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，在暴露于紫外线（UV）辐射后，由分离的黑色素细胞或痣（痣）产生。新疗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上升。传统的化学预防策略在应用于黑色素瘤时存在几个问题，包括：1)给予慢性毒性未知的药物；2)缺乏生物标志物作为长潜伏期肿瘤发展疗效的替代指标；3)缺乏关于遗传修饰物和生物标志物的详细信息，这些信息有助于评估患者的疾病风险和对药物的反应能力。我们提出了一种使用N-乙酰半胱氨酸（NAC）进行黑色素瘤化学预防的新模式，NAC是一种有效的抗氧化剂，可被代谢为半胱氨酸（Cys）并转化为谷胱甘肽（GSH）。我们认为痣的氧化应激/损伤是黑色素瘤风险的可行替代指标，并提出通过保护痣免受紫外线诱导的氧化变化可以推断出人类黑色素瘤风险的降低。我们假设，在紫外线暴露期间施用NAC将降低对紫外线诱导的氧化应激遗传易感性的高危患者人群患黑色素瘤的风险，并且检查关键的遗传变异将确定哪些个体最有可能从化学保护中受益。我们建议在100名患者中进行安慰剂对照试验，旨在验证紫外线诱导的氧化应激易感性和NAC保护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.