Topical therapy for regression and melanoma prevention of congenital giant nevi

• Published in: Cell Vol. 185; no. 12; pp. 2071 - 2085.e12
• Main Authors: Choi, Yeon Sook, Erlich, Tal H., von Franque, Max, Rachmin, Inbal, Flesher, Jessica L., Schiferle, Erik B., Zhang, Yi, Pereira da Silva, Marcello, Jiang, Alva, Dobry, Allison S., Su, Mack, Germana, Sharon, Lacher, Sebastian, Freund, Orly, Feder, Ezra, Cortez, Jose L., Ryu, Suyeon, Babila Propp, Tamar, Samuels, Yedidyah Leo, Zakka, Labib R., Azin, Marjan, Burd, Christin E., Sharpless, Norman E., Liu, X. Shirley, Meyer, Clifford, Austen, William Gerald, Bojovic, Branko, Cetrulo, Curtis L., Mihm, Martin C., Hoon, Dave S., Demehri, Shadmehr, Hawryluk, Elena B., Fisher, David E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.06.2022
• Subjects: Animals; congenital melanocytic nevus; hapten; Heterografts; Humans; melanoma; Melanoma - drug therapy; Melanoma - pathology; Mice; mole; Neoplasm Transplantation; Nevus, Pigmented - congenital; Nevus, Pigmented - drug therapy; Nevus, Pigmented - pathology; Nras; prevention; Skin Neoplasms - drug therapy; Skin Neoplasms - pathology; Skin Neoplasms - prevention & control; topical; topical; Nras; hapten; mole; melanoma; congenital melanocytic nevus; prevention
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2022.04.025

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. [Display omitted] •Models of melanocyte inducible NrasQ61R mimic human congenital melanocytic nevi•Locally delivered MEK, PI3K, and c-KIT inhibitors are able to regress the nevi•SADBE regresses nevi in mice and human CMN xenografts and prevents melanoma in mice•SADBE induces inflammation and recruits macrophages that lead to nevus clearance Large congenital nevi, or highly pigmented regions of skin, can present major cosmetic and psychosocial issues and have a significant chance of turning into malignant melanoma. However, current treatment methods provide only partial removal and can lead to scarring. Here, congenital nevus mouse models were developed and used to identify topical therapies that were highly effective at clearing nevi and protecting against melanoma formation.