Targeting NEDD8-Mediated Protein Turnover in AML

描述（由申请人提供）：急性髓性白血病（AML）是一种非常具有侵袭性的恶性肿瘤，很少有长期幸存者。迫切需要新的治疗策略来提高这种疾病患者的生存率。在癌症中，蛋白质周转的控制经常被破坏，这种现象的机制基础尚不清楚。cullin泛素连接酶是蛋白质降解的关键调控因子，通过与泛素样分子NEDD8的共价修饰进行特异性调节。Cullins控制着在细胞周期调节、DNA损伤反应和细胞死亡中起关键肿瘤抑制作用的蛋白质的周转。因此，已知一些NEDD8-cullin调控靶点的不适当丢失可促进癌症进展和耐药，这表明靶向这一途径可能是一种有效的抗癌策略。MLN4924是一种新型的NEDD8激活酶（NAE）小分子抑制剂；NEDD8介导的降解的近端调节因子。我们的初步数据表明，nedd8介导的蛋白质周转是AML进展所必需的，因为它对MLN4924的抑制可以在AML小鼠中产生稳定的疾病消退。我们假设，抑制NAE活性会抑制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Aim 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Aim 2中，我们将评估自噬在NAE抑制介导的细胞死亡中所起的作用。最后，在Aim 3中，我们将确定NAE抑制增强标准护理药物阿糖胞苷活性的机制。在这些研究的结论中，我们将大大扩展我们关于NEDD8通路在AML发病机制中的作用的知识，并将产生关键的新信息，以开发新的策略来优化靶向NEDD8通路，以治疗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.