Malignant melanoma causes the majority of skin cancer-related deaths in the UnitedStates representing a public health burden of considerable magnitude. Our recentresearch has identified artemisinins an important class of redox-antimalarials in clinicaluse worldwide as redox-directed anticancer agents that target disruption of cellular ironhomeostasis a common alteration of premalignant and malignant cells that causeshypersensitivity to cytotoxic oxidative stress. In this R01 application entitled'Repurposing Clinical ACT Antimalarials for Experimental Melanoma Intervention' wetest the hypothesis that oncogene-driven dysregulation of iron homeostasis represents amolecular Achilles heel characteristic of melanomagenesis that can be targeted byartemisinin-endoperoxide antimalarials. In this comprehensive project we also testfeasibility of using artemisinin-based combination therapeutics (ACT) FDA-approved forpharmacotherapeutic anti-malaria intervention targeting malignant melanoma in relevantdisease models: aim #1: First the mechanistic relationship between dysregulated c-MYC and transferrin receptor expression iron homeostasis and cellular hypersensitivityto artemisinin-based redox intervention will be examined in cell culture and humanpremalignant and tumor tissue interrogated in microarray format. Novel moleculartargets modulated through covalent adduction after iron-dependent artemisinin activationwill be identified based on proteomic experimentation using a fluorescently labeledartemisinin probe followed by in vivo efficacy testing in a spontaneous murine geneticmelanoma model. aim #2: Following our prior studies on antimelanoma activity of theautophagy-directed ACT antimalarial amodiaquine we explore mechanism andfeasibility of amodiaquine-based experimental chemotherapeutic intervention targetingearly and late melanomagenesis. aim #3:Finally we will test the hypothesis thatartemisinin-based intervention combined with specific autophagy-directed ACTantimalarials (amodiaquine piperaquine lumefantrine) provides improved therapeuticefficacy inhibiting tumor growth and overcoming BRAF-inhibitor resistance in preclinicalxenograft models. The proposed research guides the rational design of futurepreclinical/clinical studies that promise to facilitate repurposing of FDA-approved ACT-antimalarials for anti-melanoma intervention benefitting patients in the very near future.