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Repurposing Clinical ACT Antimalarials for Experimental Melanoma Intervention

Repurposing Clinical ACT Antimalarials for Experimental Melanoma Intervention
重新利用临床 ACT 抗疟药进行实验性黑色素瘤干预
批准号:
10549763
负责人:
Georg T Wondrak
金额:
$32.88万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
未结题
起止时间:
2019-02-01 至 2025-01-31
关键词:
Adverse effectsAmodiaquineAnimal ModelAntimalarialsAntineoplastic AgentsApoptosisArtemisia annuaArtemisininsAutophagocytosisAwardBRAF geneCell Culture TechniquesCell Death InductionCellsCessation of lifeCharacteristicsChloroquineClassificationClinicalClinical ResearchComplementDataDevelopmentDiseaseDisease modelDrug CombinationsDrug usageDysplastic NevusFDA approvedFutureGeneticHomeostasisHumanHypersensitivityInduction of ApoptosisInterventionIronLabelMalariaMalignant NeoplasmsMedicineMelanoma CellModelingMolecularMolecular TargetMusNatural ProductsNeoplasm MetastasisNeural CrestNormal CellOncogene ActivationOncogenesOncogenicOutcomeOxidation-ReductionOxidative StressOxidative Stress InductionParasitesPatientsPeroxidesPharmaceutical PreparationsPharmacodynamicsPhysiologyPrizePrognostic FactorProteomicsPublic HealthReactive Oxygen SpeciesResearchResearch Project GrantsResistanceRoleSesquiterpenesSkin CancerStarvationTFRC geneTestingTherapeuticTherapeutic InterventionTimeTreatment EfficacyTumor TissueUnited StatesUp-RegulationXenograft Modeladductanticancer activitybenflumetolc-myc Genescancer cellchemotherapyclinical efficacycytotoxiccytotoxicityefficacious treatmentefficacy evaluationefficacy testingfeasibility testinghuman diseaseimprovedin vivoinhibitormRNA Expressionmelanocytemelanomamelanomagenesismouse modelnovelpharmacologicpharmacophorepre-clinicalpremalignantrational designreceptor expressionsenescencetargeted agenttargeted treatmenttherapeutic targettranscription factortreatment strategytumortumor growth

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中文摘要
翻译
在美国,恶性黑色素瘤是导致皮肤癌相关死亡的主要原因
英文摘要
Malignant melanoma causes the majority of skin cancer-related deaths in the United States representing a public health burden of considerable magnitude. Our recent research has identified artemisinins, an important class of redox-antimalarials in clinical use worldwide, as redox-directed anticancer agents that target disruption of cellular iron homeostasis, a common alteration of premalignant and malignant cells that causes hypersensitivity to cytotoxic oxidative stress. In this R01 application entitled 'Repurposing Clinical ACT Antimalarials for Experimental Melanoma Intervention', we test the hypothesis that oncogene-driven dysregulation of iron homeostasis represents a molecular Achilles heel characteristic of melanomagenesis that can be targeted by artemisinin-endoperoxide antimalarials. In this comprehensive project, we also test feasibility of using artemisinin-based combination therapeutics (ACT), FDA-approved for pharmacotherapeutic anti-malaria intervention, targeting malignant melanoma in relevant disease models: aim #1: First, the mechanistic relationship between dysregulated c- MYC and transferrin receptor expression, iron homeostasis, and cellular hypersensitivity to artemisinin-based redox intervention will be examined in cell culture and human premalignant and tumor tissue interrogated in microarray format. Novel molecular targets modulated through covalent adduction after iron-dependent artemisinin activation will be identified based on proteomic experimentation using a fluorescently labeled artemisinin probe followed by in vivo efficacy testing in a spontaneous murine genetic melanoma model. aim #2: Following our prior studies on antimelanoma activity of the autophagy-directed ACT antimalarial amodiaquine, we explore mechanism and feasibility of amodiaquine-based experimental chemotherapeutic intervention targeting early and late melanomagenesis. aim #3:Finally, we will test the hypothesis that artemisinin-based intervention combined with specific autophagy-directed ACT antimalarials (amodiaquine, piperaquine, lumefantrine) provides improved therapeutic efficacy inhibiting tumor growth and overcoming BRAF-inhibitor resistance in preclinical xenograft models. The proposed research guides the rational design of future preclinical/clinical studies that promise to facilitate repurposing of FDA-approved ACT- antimalarials for anti-melanoma intervention, benefitting patients in the very near future.
期刊论文(1)
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会议论文
DOI: 10.1002/mc.23016
发表时间: 2019-07
期刊: Molecular carcinogenesis
影响因子: 4.6
作者: [Dickinson SE, Wondrak GT]
通讯作者: Wondrak GT
Repurposing Clinical ACT Antimalarials for Experimental Melanoma Intervention
  • 批准号:
    10093984
  • 项目类别:
  • 资助金额:
    $33.78万
  • 财政年份:
    2019
  • 负责人:
    Georg T Wondrak
  • 依托单位:
Project 1: TLR4 as a Novel Target for Skin Cancer Prevention
  • 批准号:
    10475132
  • 项目类别:
  • 资助金额:
    $19.43万
  • 财政年份:
    2019
  • 负责人:
    Georg T Wondrak
  • 依托单位:
Repurposing Clinical ACT Antimalarials for Experimental Melanoma Intervention
  • 批准号:
    10333277
  • 项目类别:
  • 资助金额:
    $32.99万
  • 财政年份:
    2019
  • 负责人:
    Georg T Wondrak
  • 依托单位:
Project 1: TLR4 as a Novel Target for Skin Cancer Prevention
  • 批准号:
    10686367
  • 项目类别:
  • 资助金额:
    $19.77万
  • 财政年份:
    2019
  • 负责人:
    Georg T Wondrak
  • 依托单位:
海外基金