Targeting NEDD8-Mediated Protein Turnover in AML

在 AML 中靶向 NEDD8 介导的蛋白质周转

• 批准号: 8632457
• 负责人: Jennifer S Carew
• 金额: $ 30.88万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-05 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632457
• 关键词: Acute Myelocytic Leukemia; Antineoplastic Agents; Antioxidants; Apoptosis; Ara-C; Autophagocytosis; Biological Markers; Blast Cell; Cell Cycle Progression; Cell Cycle Regulation; Cell Death; Cell Line; Cell Proliferation; Cell Survival; Cell physiology; Cells; Chloroquine; Clinical Trials; Cullin Proteins; Cytarabine; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA Repair Pathway; Data; Development; Disease; Disease Progression; Disease regression; Drug resistance; Enzyme Inhibition; Enzymes; Family; Future; Generations; Genes; Genetic; Glutathione; Goals; Human; In Vitro; Knowledge; Long-Term Survivors; Lucanthone; MLL-AF9; Malignant Neoplasms; Mediating; Modeling; Modification; Mus; Nutrient; Organelles; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Play; Reactive Oxygen Species; Research; Research Personnel; Resistance; Role; Safety; Signal Transduction; Stable Disease; Stress; Stress Response Signaling; Testing; Therapeutic; Ubiquitin; Validation; anticancer activity; base; chemotherapeutic agent; cytotoxic; drug sensitivity; enzyme activity; human SOD2 protein; improved; in vivo; inhibitor/antagonist; mTOR Inhibitor; mouse model; novel; novel strategies; outcome forecast; protein aggregate; protein degradation; public health relevance; resistance mechanism; response; small hairpin RNA; small molecule; standard of care; survivorship; therapeutic target; treatment strategy; tumor; tumor progression; ubiquitin ligase; ubiquitin-protein ligase

Targeting NEDD8-mediated Protein Turnover in AML PROJECT SUMMARY / ABSTRACT Acute myeloid leukemia (AML) is a very aggressive malignancy with few long-term survivors. New treatment strategies are urgently needed to improve the survivorship of patients with this disease. The control of protein turnover is frequently disrupted in cancer and the mechanistic basis for this phenomenon remains unclear. The cullin ubiquitin ligases are key regulators of protein degradation that are specifically regulated by covalent modification with the ubiquitin-like molecule NEDD8. Cullins control the turnover of proteins with key tumor suppressive roles in cell cycle regulation, DNA damage responses, and cell death. Accordingly, the inappropriate loss of several NEDD8-cullin regulated targets is known to promote cancer progression and drug resistance suggesting that targeting this pathway may be an effective anticancer strategy. MLN4924 is a novel first-in-class small molecule inhibitor of NEDD8 activating enzyme (NAE), the proximal regulator of NEDD8- mediated degradation. Our preliminary data suggest that NEDD8-mediated protein turnover is required for AML progression as its inhibition with MLN4924 produces stable disease regression in mice with AML. We hypothesize that inhibition of NAE activity will antagonize AML disease progression, disrupt cellular redox status, and increase the efficacy of standard AML therapy. In Aim 1, we will investigate whether oxidative stress induction is an essential mechanism of cell death induced by NAE inhibition. In Aim 2, we will evaluate the role that autophagy plays in NAE inhibition-mediated cell death. Finally, in Aim 3 we will determine the mechanism(s) by which NAE inhibition enhances the activity of the standard of care drug cytarabine. At the conclusion of these studies, we will have significantly expanded our knowledge regarding the role of NEDDylation in AML pathogenesis and will have generated critical new information required to develop novel strategies to optimally target the NEDD8 pathway for the treatment of AML and other forms of cancer.

AML中靶向NEDD 8介导的蛋白质转换 项目总结/摘要 急性髓细胞白血病（AML）是一种侵袭性很强的恶性肿瘤，很少有长期存活者。新的治疗 迫切需要改善患有这种疾病的患者的存活率的策略。蛋白质的控制 在癌症中，转换经常被破坏，这种现象的机制基础仍然不清楚。的 Cullin泛素连接酶是蛋白质降解的关键调节剂，其通过共价键特异性调节。 用泛素样分子NEDD 8修饰。Cullins控制关键肿瘤蛋白质的周转 在细胞周期调节、DNA损伤反应和细胞死亡中的抑制作用。因此 已知几种NEDD 8-cullin调节靶点的不适当丢失会促进癌症进展， 这表明靶向该途径可能是一种有效的抗癌策略。MLN 4924是一种新型 NEDD 8激活酶（NAE）的一流小分子抑制剂，NEDD 8的近端调节剂- 介导的降解。我们的初步数据表明，NEDD 8介导的蛋白质周转是必需的， AML进展，因为MLN 4924的抑制作用在AML小鼠中产生稳定的疾病消退。我们 假设NAE活性抑制将拮抗AML疾病进展，破坏细胞氧化还原 提高标准AML治疗的疗效。在目标1中，我们将研究氧化是否 应激诱导是NAE抑制诱导细胞死亡的重要机制。在目标2中，我们将评估 自噬在NAE抑制介导的细胞死亡中的作用。最后，在目标3中，我们将确定 NAE抑制增强标准治疗药物阿糖胞苷活性的机制。在 这些研究的结论，我们将大大扩大我们的知识的作用， NEDD化在AML发病机制中的作用，并将产生开发新的 研究人员正在寻找最佳靶向NEDD 8通路的策略，用于治疗AML和其他形式的癌症。