Targeting Ceramide Glycosylation in AML

靶向 AML 中的神经酰胺糖基化

• 批准号: 10661030
• 负责人: Myles C. Cabot
• 金额: $ 25.86万
• 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/10661030
• 关键词: ABCB1 gene; Acceleration; Acute Myelocytic Leukemia; Acute leukemia; Address; Adjuvant; Adult; Antineoplastic Agents; Apoptosis; Apoptotic; Autophagocytosis; Cell Death; Cell Line; Cell Survival; Cells; Ceramide glucosyltransferase; Ceramides; Chemoresistance; Clinical; Cytarabine; Data; Daunorubicin; Disease; Drug Targeting; Drug resistance; Elements; Employment; Enzymes; Equilibrium; Fenretinide; Generations; Glucosylceramides; Goals; Golgi Apparatus; Growth; Human; Leukemic Cell; Lipids; Malignant Neoplasms; Membrane; Metabolic; Metabolism; Molecular; Multi-Drug Resistance; Outcome; Patients; Permeability; Pharmaceutical Preparations; Phenotype; Play; Pre-Clinical Model; Property; Regimen; Relapse; Research; Resistance; Role; SPHK1 enzyme; Selection for Treatments; Sphingolipids; Therapeutic; Thinking; Time; Tumor Suppressor Proteins; Valspodar; Work; acute myeloid leukemia cell; analog; anti-cancer; anticancer activity; cancer cell; cancer therapy; chemosensitizing agent; chemotherapy; combinatorial; cytotoxicity; drug development; effective therapy; galactosylgalactosylglucosylceramidase; glycosylation; improved; inhibitor; innovation; leukemia; leukemia treatment; nanoliposome; pharmacologic; pressure; programs; refractory cancer; relapse patients; response; therapeutic target; therapeutically effective; treatment response; tumor progression

PROJECT SUMMARY The sphingolipid (SL) ceramide is a potent tumor suppressor that contributes to the promotion of apoptosis and autophagy. Management of these responses in cancer cells is dependent on the dynamic balance between ceramide and its metabolites, some of which can promote cell survival. Maintaining elevated levels of intracellular ceramide is important for supporting its unique anticancer properties. Thus, from a strategic point, controlling the metabolism of ceramide offers new opportunities for regulating cancer growth. The goal of this work is to assess innovative steps to develop ceramide into an effective anticancer agent to treat acute myelogenous leukemia (AML), the most common type of leukemia in adults, and to evaluate the role of SLs in chemotherapy resistance. There is a critical need to develop more effective therapies for AML, especially in relapse patients. Although many hypotheses have been proposed to explain therapeutic relapse, none have led to a complete understanding of the molecular mechanisms of AML resistance, and there have been few treatment advances in 40 years. Our premise is that upregulated glycosylation of ceramide is the major metabolic avenue contributing to ceramide neutralization in cancer cells, and it is also strongly associated with the multidrug- resistant phenotype in cancer. This project will focus on targeting ceramide glycosylation to enhance and propel ceramide-driven AML cell death. Two innovative strategies will be employed to increase intracellular ceramide levels: 1) use of a nanoliposomal, cell-permeable ceramide analog, C6-ceramide (CNL, ceramide nanoliposome), and 2) employment of ceramide “generators”, drugs such as 4-HPR (fenretinide) or PSC833 (valspodar), that increase intracellular levels of natural long-chain ceramides. These strategies will be evaluated separately, in combination, and in the presence of agents that inhibit ceramide glycosylation. We hypothesize that taking steps to pharmacologically increase and maintain intracellular ceramide levels will enhance the overall anticancer impact of ceramide-centric therapy. Further, given new findings on chemotherapy selection pressure in AML, we hypothesize that aberrant SL metabolism plays a key role in drug resistance and that targeting SL metabolism will potentially circumvent drug resistance. The following three Specific Aims will be pursued to achieve our goal of employing ceramide and SL therapy in AML. 1. Determine the effects of chemotherapy selection pressure on SL metabolism and the drug resistant phenotype in AML. 2. Determine the effects of inhibitors of ceramide glycosylation on cytotoxicity and mechanism of action of CNL and ceramide-generating drugs. 3. Assess the anticancer activity of ceramide-centric therapeutics in AML preclinical models. We predict that using adjuvants to block ceramide glycosylation will enhance ceramide-centric (CNL + ceramide “generators”) therapy in AML.

项目摘要 鞘脂（SL）神经酰胺是一种有效的肿瘤抑制剂，有助于促进细胞凋亡和 自噬。癌细胞中这些反应的管理取决于 神经酰胺及其代谢产物，其中一些可以促进细胞存活。维持较高的细胞内水平 神经酰胺对于支持其独特的抗癌特性很重要。从战略角度来控制 神经酰胺的代谢为控制癌症生长提供了新的机会。这项工作的目的是评估 创新的步骤将神经酰胺开发成有效的抗癌剂，以治疗急性脊髓性白血病 （AML）是成年人中最常见的白血病类型，并评估SLS在化学疗法耐药性中的作用。 对于AML开发更有效的疗法，尤其是在继电器患者中，迫切需要。虽然 已经提出了许多假设来解释治疗中继，没有一个导致完整的 了解AML耐药性的分子机制，几乎没有治疗的进展 40年。我们的前提是，神经酰胺的最新糖基化是主要的代谢大道 有助于癌细胞中的神经酰胺神经元化，并且与多药 癌症中的抗性表型。该项目将着重于靶向神经酰胺糖基化以增强和推进 神经酰胺驱动的AML细胞死亡。将聘请两种创新策略来增加细胞内神经酰胺 级别：1）使用纳米脂质体，可渗透的神经酰胺类似物，C6-陶瓷（CNL，Ceramide） 纳米脂体）和2）雇用神经酰胺“发电机”，例如4-HPR（fenretinide）或PSC833的药物 （valspodar），增加了天然长链神经酰胺的细胞内水平。这些策略将被评估 分别结合在一起，并在存在抑制神经酰胺糖基化的药物的情况下。我们假设 采取步骤以物理增加和维持细胞内神经酰胺水平将增强整体 以神经酰胺为中心的疗法的抗癌影响。此外，考虑到有关化学疗法选择压力的新发现 在AML中，我们假设异常SL代谢在耐药性中起关键作用，并且针对SL 代谢可能会避免耐药性。以下三个具体目标将被追求 实现我们在AML中采用神经酰胺和SL疗法的目标。 1。确定化学疗法选择压力对SL代谢和耐药性的影响 AML中的表型。 2。确定神经酰胺糖基化抑制剂对细胞毒性和作用机理的影响 CNL和神经酰胺生成药物。 3。评估AML临床前模型中以神经酰胺为中心疗法的抗癌活性。我们预测 使用调节器阻断神经酰胺糖基化将增强以神经酰胺为中心（CNL + Ceramide AML中的“发电机”）。