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 急性髓样白血病（AML）的发病率随着年龄的增长而增加，随着发达的人群 世界时代，整体社会发生率也将上升。 AML是一种遗传异质性疾病， 观察到会影响各种细胞过程的分子异常。有实质性 需要更好地了解有关AML治疗耐药性并发展更好治疗的过程 策略。鞘脂对它们在细胞死亡和增殖中的作用引起了人们的兴趣。神经酰胺是一个 可以促进细胞死亡的生物活性鞘脂。毫不奇怪，各种抗癌疗法已经 证明可以刺激神经酰胺的积累和神经酰胺代谢的上调与 治疗性抗性。我们和其他人一直在努力开发神经酰胺纳米型体（LIP-C6） 抗癌治疗可提供与恶性细胞类似物的C6-陶瓷类似物。 Lip-C6目前处于I期 实体肿瘤恶性肿瘤的临床试验（临床Trialtrials.gov标识符：NCT02834611）。不幸的是，抵抗 由于神经酰胺代谢增强，可以发展为LIP-C6。长期，该提议的目的是改善 通过识别和靶向途径（例如功能失调），治疗剂（例如LIP-C6）的抗AML功效 表观遗传学，这限制了它们的有效性。因此，该提议的总体目标是确定 表观遗传连接的鞘脂代谢功能障碍是AML中对LIP-C6治疗的抗性介体。我们的 初步研究表明，从Novo AML（DN-AML）（例如FLT3Itd-Mutated AML）对LIP-C6具有抵抗力 治疗，可以通过总体鞘脂代谢通量的增加来定义。其次，此应用程序将 研究低甲基化剂去甲他滨与LIP-C6结合使用的抗AML功效。最初的目标 该建议的是将AML中功能失调的鞘脂代谢与异常的DNA甲基化联系起来。这会 检验以下假设，即AML中对LIP-C6的耐药性可能是由于表观遗传功能障碍引起的。 神经酰胺代谢的途径。这很重要，因为唇-C6对神经酰胺的抗性为 在DN-AML中突出的，可能发生对表观遗传调节剂的改变。重要的是，促凋亡 鞘脂神经酰胺也可以通过标准护理化学治疗剂提升，这突出了相关性 这种代谢途径的重要性。该提议的第二个目的是研究 Decitabine和Lip-C6的组合抗AML功效。这个目的假设DNA降甲基化 诸如Decitabine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。 总体而言，这很重要，因为低甲基化剂可能会克服持续的治疗性抗性 DN-AML由于表观遗传驱动的神经酰胺代谢。总体而言，这项研究将提高我们的理解 AML中涉及鞘脂和表观遗传功能障碍的合作治疗抗性机制 这将是开发更好组合治疗方法的基础。