Targeting Ceramide Glycosylation in AML

靶向 AML 中的神经酰胺糖基化

• 批准号: 10430090
• 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/10430090
• 关键词: ABCB1 gene; Acute Myelocytic Leukemia; Acute leukemia; Address; Adjuvant; Adult; Antineoplastic Agents; Apoptosis; 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; N-caproylsphingosine; Outcome; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Pre-Clinical Model; Property; Regimen; Relapse; Research; Resistance; Role; SPHK1 enzyme; Sphingolipids; Therapeutic; Thinking; Time; Tumor Suppressor Proteins; Valspodar; Work; acute myeloid leukemia cell; analog; anti-cancer; anticancer activity; base; cancer cell; cancer therapy; chemosensitizing agent; chemotherapy; combinatorial; cytotoxicity; drug development; effective therapy; galactosylgalactosylglucosylceramidase; glycosylation; improved; inhibitor; innovation; leukemia; nanoliposome; 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.

项目概要 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之间的动态平衡 神经酰胺及其代谢物，其中一些可以促进细胞存活。维持细胞内的高水平 神经酰胺对于支持其独特的抗癌特性非常重要。因此，从战略角度看，控制 神经酰胺的代谢为调节癌症生长提供了新的机会。这项工作的目标是评估 将神经酰胺开发为治疗急性髓性白血病的有效抗癌剂的创新步骤 (AML)，成人最常见的白血病类型，并评估 SL 在化疗耐药中的作用。 迫切需要开发更有效的 AML 治疗方法，尤其是复发患者。虽然 人们提出了许多假设来解释治疗复发，但没有一个能够得出完整的结论 了解 AML 耐药的分子机制，但治疗进展甚少 40年后。我们的前提是神经酰胺的糖基化上调是主要的代谢途径 有助于癌细胞中的神经酰胺中和，并且它也与多药密切相关 癌症中的耐药表型。该项目将重点关注神经酰胺糖基化，以增强和推动 神经酰胺驱动的 AML 细胞死亡。将采用两种创新策略来增加细胞内神经酰胺 水平：1) 使用纳米脂质体、细胞可渗透的神经酰胺类似物、C6-神经酰胺（CNL、神经酰胺 纳米脂质体），2）使用神经酰胺“发生器”，药物如 4-HPR（芬维A胺）或 PSC833 （valspodar），可增加天然长链神经酰胺的细胞内水平。这些策略将被评估 单独地、组合地以及在抑制神经酰胺糖基化的试剂存在下。我们假设 采取药物措施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治疗的抗癌作用。此外，考虑到化疗选择压力的新发现 在 AML 中，我们假设异常的 SL 代谢在耐药性中起着关键作用，并且靶向 SL 新陈代谢将有可能规避耐药性。将努力实现以下三个具体目标： 实现我们在 AML 中采用神经酰胺和 SL 疗法的目标。 1.确定化疗选择压力对SL代谢和耐药的影响 AML 的表型。 2. 确定神经酰胺糖基化抑制剂对细胞毒性的影响及其作用机制 CNL 和神经酰胺生成药物。 3. 评估以神经酰胺为中心的疗法在 AML 临床前模型中的抗癌活性。我们预测 使用佐剂阻断神经酰胺糖基化将增强神经酰胺中心（CNL + 神经酰胺 “发电机”）治疗 AML。