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: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549763
• 关键词: Adverse effects; Amodiaquine; Animal Model; Antimalarials; Antineoplastic Agents; Apoptosis; Artemisia annua; Artemisinins; Autophagocytosis; Award; BRAF gene; Cell Culture Techniques; Cell Death Induction; Cells; Cessation of life; Characteristics; Chloroquine; Classification; Clinical; Clinical Research; Complement; Data; Development; Disease; Disease model; Drug Combinations; Drug usage; Dysplastic Nevus; FDA approved; Future; Genetic; Homeostasis; Human; Hypersensitivity; Induction of Apoptosis; Intervention; Iron; Label; Malaria; Malignant Neoplasms; Medicine; Melanoma Cell; Modeling; Molecular; Molecular Target; Mus; Natural Products; Neoplasm Metastasis; Neural Crest; Normal Cell; Oncogene Activation; Oncogenes; Oncogenic; Outcome; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Parasites; Patients; Peroxides; Pharmaceutical Preparations; Pharmacodynamics; Physiology; Prize; Prognostic Factor; Proteomics; Public Health; Reactive Oxygen Species; Research; Research Project Grants; Resistance; Role; Sesquiterpenes; Skin Cancer; Starvation; TFRC gene; Testing; Therapeutic; Therapeutic Intervention; Time; Treatment Efficacy; Tumor Tissue; United States; Up-Regulation; Xenograft Model; adduct; anticancer activity; benflumetol; c-myc Genes; cancer cell; chemotherapy; clinical efficacy; cytotoxic; cytotoxicity; efficacious treatment; efficacy evaluation; efficacy testing; feasibility testing; human disease; improved; in vivo; inhibitor; mRNA Expression; melanocyte; melanoma; melanomagenesis; mouse model; novel; pharmacologic; pharmacophore; pre-clinical; premalignant; rational design; receptor expression; senescence; targeted agent; targeted treatment; therapeutic target; transcription factor; treatment strategy; tumor; tumor growth

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.

在美国，恶性黑色素瘤是导致皮肤癌相关死亡的主要原因

项目成果

TLR4 in skin cancer: From molecular mechanisms to clinical interventions.

• 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