Repurposing Clinical ACT Antimalarials for Experimental Melanoma Intervention

恶性黑色素瘤是美国皮肤癌相关死亡的主要原因 这些国家的公共卫生负担相当大。我们最近 研究发现，青蒿素是临床上一类重要的氧化还原抗疟疾药物 在全球范围内用作氧化还原导向的抗癌剂，靶向破坏细胞铁 动态平衡，一种常见的癌前细胞和恶性细胞的改变，导致 “推荐临床抗疟疾药物用于实验性黑色素瘤干预”，我们 检验癌基因驱动的铁稳态失调代表一种 黑色素瘤发生的分子阿喀琉斯跟特征可作为靶点 青蒿素-过氧化内酯抗疟疾药。在这个综合项目中，我们还测试了 使用基于青蒿素的联合疗法(ACT)的可行性，FDA批准用于 针对恶性黑色素瘤的药物治疗抗疟疾干预 疾病模型：目标1：首先，调节失调的c-受体之间的机制关系。 MYC和转铁蛋白受体表达、铁稳态与细胞超敏反应 以青蒿素为基础的氧化还原干预将在细胞培养和人类中进行检验 以微阵列格式询问癌前和肿瘤组织。新型分子 铁依赖青蒿素激活后通过共价加合调节的靶点 将根据蛋白质组实验使用荧光标记的 青蒿素探针在小鼠自发遗传中的体内药效试验 黑色素瘤模型。目标2：根据我们先前关于黑色素瘤活性的研究， 自噬导向的ACT抗疟疾药物阿莫地喹的作用机制和机制 阿莫地喹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，我们将检验假设 青蒿素干预联合特异性自噬导向的ACT 抗疟药(阿莫地喹、哌喹、鲁米芬)提供更好的治疗效果 临床前期抑制肿瘤生长和克服BRAF抑制剂耐药性的疗效 异种移植模型。所提出的研究对未来的合理设计具有指导意义。 临床前/临床研究承诺促进FDA批准的ACT的再利用- 用于抗黑色素瘤干预的抗疟疾药物，使患者在不久的将来受益。

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.