Cytotoxicity of MLN4924 in Acute Myeloid Leukemia

描述(申请人提供)：急性髓系白血病(AML)是一种以细胞异常生长和增殖为特征的血癌，主要见于成人。据估计，2013年美国将新增14,590例急性髓系白血病病例。目前的化疗能够治愈一小部分AML患者；60岁以上患者的五年存活率低得令人沮丧，只有12%。如果白血病继发于一种被称为骨髓增生性肿瘤(MPN)的现有血液疾病，患者的平均生存时间不到3个月，则预后更差。幸运的是，一种新的化疗药物MLN4924已经进入急性髓细胞白血病的临床测试，并在不同疾病阶段的患者中显示出抗白血病效果。MLN4924影响恶性细胞内失调的细胞内途径，导致它们经历“程序性细胞死亡”，也称为凋亡。我们的实验室专门研究MLN4924等化疗药物如何诱导细胞凋亡。本申请中提出的研究计划是分子药理学领域更大的研究培训计划的一部分，将使用AML细胞系和临床 从新诊断的AML患者中提取样本，研究MLN4924诱导细胞凋亡的确切机制。具体地说，我们将研究MLN4924如何导致已知对细胞凋亡有正向和负向调节作用的Bcl-2蛋白家族的变化。我们还将研究这些蛋白质在从先前存在MPN的患者发展而来的白血病细胞系中的变化。通过了解这些蛋白是如何受到影响的，我们可能能够预测哪些AML患者会对MLN4924产生反应。MPN患者中的大多数白血病还在一种名为JAK2的信号蛋白中存在突变，这种突变导致该分子不断发出信号，促进细胞生长和存活。鲁索利替尼是一种旨在抑制这种信号转导的药物，已经进入临床试验，用于治疗MPN和由MPN引起的白血病。我们还将在具有JAK2突变的MPN白血病细胞系中测试MLN4924和Ruxolitinib的组合。这些研究将更好地定义这些药物的治疗潜力，并在分子水平上促进我们对它们如何杀死癌细胞的理解。这些研究的长期目标是产生有助于科学家和临床医生开发和实施改进的癌症疗法的知识。

DESCRIPTION (provided by applicant): Acute myelogenous leukemia (AML) is a blood cancer found mostly in adults that is characterized by abnormal cell growth and proliferation. It is estimated there will be 14,590 new cases of AML in the U.S. in 2013. Current chemotherapy treatments are able to cure on a fraction of all AML patients; and the five-year survival rate in patients over the age of 60 is a dismal 12%. The prognosis is worse if leukemia occurs secondary to an existing blood disease, known as a Myeloproliferative Neoplasm (MPN), with patients surviving an average of less than 3 months. Fortunately, a new chemotherapy agent, MLN4924, has entered clinical testing in AML and has demonstrated anti-leukemic effects in patients with various stages of disease. MLN4924 affects the intracellular pathways dysregulated in malignant cells to cause them to undergo "programed cell death," also known as apoptosis. Our laboratory specializes in studying how chemotherapeutics such as MLN4924 induce apoptosis. The research plan proposed in this application, which is part of a larger research training plan in the field of molecular pharmacology, will use AML cell lines and clinical samples from newly diagnosed AML patients to investigate the exact mechanism by which MLN4924 induces apoptosis. Specifically, we will be studying how MLN4924 causes changes in the Bcl-2 family of proteins that are known to both positively and negatively regulate apoptosis. We will also study how these proteins change in leukemia cell lines developed from patients with pre-existing MPN. By understanding how these proteins are affected, we may be able to predict which AML patients will respond to MLN4924. Most of the leukemias in MPN patients also have a mutation in a signaling protein called JAK2, which causes the molecule to signal continually and enhance cell growth and survival. Ruxolitinib, a drug designed to inhibit this signaling, has entered clinical trials for treatment of MPN and leukemia arising from MPN. We will also test the combination of MLN4924 and Ruxolitinib in our MPN leukemia cell lines that have this JAK2 mutation. These studies will better define the therapeutic potential of these agents and advance our understanding of how they kill cancer cells on a molecular level. The long-term goal of these studies is to generate knowledge that will help scientists and clinicians develop and implement improved cancer therapies.