Personalized melanoma chemoprevention

描述（由申请人提供）：黑色素瘤是一种潜在的致命形式的皮肤癌，由暴露于紫外线（UV）辐射后孤立的黑色素细胞或痣（痣）引起。新的治疗方法并没有显著提高大多数晚期黑色素瘤患者的生存率，尽管医疗保健专业人员长期以来一直提倡光保护，但黑色素瘤的发病率仍在继续上升。当应用于黑素瘤时，常规化学预防策略造成几个问题，包括：1）施用未知慢性毒性的药物，2）缺乏用作长潜伏期肿瘤发展的功效的替代指标的生物标志物，和3）缺乏关于促进评估患者疾病风险和对药剂应答的能力的遗传修饰剂和生物标志物的详细信息。我们提出了一种新的黑色素瘤化学预防的范例，使用N-乙酰半胱氨酸（NAC），一种有效的抗氧化剂，代谢为半胱氨酸（Cys）和谷胱甘肽（GSH）。我们认为氧化应激/损伤痣是一个可行的替代黑色素瘤的风险，并提出，在人类黑色素瘤的风险降低可以推断从紫外线诱导的氧化变化的保护痣。我们假设，在紫外线暴露前后给予NAC将降低对紫外线诱导的氧化应激具有遗传易感性的高危患者人群中的黑色素瘤风险，并且检查关键遗传变异将确定哪些个体最有可能从化学保护中获益。我们建议在100例患者中进行安慰剂对照试验，旨在验证对UV诱导的氧化应激和NAC保护的易感性的潜在遗传和功能标记。

DESCRIPTION (provided by applicant): Melanoma is a potentially fatal form of skin cancer that arises from isolated melanocytes or nevi (moles), after exposure to ultraviolet (UV) radiation. New therapies have not significantly improved survival for most patients with advanced melanoma, and although photoprotection has long been promoted by healthcare professionals, melanoma incidence continues to rise. Conventional chemoprevention strategies pose several problems when applied to melanoma, including: 1) administration of a drug of unknown chronic toxicity, 2) lack of biomarkers serving as surrogate indicators of efficacy for tumor development of long latency, and 3) lack of detailed information about genetic modifiers and biomarkers that facilitate assessment of patient risk for disease and capacity to respond to the agent. We propose a novel paradigm for melanoma chemoprevention using N- acetylcysteine (NAC), a potent antioxidant that is metabolized to cysteine (Cys) and converted to glutathione (GSH). We believe oxidative stress/damage in nevi is a viable surrogate for melanoma risk, and propose that reduced melanoma risk in humans can be inferred by protection of nevi from UV-induced oxidative changes. We hypothesize that administration of NAC around the time of UV exposure will reduce melanoma risk in high- risk patient populations with genetic susceptibility to UV-induced oxidative stress, and examination of key genetic variants will identify which individuals are most likely to benefit from chemoprotection. We propose a placebo-controlled trial in 100 patients designed to validate potential genetic and functional markers of susceptibility to UV-induced oxidative stress and protection by NAC.