Personalized melanoma chemoprevention

描述(申请人提供)：黑色素瘤是一种潜在的致命形式的皮肤癌，由孤立的黑素细胞或痣(痣)，暴露在紫外线(UV)辐射后产生。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在推广光保护，但黑色素瘤的发病率仍在继续上升。传统的化学预防策略在应用于黑色素瘤时会遇到几个问题，包括：1)使用一种慢性毒性未知的药物，2)缺乏作为长潜伏期肿瘤发展有效性的替代指标的生物标记物，以及3)缺乏关于遗传修饰物和生物标记物的详细信息，这些信息有助于评估患者的疾病风险和对该药物的反应能力。我们提出了一种使用N-乙酰半胱氨酸(NAC)化学预防黑色素瘤的新范例，N-乙酰半胱氨酸(NAC)是一种有效的抗氧化剂，可代谢为半胱氨酸(Cys)并转化为谷胱甘肽(GSH)。我们认为色素痣的氧化应激/损伤是黑色素瘤风险的一个可行的替代指标，并建议可以通过保护色素痣免受紫外线诱导的氧化改变来推断人类黑色素瘤风险的降低。我们假设，在紫外线暴露期间给予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群体中黑色素瘤的风险，并且对关键基因变异的检查将确定哪些个人最有可能从化学保护中受益。我们提出了一项在100名患者中进行的安慰剂对照试验，旨在验证潜在的紫外线诱导氧化应激易感性的遗传和功能标记物以及NAC的保护作用。

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.