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.

项目总结 急性髓系白血病(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 人口老龄化带来的负担。剂量密集型诱导和巩固化疗显著减少 在大多数年轻人中，肿瘤负担和诱导临床完全缓解。然而，AML 患者很少能获得持久的反应，通常会复发，并伴有化疗耐药疾病。因此，改进了 治疗方法势在必行。急性髓细胞白血病在临床行为和 分子变化。该领域越来越多地利用分子图谱来提供预测 结果并确定选择性抑制剂的靶点。该计划项目的首要假设是 鞘磷脂代谢在急性髓细胞白血病中是失调的，是一个有希望的治疗靶点。酸性神经酰胺酶 (Ac)是鞘磷脂代谢的中心介质，控制促凋亡的脂质神经酰胺的水平。 促存活的磷脂鞘氨醇1-磷酸(S1P)。AC的表达和酶活性显著 在原发AML样本中升高。我们最近的数据表明，该项目的前提是 表现出高AC活性的患者也显示出无进展和总体存活率降低。AC抑制剂和 基因敲除在人AML细胞系、原代AML样本和小鼠AML中显示出治疗益处 模型，从而证实AC是治疗这种疾病的有希望的靶点。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，并且分子改变改变 对AC靶向剂的敏感性。具体目标1将描述新的AC抑制剂改变 鞘磷脂代谢及其在急性髓系白血病细胞系和患者样本中诱导杀伤的机制。 将优化纳米包囊策略，以增强这些化合物的体内药物输送。这个 这些抑制剂的有效性将与C6-神经酰胺纳米脂质体(CNL)、Bcl-2联合进行测试 抑制剂万乃馨，以及在所有项目中都进行研究的AraC/万诺克拉克斯联合方案。我们 证明AC抑制剂可以提高这些药物的疗效。这些方法将应用于 到最先进的人类AML异种移植模型，以展示临床前的疗效，并将与 标准护理化疗模式。特异靶向2将决定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 LINES和初级患者样本，并将包括合作分析和系统代谢组学 核心(核心C)。接下来，AC与频繁发生的突变(NPM1c、Flt3-ITD、DNMT3AR882H)之间的联系 在急性髓系白血病中检测到的将具有特征性。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的背景下在体内验证AC靶向的机会 司机。拟议的研究将有助于AC抑制剂未来在AML中的临床应用，因为它确定了 最佳的治疗剂以及易受感染的患者群体。