Abstract：
Giant congenital melanocytic nevi are NRAS-driven proliferations that may cover up to 80% of the body surface. Their most dangerous consequence is progression to melanoma. This risk often triggers preemptive extensive surgical excisions in childhood, producing severe lifelong challenges. We have presented preclinical models, including multiple genetically engineered mice and xenografted human lesions, which enabled testing locally applied pharmacologic agents to avoid surgery. The murine models permitted the identification of proliferative versus senescent nevus phases and treatments targeting both. These nevi recapitulated the histologic and molecular features of human giant congenital nevi, including the risk of melanoma transformation. Cutaneously delivered MEK, PI3K, and c-KIT inhibitors or proinflammatory squaric acid dibutylester (SADBE) achieved major regressions. SADBE triggered innate immunity that ablated detectable nevocytes, fully prevented melanoma, and regressed human giant nevus xenografts. These findings reveal nevus mechanistic vulnerabilities and suggest opportunities for topical interventions that may alter the therapeutic options for children with congenital giant nevi.
摘要：
巨大的先天性黑素细胞痣是NRAS驱动的增生，可能覆盖高达80％的体表。它们最危险的后果是进展为黑色素瘤。这种风险通常会在儿童时期引发先发制人的广泛手术切除，产生严峻的终身挑战。我们已经提出了临床前模型，包括多个基因工程小鼠和异种移植的人类病变，这使得测试当地应用的药物以避免手术。鼠模型允许鉴定增殖性痣和衰老痣阶段以及靶向两者的治疗。这些痣概括了人类巨大的先天性痣的组织学和分子特征，包括黑色素瘤转化的风险。立即交付MEK，PI3K,和c-KIT抑制剂或促炎方酸二丁酯（SADBE）实现了主要的消退。SADBE触发先天免疫，消融可检测的痣细胞，完全预防黑色素瘤，回归人类巨大的痣异种移植物。这些发现揭示了痣机制的脆弱性，并为可能改变先天性巨痣儿童的治疗选择的局部干预提供了机会。
