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 这种癌症和其他恶性肿瘤的治疗途径尚未得到充分研究。该项目源于假设 基于神经酰胺的疗法可用作选择性和敏感的抗癌剂。 不幸的是，基于神经酰胺的疗法的潜力受到细胞不渗透性和 疏水性。我们率先使用纳米技术将神经酰胺从疏水剂转变为疏水剂 转化为亲水性药物，设计出在癌症模型中具有明显功效的 C6-神经酰胺纳米脂质体。 初步数据表明，神经酰胺纳米脂质体在多种 AML 细胞系和原代细胞中具有活性。 例，但敏感性差异很大。因此，该项目的目标是设计第二代 神经酰胺纳米脂质体对传统药物耐药的 AML 患者发挥功效 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疗法 AML 的治疗。为了最大限度地发挥功效，神经酰胺纳米脂质体将通过重新设计 封装药物以抑制神经酰胺代谢或自噬。我们也将积极 最初通过抗 CD117 (c-kit) 缀合，将神经酰胺纳米脂质体靶向 AML 祖细胞群， 它优先在造血干细胞中表达。在具体目标 2 中，我们将调查 神经酰胺纳米脂质体和药理学之间增强功效的机制 抑制神经酰胺代谢或自噬的药物。具体来说，根据初步数据，我们将 研究这种协同作用是否是通过基于分子的从自噬到细胞凋亡的转换和/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 选择性神经酰胺合酶对特定 AML 患者长链神经酰胺种类升高的影响 亚型。在规划项目和核心项目不可或缺的支持下，该项目将迅速 表征并验证第二代神经酰胺纳米脂质体在特定 AML 中的功效 人口。 相关性（参见说明）： 急性髓性白血病 (AML) 具有生物学异质性，并且表现出显着的变异性 鞘脂代谢。目前的 AML 疗法具有剧毒，且效果不一，最终 结果不充分。 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 预后不良类别的 AML 患者的治疗。最先进的 AML 母细胞体内模型 允许评估基于神经酰胺的疗法。