Targeting Ceramide Metabolism in AML

靶向 AML 中的神经酰胺代谢

• 批准号: 8554594
• 负责人: MARK KESTER
• 金额: $ 30.57万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8554594
• 关键词: Acute Myelocytic Leukemia; Antineoplastic Agents; Apoptosis; Apoptotic; Autophagocytosis; Blast Cell; C-KIT Gene; Cancer Model; Categories; Cell Line; Cells; Ceramides; Data; Disease; Engineering; Exhibits; Generations; Goals; Hydrophobicity; Instruction; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolism; Modeling; Molecular; N-caproylsphingosine; Nanotechnology; Outcome; Patients; Pharmaceutical Preparations; Population; Proto-Oncogene Protein c-kit; Resistance; Sphingolipids; Stem cells; Therapeutic; base; chemotherapy; design; dihydroceramide desaturase; in vivo Model; nanoliposome; progenitor; prognostic; stem; synergism

AML is a heterogeneous group of malignant disorders whose primary therapy has changed little in recent decades. Sphingolipid metabolism, centered on the pro-apoptotic molecule ceramide, represents an understudied therapeutic avenue in this and other malignancies. This project stems from the hypothesis that ceramide-based therapeutics can be utilized as selective and sensitive anti-cancer agents. Unfortunately, the potential of ceramide-based therapeutics is severely limited by cell-impermeability and hydrophobicity. We have pioneered the use of nanotechnology to turn ceramide from a hydrophobic agent into a hydrophilic drug, engineering a C6-ceramide nanoliposome with clear efficacy in cancer models. Preliminary data suggest that ceramide nanoliposomes are active in multiple AML cell lines and primary cases, but sensitivity is highly variable. Thus, the goal of the project is the design of second-generation ceramide nanoliposomes that exert efficacy in AML patients who are resistant to conventional chemotherapy. In Specific Aim 1, we will optimize second-generation nanoliposomal ceramide therapy for the treatment of AML. To maximize efficacy, ceramide nanoliposomes will be re-engineered via encapsulation of pharmacological agents to inhibit ceramide metabolism or autophagy. We will also actively target ceramide nanoliposomes to AML progenitor populations, initially via conjugation of anti-CD117 (c-kit), which is preferentially expressed in hematopoitic stem cells. In Specific Aim 2, we will investigate mechanisms underlying the enhanced efficacy between ceramide nanoliposomes and pharmacological agents that inhibit ceramide metabolism or autophagy. Specifically, based upon preliminary data, we will investigate if this synergism is mediated via a molecular-based switch from autophagy to apoptosis and/or a synergistic elevation of long chain pro-apoptotic ceramide species. We will also characterize the contribution of selective ceramide synthases to the elevation of long chain ceramide species in defined AML patient subtypes. With the indispensable support of programmatic projects and cores, this project will rapidly characterize and validate the efficacy of second-generation ceramide nanoliposomes in defined AML populations. RELEVANCE (See instructions): Acute myelogenous leukemia (AML) is biologically heterogeneous and exhibits significant variability in sphingolipid metabolism. Current therapy of AML is highly toxic and yields variable and ultimately inadequate outcomes. Additional therapeutic options are necessary for AML. The present project engineers, characterizes and validates second-generation ceramide nanoliposomes as selective and sensitive therapeutics in AML patients in poor prognostic categories. State of the art in-vivo models of AML blasts will allow assessment of ceramide-based therapeutics.

AML是一组异质性的恶性疾病，其主要治疗方法近年来变化不大 几十年以促凋亡分子神经酰胺为中心的鞘脂代谢，代表了一种新的细胞凋亡机制。 在这种和其他恶性肿瘤的治疗途径上研究不足。这个项目源于一个假设 基于神经酰胺的治疗剂可用作选择性和敏感的抗癌剂。 不幸的是，基于神经酰胺的治疗剂的潜力受到细胞不渗透性和细胞毒性的严重限制。 疏水性我们率先使用纳米技术将神经酰胺从疏水剂 将C6-神经酰胺纳米脂质体改造成亲水性药物，在癌症模型中具有明确的疗效。 初步数据表明，神经酰胺纳米脂质体在多种AML细胞系和原发性AML细胞系中具有活性。 病例，但敏感性变化很大。因此，该项目的目标是设计第二代 神经酰胺纳米脂质体在对常规化疗耐药的AML患者中发挥功效 化疗在具体目标1中，我们将优化第二代纳米脂质体神经酰胺治疗， AML的治疗。为了最大限度地提高疗效，神经酰胺纳米脂质体将通过以下方式进行重新设计： 包封药理学试剂以抑制神经酰胺代谢或自噬。我们还将积极 将神经酰胺纳米脂质体靶向AML祖细胞群体，最初通过抗CD 117（c-kit）缀合， 其优先在造血干细胞中表达。在第二阶段，我们将研究 神经酰胺纳米脂质体和药理学之间增强功效的潜在机制 抑制神经酰胺代谢或自噬的药剂。根据初步数据，我们将 研究这种协同作用是否是通过从自噬到凋亡的基于分子的开关和/或 长链促凋亡神经酰胺种类的协同升高。我们还将描述贡献 选择性神经酰胺转移酶对确定的AML患者中长链神经酰胺种类升高的影响 亚型在不可或缺的纲领性项目和核心的支持下，该项目将迅速 表征和验证第二代神经酰胺纳米脂质体在确定的AML中的疗效 人口。 相关性（参见说明）： 急性髓性白血病（AML）是生物学异质性的，并且在以下方面表现出显著的变异性： 鞘脂代谢目前的AML治疗是高毒性的，并产生可变的， 不充分的结果。AML需要额外的治疗选择。现任项目工程师， 表征并验证第二代神经酰胺纳米脂质体的选择性和敏感性 在预后不良类别的AML患者中，AML原始细胞的最新体内模型将 允许评估基于神经酰胺的治疗剂。