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

基本信息

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
项目类别：
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

项目摘要

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.

在美国，恶性黑色素瘤导致大部分皮肤癌相关死亡各州承担着相当大的公共卫生负担。我们最近的研究发现青蒿素是临床上一类重要的氧化还原抗疟药在全球范围内使用，作为氧化还原定向抗癌剂，以破坏细胞铁为目标稳态，癌前细胞和恶性细胞的常见改变，导致对细胞毒性氧化应激过敏。在此 R01 申请中，标题为 “重新利用临床 ACT 抗疟药进行实验性黑色素瘤干预”，我们检验以下假设：癌基因驱动的铁稳态失调代表了黑色素瘤发生的分子致命弱点，可以通过青蒿素-内过氧化物抗疟药。在这个综合项目中，我们还测试了使用 FDA 批准的基于青蒿素的联合疗法 (ACT) 的可行性药物治疗抗疟疾干预，针对相关的恶性黑色素瘤疾病模型：目标#1：首先，c-失调之间的机制关系 MYC 和转铁蛋白受体表达、铁稳态和细胞超敏反应将在细胞培养物和人体中检查基于青蒿素的氧化还原干预以微阵列形式检查癌前组织和肿瘤组织。新型分子铁依赖性青蒿素激活后通过共价加合调节靶点将基于使用荧光标记的蛋白质组学实验进行鉴定青蒿素探针随后在自发性小鼠遗传中进行体内功效测试黑色素瘤模型。目标#2：根据我们之前对抗黑色素瘤活性的研究自噬导向的 ACT 抗疟药阿莫地喹，我们探索机制和基于阿莫地喹的实验性化疗干预靶向的可行性早期和晚期黑色素瘤发生。目标#3：最后，我们将检验以下假设：以青蒿素为基础的干预联合特异性自噬导向的 ACT 抗疟药（阿莫地喹、哌喹、本芴醇）可改善治疗效果临床前抑制肿瘤生长和克服 BRAF 抑制剂耐药性的功效异种移植模型。所提出的研究指导未来的合理设计有望促进 FDA 批准的 ACT 重新利用的临床前/临床研究用于抗黑色素瘤干预的抗疟药，在不久的将来使患者受益。