Targeting Ceramide Metabolism in AML

靶向 AML 中的神经酰胺代谢

• 批准号: 8919675
• 负责人: MARK KESTER
• 金额: $ 30.68万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8919675
• 关键词: Acute Myelocytic Leukemia; Animal Model; Antineoplastic Agents; Apoptosis; Apoptotic; Autophagocytosis; Autophagosome; Biological Assay; Blast Cell; C-KIT Gene; Cancer Model; Categories; Cell Death; Cell Line; Cell model; Cells; Ceramide glucosyltransferase; Ceramides; Collaborations; Cytotoxic agent; Data; Disease; Drug Formulations; Encapsulated; Engineering; Exhibits; Gene Silencing; Generations; Goals; Hydrophobicity; In Vitro; Lipids; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolism; Microtubules; Modeling; Molecular; Mus; N-caproylsphingosine; Nanotechnology; Outcome; P-Glycoprotein; P-Glycoproteins; Patients; Pharmaceutical Preparations; Population; Prognostic Marker; Proto-Oncogene Protein c-kit; Proto-Oncogene Proteins c-akt; Publishing; Resistance; Sampling; Solutions; Sphingolipids; Stem cells; Tamoxifen; Therapeutic; Vinblastine; base; cancer cell; caspase-8; chemotherapy; combinatorial; design; dihydroceramide; dihydroceramide desaturase; galactosylgalactosylglucosylceramidase; in vivo; in vivo Model; inhibitor/antagonist; killings; leukemic stem cell; nano; nanoliposome; nanotherapy; progenitor; prognostic; sphingosine kinase; stem; survivin; synergism; trafficking; tumor

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.

AML是一组异质性的恶性疾病，其主要疗法在最近发生了什么变化 几十年。鞘脂代谢以促凋亡分子神经酰胺为中心，代表 在这一和其他恶性肿瘤中正在研究的治疗大道。这个项目源于假设 该基于神经酰胺的疗法可以用作选择性和敏感的抗癌药。 不幸的是，基于神经酰胺的治疗剂的潜力受到细胞覆盖性和 疏水性。我们开创了使用纳米技术从疏水剂转动神经酰胺的使用 作为亲水性药物，在癌症模型中设计了具有明显疗效的C6-粘酰胺纳米型纳米酰胺。 初步数据表明，神经酰胺纳米脂质体在多个AML细胞系中活跃 情况，但是灵敏度高度可变。因此，该项目的目标是第二代的设计 神经酰胺纳米叶胶体在对常规抗性的AML患者中发挥疗效 化学疗法。在特定目标1中，我们将优化第二代纳米脂质体神经酰胺治疗 AML的处理。为了最大化疗效，将通过 封装药理学剂以抑制神经酰胺代谢或自噬。我们也会积极 靶向神经酰胺纳米脂质体至AML祖细胞种群，最初是通过抗CD117（C-KIT）的结合来 优先表达在造血干细胞中。在特定目标2中，我们将调查 神经酰胺纳米注合体与药理学之间有效性增强的机制 抑制神经酰胺代谢或自噬的药物。具体来说，基于初步数据，我们将 研究该协同作用是否是通过从自噬到凋亡和/或A的分子开关介导的 长链促凋亡神经酰胺物种的协同升高。我们还将表征贡献 在定义的AML患者中，选择性神经酰胺合酶至长链神经酰胺物种的升高 亚型。在编程项目和核心的必不可少的支持下，该项目将迅速 表征和验证第二代神经酰胺纳米脂质体在定义的AML中的疗效 人群。