Targeting NEDD8-Mediated Protein Turnover in AML

描述（由申请人提供）：急性髓性白血病（AML）是一种侵袭性很强的恶性肿瘤，很少有长期存活者。迫切需要新的治疗策略来提高这种疾病患者的生存率。蛋白质周转的控制在癌症中经常被破坏，这种现象的机制基础仍然不清楚。cullin泛素连接酶是蛋白质降解的关键调节因子，其通过与泛素样分子NEDD 8的共价修饰而特异性调节。Cullin控制蛋白质的周转，在细胞周期调节、DNA损伤反应和细胞死亡中具有关键的肿瘤抑制作用。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和耐药性，这表明靶向该途径可能是有效的抗癌策略。MLN 4924是一类新型NEDD 8激活酶（NAE）的小分子抑制剂; NAE是NEDD 8介导降解的近端调节剂。我们的初步数据表明，NEDD 8介导的蛋白质转换是AML进展所必需的，因为MLN 4924对其的抑制可在AML小鼠中产生稳定的疾病消退。我们假设抑制NAE活性将拮抗AML疾病进展，破坏细胞氧化还原状态，并增加标准AML治疗的疗效。在目的1中，我们将研究氧化应激诱导是否是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。在这些研究结束时，我们将大大扩展我们对NEDD化在AML发病机制中作用的认识，并将产生开发新策略所需的关键新信息，以最佳靶向NEDD 8途径治疗AML和其他形式的癌症。

DESCRIPTION (provided by applicant): 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.