Targeting Ceramide Metabolism in AML

AML是一组不同种类的恶性疾病，其主要治疗方法在最近几年几乎没有改变。 几十年。神经鞘磷脂代谢以促凋亡分子神经酰胺为中心，代表着一种 对这种和其他恶性肿瘤的治疗途径研究不足。这个项目源于这样一个假设 神经酰胺类药物可作为选择性和敏感性的抗癌药物。 不幸的是，神经酰胺治疗的潜力受到细胞不通透性和 疏水性。我们率先使用纳米技术将神经酰胺从疏水剂转化为神经酰胺。 转化为亲水性药物，设计出在癌症模型中具有明显疗效的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个AML细胞系和原代细胞中具有活性 病例，但敏感性是高度可变的。因此，该项目的目标是设计第二代 神经酰胺纳米脂质体对耐药的急性髓系白血病患者的疗效 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 急性髓系白血病的治疗。为了最大限度地提高疗效，神经酰胺纳米脂质体将通过 包裹抑制神经酰胺代谢或自噬的药理制剂。我们还将积极 靶向AML祖细胞群体的神经酰胺纳米脂质体，最初通过抗CD117(c-kit)的偶联， 它在造血干细胞中优先表达。在具体目标2中，我们将调查 神经酰胺纳米脂质体与药理作用增强效应的机制 抑制神经酰胺代谢或自噬的药物。具体地说，根据初步数据，我们将 研究这种协同作用是否通过基于分子的开关从自噬到凋亡和/或 长链促细胞凋亡神经酰胺种类的协同升高。我们还将描述这些贡献的特征 选择性神经酰胺合成酶对确诊急性髓系白血病患者长链神经酰胺种类的影响 子类型。在方案项目和核心的不可或缺的支持下，该项目将迅速 第二代神经酰胺纳米脂质体治疗急性髓系白血病的疗效鉴定和验证 人口。 相关性(请参阅说明)： 急性髓系白血病(AML)在生物学上是异质性的，表现出显著的变异性 鞘脂代谢。目前对急性髓细胞白血病的治疗是剧毒的，产生的结果多种多样，最终 结果不充分。对于AML来说，其他治疗选择是必要的。现在的项目工程师， 表征和验证第二代神经酰胺纳米脂质体的选择性和敏感性 预后不良的急性髓细胞白血病患者的治疗。最先进的急性髓系白血病爆炸体内模型将 允许评估以神经酰胺为基础的治疗方法。

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.