Combinatorial Decitabine and Liposomal Ceramide for Acute Myeloid Leukemia

地西他滨和脂质体神经酰胺联合治疗急性髓系白血病

• 批准号: 10047258
• 负责人: Brian Michael Barth
• 金额: $ 7.67万
• 依托单位: UNIVERSITY OF NEW HAMPSHIRE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10047258
• 关键词: Aberrant DNA Methylation; Acute Myelocytic Leukemia; Age; Apoptotic; Biochemical Pathway; Biology; Blood; Cell Death; Cell Proliferation; Cell physiology; Ceramides; Cessation of life; Clinical Trials; DNA; DNA Methylation; Decitabine; Disease; Dysmyelopoietic Syndromes; Effectiveness; Epigenetic Process; Exhibits; Functional disorder; Goals; Incidence; Link; Lip structure; Liposomes; Malignant Neoplasms; Mediator of activation protein; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Molecular; Molecular Abnormality; Mutate; Myelogenous; N-caproylsphingosine; Pathway interactions; Phase I Clinical Trials; Phenotype; Population; Process; Regulation; Research; Resistance; Role; Solid Neoplasm; Sphingolipids; Testing; Therapeutic; Tissues; Treatment Efficacy; Up-Regulation; Work; analog; base; cancer cell; cancer therapy; combinatorial; improved; inhibitor/antagonist; innovation; interest; nanoliposome; novel therapeutic intervention; progenitor; resistance mechanism; standard care; therapy resistant

Summary The incidence of acute myeloid leukemia (AML) increases through age, and as the population of the developed world ages, the overall societal incidence will also rise. AML is a genetically heterogeneous disease with molecular abnormalities being observed that influence a wide array of cellular processes. There is substantial need to better understand the processes governing AML therapeutic resistance and to develop better therapeutic strategies. Sphingolipids have gained interest for their roles in cell death and proliferation. Ceramide is a bioactive sphingolipid that can promote cell death. Not surprisingly, various anticancer therapies have been shown to stimulate ceramide accumulation and upregulation of ceramide metabolism has been associated with therapeutic resistance. We and others have worked to develop the ceramide nanoliposome (Lip-C6) as an anticancer therapy that delivers the C6-ceramide analog to malignant cells. Lip-C6 is presently in a phase I clinical trial for solid tumor malignancies (ClinicalTrials.gov identifier: NCT02834611). Unfortunately, resistance to Lip-C6 can develop due to enhanced ceramide metabolism. Long-term, the goal of this proposal is to improve the anti-AML efficacy of therapeutics such as Lip-C6 by identifying and targeting pathways, such as dysfunctional epigenetics, that limit their effectiveness. Therefore, the overarching objective of this proposal is to identify epigenetic-linked sphingolipid metabolic dysfunction as a mediator of resistance to Lip-C6 therapy in AML. Our preliminary studies show that De Novo AML (DN-AML), such as FLT3ITD-mutated AML, is resistant to Lip-C6 therapy and can be defined by an increase in overall sphingolipid metabolic flux. Secondly, this application will study the anti-AML efficacy of the hypomethylating agent decitabine in combination with Lip-C6. The initial aim of this proposal is to link dysfunctional sphingolipid metabolism in AML with aberrant DNA methylation. This will test the hypothesis that resistance to Lip-C6 in of AML can be due to epigenetic dysfunction that upregulates pathways of ceramide metabolism. This is significant given that resistance to ceramide-elevation by Lip-C6 is prominent in DN-AML where alterations to epigenetic regulators can occur. Importantly, the pro-apoptotic sphingolipid ceramide can also be elevated by standard care chemotherapeutics, which highlights the relevance and importance of this metabolic pathway of resistance. The second aim of this proposal is to study the combinatorial anti-AML efficacy of decitabine and Lip-C6. This aim hypothesizes that DNA hypomethylating agents, such as decitabine, can restore the anti-AML efficacy of Lip-C6 for AML with epigenetic dysfunction. Overall, this is important because hypomethylating agents may overcome therapeutic resistance that persists in DN-AML due to epigenetic-driven ceramide metabolism. Overall, this research will advance our understanding of a cooperative therapeutic resistance mechanism involving sphingolipids and epigenetic dysfunction in AML, which will serve as the basis to develop better combinatorial therapeutic approaches.

摘要 急性髓系白血病(AML)的发病率随着年龄的增长而增加，随着人口的发展 随着世界时代的到来，社会总发病率也将上升。AML是一种遗传异质性疾病， 观察到影响广泛的细胞过程的分子异常。有大量的 需要更好地了解AML治疗耐药的过程，并开发更好的治疗方法 战略。鞘磷脂因其在细胞死亡和增殖中的作用而引起人们的兴趣。神经酰胺是一种 能促进细胞死亡的生物活性鞘脂。不足为奇的是，各种抗癌疗法 研究表明，刺激神经酰胺的堆积和上调神经酰胺的代谢与 治疗抵抗力。我们和其他人致力于开发神经酰胺纳米脂质体(Lip-C6)作为一种 将C6-神经酰胺类似物输送到恶性肿瘤细胞的抗癌疗法。Lip-C6目前处于I期 实体肿瘤临床试验(ClinicalTrials.gov识别码：NCT02834611)。不幸的是，抵抗运动 TO Lip-C6可由于神经酰胺代谢增强而发展。从长远来看，这项提议的目标是改善 Lip-C6等治疗药物通过识别和靶向功能障碍等途径而抗AML的疗效 表观遗传学，这限制了它们的有效性。因此，这项提案的首要目标是确定 表观遗传相关的鞘磷脂代谢功能障碍是急性髓细胞白血病患者对Lip-C6治疗抵抗的媒介。我们的 初步研究表明，De Novo AML(Dn-AML)，如Flt3ITD突变的AML，对Lip-C6具有耐药性 治疗，并可定义为总体鞘脂代谢流量的增加。其次，此应用程序将 研究去甲基化药物地西他滨联合Lip-C6抗急性髓系白血病的疗效。最初的目标是 这项建议的目的是将急性髓系白血病的鞘脂代谢功能障碍与DNA甲基化异常联系起来。这将是 验证AML对Lip-C6的抵抗可能是由于上调的表观遗传功能障碍所致的假设 神经酰胺代谢途径。这一点很重要，因为Lip-C6对神经酰胺升高的抵抗性是 在可能发生表观遗传调节改变的DN-AML中表现突出。重要的是，支持细胞凋亡的人 神经鞘脂神经酰胺也可以通过标准护理化疗药物升高，这突出了相关性 以及这种抗药性代谢途径的重要性。这项建议的第二个目的是研究 地西他滨与Lip-C6联合抗AML疗效观察这一目的假设DNA低甲基化 地西他滨等药物可以恢复Lip-C6对有表观遗传功能障碍的AML的抗AML效果。 总体而言，这一点很重要，因为去甲基化药物可能会克服持续存在的治疗耐药性。 由于表观遗传驱动的神经酰胺代谢导致的DN-AML。总体而言，这项研究将增进我们对 AML中涉及鞘磷脂和表观遗传功能障碍的协同治疗耐药机制， 这将为开发更好的联合治疗方法奠定基础。