways are required for NEK2-mediated cell growth and drug resistance in multiple myeloma. We will examine key substrates that directly interact with the NEK2 protein. Furthermore, gene expression profiling (GEP) will be performed on myeloma samples in remission and at relapse who also have GEP at baseline to identify genes that are regulated by NEK2 at different myeloma stages. Aim 3: to develop novel treatments based on targeting NEK2 or its signaling pathways. Through the screen of kinase inhibitor libraries, we have identified two small molecules that can specifically inhibit NEK2 kinase activity, and induce dramatic cancer cell death in vitro. We will use these molecules as a tool to explore their efficacy in killing myeloma cells in vivo. Inhibitors targeting these signaling pathways will be used alone or in combination with the current used chemotherapeutic drugs to evaluate their antimyeloma activities in vitro and in vivo. PUBLIC HEALTH RELEVANCE: Multiple myeloma is the second most common hematological malignant. There is no effective therapy to cure this cancer. Thus, research is urgently needed to determine how this cancer develop and progress in order to design better therapies. In this grant, we propose studies to identify a novel protein target that may lead to develop better therapies for those aggressive myelomas.

描述（由申请人提供）： 这项工作的长期目标是确定 NEK2 在促进癌症进展中的功能作用，并利用这些知识开发新疗法。多发性骨髓瘤患者的生存期变异性从几个月到>10年不等。我们之前已经表明，NEK2- 表达在包括骨髓瘤在内的多种癌症中增加。较高水平的 NEK2 表达会诱导细胞快速生长和对多种化疗药物的耐药性。该项目基于我们的发现，即当调节细胞周期的特定基因 (NEK2) 过度表达时，患者会经历临床侵袭性的骨髓瘤和其他癌症并快速死亡。我们取得了几项惊人的发现，支持这样的假设：NEK2 过度表达会破坏肿瘤细胞增殖的正常周期，导致骨髓瘤患者的生存率较差。我们检验该假设的目标将通过使用体外和体内模型执行三个特定目标来实现。目的1：研究NEK2在骨髓瘤发生和进展中的作用。我们建议在大量不同阶段的骨髓瘤患者中评估高NEK2表达的骨髓瘤细胞是否具有耐药性；我们还将在体外和体内测试NEK2高表达或NEK2低表达的原发性骨髓瘤细胞的生长和耐药性；我们将把NEK2引入具有低内源性NEK2表达的正常成纤维细胞和小鼠癌症衍生的骨髓瘤细胞系中，然后我们将分析这种改变对细胞转化、细胞生长和对化疗药物的反应的影响。目标 2：确定 NEK2 介导的癌细胞增殖和存活的信号通路。为了实现这一目标，我们将确定一些细胞生长相关的信号通路是否是 NEK2 介导的多发性骨髓瘤细胞生长和耐药性所必需的。我们将检查与 NEK2 蛋白直接相互作用的关键底物。此外，还将对基线时也有 GEP 的缓解期和复发期骨髓瘤样本进行基因表达谱 (GEP)，以识别不同骨髓瘤阶段受 NEK2 调控的基因。目标 3：开发基于靶向 NEK2 或其信号通路的新疗法。通过激酶抑制剂库的筛选，我们发现了两种可以特异性抑制NEK2激酶活性并在体外诱导癌细胞戏剧性死亡的小分子。我们将使用这些分子作为工具来探索它们在体内杀死骨髓瘤细胞的功效。针对这些信号通路的抑制剂将单独使用或与目前使用的化疗药物联合使用，以评估其体外和体内的抗骨髓瘤活性。 公共卫生相关性： 多发性骨髓瘤是第二常见的血液恶性肿瘤。没有有效的疗法可以治愈这种癌症。因此，迫切需要研究确定这种癌症如何发展和进展，以便设计更好的疗法。在这笔资助中，我们提出研究来确定一种新的蛋白质靶点，该靶点可能会为那些侵袭性骨髓瘤开发出更好的疗法。