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.

概括 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 世界范围内，社会整体发病率也将上升。 AML 是一种遗传异质性疾病， 观察到影响多种细胞过程的分子异常。有大量的 需要更好地了解控制 AML 治疗耐药的过程并开发更好的治疗方法 策略。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。毫不奇怪的是，各种抗癌疗法已经出现 显示可刺激神经酰胺积累和神经酰胺代谢上调与 治疗抵抗。我们和其他人致力于开发神经酰胺纳米脂质体（Lip-C6）作为 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：NCT02834611）。不幸的是，抵抗 由于神经酰胺代谢增强，可形成 Lip-C6。从长远来看，该提案的目标是改善 通过识别和靶向通路（例如功能失调的通路）来提高 Lip-C6 等疗法的抗 AML 功效 表观遗传学，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是 AML 中 Lip-C6 治疗耐药的介质。我们的 初步研究表明 De Novo AML (DN-AML)，例如 FLT3ITD 突变的 AML，对 Lip-C6 具有耐药性 治疗，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 联合使用的抗 AML 功效。最初的目标 该提案的目的是将 AML 中功能失调的鞘脂代谢与异常 DNA 甲基化联系起来。这将 检验以下假设：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 神经酰胺代谢途径。鉴于 Lip-C6 对神经酰胺升高的抵抗力，这一点很重要 在 DN-AML 中很突出，表观遗传调节因子可能发生改变。重要的是，促凋亡 标准护理化疗也可以提高鞘脂神经酰胺的水平，这凸显了相关性 以及这种抵抗代谢途径的重要性。本提案的第二个目的是研究 地西他滨和 Lip-C6 的组合抗 AML 功效。该目标假设 DNA 低甲基化 诸如地西他滨之类的药物可以恢复 Lip-C6 对具有表观遗传功能障碍的 AML 的抗 AML 功效。 总的来说，这很重要，因为低甲基化药物可以克服持续存在的治疗耐药性 由表观遗传驱动的神经酰胺代谢引起的 DN-AML。总的来说，这项研究将增进我们的理解 涉及 AML 中鞘脂和表观遗传功能障碍的协同治疗耐药机制， 这将作为开发更好的组合治疗方法的基础。