Targeting Acid Ceramidase in AML

靶向 AML 中的酸性神经酰胺酶

• 批准号: 10430089
• 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/10430089
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult; Age; Age-Years; Apoptosis; Apoptotic; BCL2 gene; Behavior; Biochemical; Biochemical Genetics; Biology; Caspase; Cell Line; Cell Survival; Cells; Ceramides; Chemoresistance; Clinic; Clinical; DNMT3a mutation; Data; Diagnosis; Disease; 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; Knowledge; Lead; Leukemic Cell; Link; Lipids; MCL1 gene; Mediator of activation protein; Metabolism; Minority; Modeling; Molecular; Molecular Profiling; Molecular Target; Mus; Mutation; Myelogenous; N-caproylsphingosine; Patients; Pharmacology; Population; Preclinical Testing; Predisposition; 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; 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.

项目概要 急性髓系白血病 (AML) 是成人中最常见的急性白血病，是一个日益严重的公共卫生问题 人口老龄化带来的负担。剂量密集型诱导和巩固化疗可显着减少 肿瘤负荷并诱导大多数年轻人的临床完全缓解。然而，反洗钱 患者很少获得持久的缓解，并且通常会因耐药性疾病而复发。由此，改进了 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分析来提供预后预测因子 结果并确定选择性抑制剂的目标。该计划项目的总体假设是 急性髓性白血病中鞘脂代谢失调，是一个有希望的治疗靶点。酸性神经酰胺酶 (AC) 是鞘脂代谢的中心介质，控制促凋亡脂质神经酰胺的水平 和促生存脂质 1-磷酸鞘氨醇 (S1P)。 AC 表达和酶活性显着 在原发性 AML 样本中升高。我们最近的数据支持了该项目的前提，表明 表现出高 AC 活性的患者也表现出无进展生存期和总生存期降低。 AC抑制剂和 基因敲除在人类 AML 细胞系、原发性 AML 样本和小鼠 AML 中表现出治疗效果 模型，从而验证 AC 作为这种疾病的一个有希望的目标。将追求两个具体目标来探索 假设新的 AC 抑制剂将在 AML 中表现出更强的效力，并且分子改变会改变 对AC靶向剂的敏感性。具体目标 1 将描述新型 AC 抑制剂改变的能力 鞘脂代谢及其在 AML 细胞系和患者样本中诱导杀伤的机制。 纳米封装策略将得到优化，以增强这些化合物的体内药物输送。这 然后将与 C6-神经酰胺纳米脂质体 (CNL)、Bcl-2 结合测试这些抑制剂的功效 抑制剂 Venetoclax，以及在所有项目中进行研究的 AraC/venetoclax 组合方案。我们 证明 AC 抑制剂可提高每种药物的功效。这些方法将被应用 与最先进的人类 AML 异种移植模型一起展示临床前疗效，并将与 标准护理化疗模型。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 品系和主要患者样本，并将包括与系统代谢组学的合作分析 核心（核心C）。接下来，AC 与经常出现的突变（NPM1c、FLT3-ITD、DNMT3AR882H）之间的联系 AML 中检测到的特征将被描述。这些研究将利用基因工程细胞系和小鼠 模型，这也提供了在定义的分子背景下验证体内 AC 靶向的机会 司机。拟议的研究将通过确定 AC 抑制剂在 AML 中的未来临床应用 最佳治疗剂以及易感患者群体。