Testing feasibility of artemisinin-based synthetic-lethal suppression of skin pho

描述（由申请人提供）：非黑色素瘤皮肤癌（NMSC）是美国最常见的恶性肿瘤，对公共卫生造成相当大的负担。涉及药物抑制皮肤光致癌作用的化学预防策略已在临床前和临床研究中显示出前景，但需要更有效的药物。最近的研究表明，癌基因在癌前病变和癌细胞中的表达可能代表了一种特定的分子脆弱性，可以通过个性化的遗传或药理学干预来靶向该分子脆弱性，而不会损害不表达特定癌基因的细胞的活力，这是一种被称为“合成致死”的条件性细胞毒性模式。我们最近的研究已经确定了青蒿素，一种在世界范围内临床使用的重要类别的氧化还原抗疟疾药，作为靶向破坏细胞铁稳态的合成致死抗癌剂，这是转化细胞的一种常见改变，导致对细胞毒性氧化应激的超敏反应。在继续我们目前的研究，旨在阐明青蒿素靶向灭活非黑色素瘤和黑色素瘤皮肤癌细胞的分子机制，我们提出了试点实验，测试的假设，青蒿素为基础的局部干预可以抑制皮肤光致癌的癌前和恶性皮肤角质形成细胞的合成-致死消除。首先，将使用离体小鼠皮肤室模型建立青蒿素衍生物的皮肤药代动力学（皮肤吸收曲线）（目的#1）。第二，然后将在太阳紫外线B诱导的鳞状细胞癌的SKH-1鼠模型中测试基于青蒿素的局部抑制光致癌作用的可行性（目的#2）。关键的原理证明数据将产生指导合理设计未来的机制和临床前研究，验证合成致死方法的光化学预防。 公共卫生相关性：非黑色素瘤皮肤癌（NMSC）是美国最常见的恶性肿瘤，迫切需要更有效的对抗皮肤癌发生的策略。我们的研究追求一种新的药理学干预机制，杀死癌前和癌性人类皮肤细胞，而不会对正常皮肤细胞产生毒性作用。在这个试点项目中，我们将首先优化利用这种新的分子机制的prototpe试剂（称为“青蒿素”）的皮肤递送，然后首次在该疾病的动物模型中测试基于青蒿素的抑制阳光诱导的皮肤癌的可行性，这代表了抑制皮肤癌的新治疗选择的开发的潜在重大进展。

DESCRIPTION (provided by applicant): Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States presenting a public health burden of considerable magnitude. Chemoprevention strategies that involve pharmacological suppression of skin photocarcinogenesis have shown promise in preclinical and clinical studies, but more efficacious agents are needed. Recent research indicates that oncogene expression in premalignant and cancerous cells may represent a specific molecular vulnerability that can be targeted by personalized genetic or pharmacological intervention without impairing viability of cells that do not express the specific oncogene, a mode of conditional cytotoxicity referred to as 'synthetic-lethal'. Our recent research has identified artemisinins, an important class of redox-anti-malarials in clinical use worldwide, as synthetic- lethal anticancer agents that target disruption of cellular iron homeostasis, a common alteration of transformed cells that causes hypersensitivity to cytotoxic oxidative stress. In continuation of our current research aiming at elucidating molecular mechanisms underlying targeted inactivation of nonmelanoma and melanoma skin cancer cells by artemisinins, we propose pilot experimentation that tests the hypothesis that artemisinin-based topical intervention can suppress skin photocarcinogenesis by synthetic-lethal elimination of premalignant and malignant cutaneous keratinocytes. First, skin pharmacokinetics (cutaneous absorption profile) of artemisinin-derivatives will be established using an ex-vivo mouse skin chamber model (aim #1). Second, feasibility of artemisinin-based topical suppression of photocarcinogenesis will then be tested in the SKH-1 murine model of solar ultraviolet B-induced squamous cell carcinoma (aim #2). Critical proof-of-principle data will be generated guiding the rational design of future mechanistic and preclinical studies that validate synthetic-lethal approaches for photochemoprevention. PUBLIC HEALTH RELEVANCE: Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States creating an urgent need for more efficacious strategies antagonizing skin carcinogenesis. Our studies pursue a novel mechanism of pharmacological intervention that kills precancerous and cancerous human skin cells without causing toxic effects in normal skin cells. In this pilot project, we will first optimize skin delivery of prototpe agents (called 'artemisinins') that harness this novel molecular mechanism and then test for the first time feasibility of artemisinin-based suppression of sun light-induced skin cancer in an animal model of the disease, representing a potentially significant advance in the development of novel treatment options suppressing skin cancer.