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，对公共卫生造成了相当大的负担。包括药理抑制皮肤光致癌作用的化学预防策略已经在临床前和临床研究中显示出前景，但还需要更有效的药物。最近的研究表明，癌前细胞和癌细胞中的癌基因表达可能代表了一种特定的分子易感性，可以通过个性化的遗传或药物干预来靶向，而不会损害不表达特定癌基因的细胞的生存能力，这是一种被称为“合成致死”的条件细胞毒性模式。我们最近的研究发现，青蒿素是世界范围内临床使用的一类重要的氧化还原抗疟疾药物，可作为合成致死性抗癌药物，靶向破坏细胞铁稳态，这是转化细胞的一种常见改变，可导致对细胞毒性氧化应激的超敏反应。在我们目前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的研究中，我们提出了试点实验，以验证基于青蒿素的局部干预可以通过合成致死消除癌前和恶性皮肤角质形成细胞来抑制皮肤光致癌的假设。首先，将使用离体小鼠皮肤腔模型（目的1）建立青蒿素衍生物的皮肤药代动力学（皮肤吸收谱）。其次，以青蒿素为基础的局部抑制光致癌的可行性将在太阳紫外线b诱导的鳞状细胞癌的SKH-1小鼠模型中进行测试（目的2）。关键的原理证明数据将产生，指导未来机制和临床前研究的合理设计，以验证光化学预防的合成致死方法。

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.