Targeting Acid Ceramidase in AML

靶向 AML 中的酸性神经酰胺酶

• 批准号: 10661022
• 负责人: Thomas Patrick Loughran
• 金额: $ 32.84万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661022
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult; Age; Age Years; Apoptosis; Apoptotic; BCL2 gene; Behavior; Biochemical; Biology; Caspase; Cell Line; Cell Survival; Cells; Ceramides; Chemoresistance; Clinic; Clinical; DNMT3a mutation; Data; Diagnosis; Disease; Disease Resistance; Dose; Drug Delivery Systems; Drug Kinetics; Enzymes; Exhibits; FLT3 gene; Formulation; Funding; Future; Genes; Genetic; Genetically Engineered Mouse; Goals; Hematopoietic stem cells; Human; In complete remission; Individual; Induction of Apoptosis; Knowledge; Leukemic Cell; Link; Lipids; MCL1 gene; Mediator; Metabolism; Minority; Modeling; Molecular; Molecular Profiling; Molecular Target; Mus; Mutation; Myelogenous; N-caproylsphingosine; Patients; Population; Preclinical Testing; Predisposition; Proliferating; Protein Isoforms; Proteins; Public Health; Regimen; Relapse; Role; Sampling; Sphingolipids; Standardization; System; Technology; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Translating; Tumor Burden; Work; Xenograft Model; acute myeloid leukemia cell; aggressive therapy; chemotherapy; clinical application; combinatorial; design; drug development; experience; galactosylgalactosylglucosylceramidase; genetically modified cells; improved; in vivo; inhibitor; knock-down; leukemia; leukemia treatment; metabolomics; molecular subtypes; mouse model; nanoencapsulated; nanoliposome; non-genetic; novel; novel therapeutics; older patient; outcome prediction; overexpression; patient population; patient subsets; pharmacologic; pre-clinical; preclinical efficacy; preclinical study; prognostic; programs; response; small molecule inhibitor; sphingosine 1-phosphate; standard of care; success; synergism; targeted agent; targeted treatment; treatment strategy

PROJECT SUMMARY Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is a growing public health burden as the population ages. Dose-intensive induction and consolidation chemotherapy dramatically reduces tumor burden and induces clinical complete remission in the majority of younger individuals. However, AML patients rarely achieve durable response and typically relapse with chemoresistant disease. Thus, improved therapeutic approaches are imperative. AML is extremely heterogeneous in terms of clinical behavior as well as molecular alterations. The field increasingly utilizes molecular profiling to provide prognostic predictors of outcome and identify targets for selective inhibitors. The overarching hypothesis of this Program Project is that sphingolipid metabolism is dysregulated in AML and represents a promising target for therapy. Acid ceramidase (AC) is a central mediator in sphingolipid metabolism that controls the levels of the pro-apoptotic lipid ceramide and pro-survival lipid sphingosine 1-phosphate (S1P). AC expression and enzymatic activity are significantly elevated in primary AML samples. The premise of the project is supported by our recent data demonstrating that patients exhibiting high AC activity also showed reduced progression-free and overall survival. AC inhibitors and gene knockdown exhibited therapeutic benefit in human AML cell lines, primary AML samples, and murine AML models, thereby validating AC as a promising target in this disease. Two specific aims will be pursued to explore the hypothesis that new AC inhibitors will exhibit increased potency in AML and that molecular alterations modify the susceptibility to AC targeting agents. Specific Aim 1 will characterize the ability of new AC inhibitors to alter sphingolipid metabolism and the mechanism whereby they induce killing in AML cell lines and patient samples. Nano-encapsulation strategies will be optimized to enhance in vivo drug delivery of these compounds. The efficacy of these inhibitors will then be tested in combination with C6-ceramide nanoliposomes (CNL), the Bcl-2 inhibitor venetoclax, and the AraC/venetoclax combinatorial regimen that is investigated across all Projects. We demonstrate that AC inhibitors increase the efficacy of each of these agents. These approaches will be applied to state-of-the-art human AML xenograft models to demonstrate preclinical efficacy and will be compared to standard-of-care chemotherapy models. Specific Aim 2 will determine the relationship between AML molecular subtypes, AC activity, and sensitivity to AC inhibitors. These studies will be completed across diverse AML cell lines and primary patient samples and will include cooperative analysis together with the Systems Metabolomics Core (Core C). Next, the link between AC and mutations (NPM1c, FLT3-ITD, DNMT3AR882H) that are frequently detected in AML will be characterized. These studies will utilize genetically engineered cell lines and mouse models, which also provide the opportunity to validate AC targeting in vivo in the context of defined molecular drivers. The proposed studies will facilitate future clinical application of AC inhibitors in AML by identifying the optimal therapeutic agent as well as susceptible patient populations.

项目摘要 急性髓细胞白血病（AML）是成人最常见的急性白血病，是一种日益严重的公共卫生问题 随着人口老龄化。剂量强化诱导和巩固化疗可显著降低 肿瘤负荷，并诱导临床完全缓解，在大多数年轻人。然而，AML 患者很少达到持久的反应，并且通常复发化疗耐药疾病。因此改进的 治疗方法势在必行。AML在临床行为以及 分子改变该领域越来越多地利用分子谱来提供预后预测因子 结果和确定选择性抑制剂的目标。本计划项目的首要假设是， 鞘脂代谢在AML中失调，代表了有希望的治疗靶点。酸性神经酰胺酶 (AC)是鞘脂代谢的中心介质，其控制促凋亡脂质神经酰胺的水平 和促存活脂质鞘氨醇1-磷酸（S1 P）。AC表达和酶活性显著降低。 在原发性AML样本中升高。该项目的前提是支持我们最近的数据表明， 表现出高AC活性的患者也表现出降低的无进展生存期和总生存期。AC抑制剂和 基因敲除在人AML细胞系、原发性AML样品和鼠AML中表现出治疗益处， 模型，从而验证AC作为这种疾病的一个有前途的目标。为了探讨两个具体目标， 假设新的AC抑制剂将在AML中表现出更高的效力，并且分子改变修饰了 对AC靶向剂的敏感性。具体目标1将表征新AC抑制剂改变 鞘脂代谢及其诱导AML细胞系和患者样品杀伤的机制。 纳米封装策略将被优化，以增强这些化合物的体内药物递送。的 然后将这些抑制剂与C6-神经酰胺纳米脂质体（CNL）、Bcl-2 抑制剂venetoclax和所有项目中研究的AraC/venetoclax组合方案。我们 证明AC抑制剂增加这些药剂中的每一种的功效。将采用这些方法 最先进的人AML异种移植模型，以证明临床前疗效，并将与 标准治疗化疗模型。具体目标2将确定AML分子之间的关系 亚型、AC活性和对AC抑制剂的敏感性。这些研究将在不同的AML细胞中完成。 线和主要患者样本，并将包括与系统代谢组学一起进行的合作分析 核心（核心C）。接下来，AC和突变（NPM 1c，FLT 3-ITD，DNMT 3AR 882 H）之间的联系，这些突变经常被 将对AML中检测到的抗体进行表征。这些研究将利用基因工程细胞系和小鼠 模型，这也提供了机会，以验证AC靶向在体内的背景下，确定的分子 司机拟议的研究将通过确定AC抑制剂在AML中的作用，促进AC抑制剂未来的临床应用。 最佳治疗剂以及易感患者群体。