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: 10602102
• 负责人: Brian Michael Barth
• 金额: $ 7.38万
• 依托单位: SOUTH DAKOTA SCHOOL OF MINES AND TECHN'Y
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602102
• 关键词: Combinatorial; Decitabine; Liposomal; Ceramide; Acute

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.

总结 急性髓性白血病（AML）的发病率随着年龄的增长而增加，并且随着发达国家人口的增加， 随着世界人口老龄化，整个社会的发病率也将上升。AML是一种遗传异质性疾病， 观察到的分子异常影响了广泛的细胞过程。有大量 我们需要更好地了解AML治疗耐药性的控制过程，并开发更好的治疗方法， 战略布局鞘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 具有生物活性的鞘脂，可以促进细胞死亡。毫不奇怪，各种抗癌疗法已经被广泛应用于癌症治疗。 显示刺激神经酰胺积累和神经酰胺代谢的上调与 治疗抵抗我们和其他人一直致力于开发神经酰胺纳米脂质体（Lip-C6）， 将C6-神经酰胺类似物递送至恶性细胞的抗癌疗法。Lip-C6目前处于I期 实体瘤恶性肿瘤的临床试验（ClinicalTrials.gov标识符：NCT 02834611）。不幸的是， 到Lip-C6可以发展由于增强神经酰胺代谢。从长远来看，该提案的目标是改善 通过鉴定和靶向途径，如功能障碍的， 表观遗传学，这限制了它们的有效性。因此，本提案的总体目标是确定 表观遗传相关的鞘脂代谢功能障碍作为AML中Lip-C6疗法抗性的介导物。我们 初步研究表明，新发AML（DN-AML），如FLT 3 ITD突变的AML，对Lip-C6耐药 在某些实施方案中，鞘脂代谢是治疗的一部分，并且可以通过总体鞘脂代谢通量的增加来定义。其次，该应用程序将 研究低甲基化剂地西他滨与Lip-C6组合的抗AML功效。最初的目标 这一建议的一个重要方面是将AML中的功能失调的鞘脂代谢与异常的DNA甲基化联系起来。这将 检验AML对Lip-C6的耐药性可能是由于表观遗传功能障碍， 神经酰胺代谢途径。考虑到Lip-C6对神经酰胺升高的抗性， 在DN-AML中表现突出，其中可能发生表观遗传调节因子的改变。重要的是， 鞘脂神经酰胺也可以通过标准护理化疗剂升高，这突出了 以及这种抵抗代谢途径的重要性本建议的第二个目的是研究 地西他滨和Lip-C6的组合抗AML功效。这一目标假设DNA低甲基化 药物如地西他滨可以恢复Lip-C6对具有表观遗传功能障碍的AML的抗AML功效。 总的来说，这是重要的，因为低甲基化剂可以克服持续存在的治疗抗性。 DN-AML由于表观遗传驱动的神经酰胺代谢。总的来说，这项研究将促进我们的理解， AML中涉及鞘脂和表观遗传功能障碍的协同治疗耐药机制， 这将成为开发更好的组合治疗方法的基础。