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

描述(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，对公众健康造成相当大的负担。包括药物抑制皮肤光癌的化学预防策略已经在临床前和临床研究中显示出希望，但还需要更有效的药物。最近的研究表明，癌基因在癌前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，这种有条件的细胞毒性模式被称为合成致死。我们最近的研究发现，青蒿素是一类重要的氧化还原抗疟疾药物，是一种合成致命的抗癌药物，其靶向是破坏细胞铁稳态，这是转化细胞的一种常见变化，导致对细胞毒性氧化应激的超敏。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基础上，我们提出了初步实验，以检验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癌的发生。首先，将使用体外小鼠皮肤室模型(AIM#1)建立青蒿素衍生物的皮肤药代动力学(皮肤吸收曲线)。其次，基于青蒿素的局部抑制光癌的可行性将在SKH-1小鼠太阳紫外线B诱导的鳞状细胞癌模型中进行测试(目标2)。将产生关键的原则证明数据，指导未来的机制和临床前研究的合理设计，以验证用于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.