Repurposing Clinical ACT Antimalarials for Experimental Melanoma Intervention

在美国，恶性黑色素瘤是导致大多数皮肤癌相关死亡的原因。 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应用中一类重要的氧化还原抗疟药， 在世界范围内使用，作为氧化还原导向的抗癌剂，靶向破坏细胞铁 稳态，一种癌前和恶性细胞的常见改变， 对细胞毒性氧化应激的超敏反应。在这个R 01申请中， “将临床ACT抗疟药用于实验性黑色素瘤干预”，我们 测试假设，癌基因驱动的铁稳态失调代表了一种 黑色素瘤的分子阿基里斯之踵特征，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 使用青蒿素为基础的联合疗法（ACT）的可行性，FDA批准用于 抗疟疾药物干预，针对恶性黑色素瘤， 疾病模型：目的#1：首先，失调的c- MYC和转铁蛋白受体表达、铁稳态和细胞超敏性 青蒿素为基础的氧化还原干预将在细胞培养和人类 以微阵列形式询问癌前病变和肿瘤组织。新型分子 铁依赖性青蒿素活化后通过共价加合调节的靶点 将基于蛋白质组学实验使用荧光标记的 青蒿素探针随后在自发性鼠遗传学中进行体内功效测试 黑素瘤模型。目的#2：根据我们先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，我们探索其机制， 以阿莫地喹为基础的实验性化疗靶向干预的可行性 早期和晚期黑色素瘤。目标#3：最后，我们将测试假设， 青蒿素干预联合特异性自噬导向ACT 抗疟药（阿莫地喹、哌喹、苯芴醇）提供改善的治疗效果， 临床前研究中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。本文的研究为今后的合理设计提供了指导 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药，在不久的将来使患者受益。

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.