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
基本信息
- 批准号:10047258
- 负责人:
- 金额:$ 7.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Aberrant DNA MethylationAcute Myelocytic LeukemiaAgeApoptoticBiochemical PathwayBiologyBloodCell DeathCell ProliferationCell physiologyCeramidesCessation of lifeClinical TrialsDNADNA MethylationDecitabineDiseaseDysmyelopoietic SyndromesEffectivenessEpigenetic ProcessExhibitsFunctional disorderGoalsIncidenceLinkLip structureLiposomesMalignant NeoplasmsMediator of activation proteinMetabolicMetabolic PathwayMetabolic dysfunctionMetabolismMolecularMolecular AbnormalityMutateMyelogenousN-caproylsphingosinePathway interactionsPhase I Clinical TrialsPhenotypePopulationProcessRegulationResearchResistanceRoleSolid NeoplasmSphingolipidsTestingTherapeuticTissuesTreatment EfficacyUp-RegulationWorkanalogbasecancer cellcancer therapycombinatorialimprovedinhibitor/antagonistinnovationinterestnanoliposomenovel therapeutic interventionprogenitorresistance mechanismstandard caretherapy resistant
项目摘要
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
项目成果
期刊论文数量(0)
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Brian Michael Barth其他文献
Brian Michael Barth的其他文献
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{{ truncateString('Brian Michael Barth', 18)}}的其他基金
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 - 财政年份:2020
- 资助金额:
$ 7.67万 - 项目类别:
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