Topical therapy for regression and melanoma prevention of congenital giant nevi
| Autor: | Yeon Sook Choi, Tal H. Erlich, Max von Franque, Inbal Rachmin, Jessica L. Flesher, Erik B. Schiferle, Yi Zhang, Marcello Pereira da Silva, Alva Jiang, Allison S. Dobry, Mack Su, Sharon Germana, Sebastian Lacher, Orly Freund, Ezra Feder, Jose L. Cortez, Suyeon Ryu, Tamar Babila Propp, Yedidyah Leo Samuels, Labib R. Zakka, Marjan Azin, Christin E. Burd, Norman E. Sharpless, X. Shirley Liu, Clifford Meyer, William Gerald Austen, Branko Bojovic, Curtis L. Cetrulo, Martin C. Mihm, Dave S. Hoon, Shadmehr Demehri, Elena B. Hawryluk, David E. Fisher |
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| Rok vydání: | 2022 |
| Předmět: |
Pediatric
mole Nevus Pigmented congenital melanocytic nevus Skin Neoplasms Prevention Nras Biological Sciences Medical and Health Sciences General Biochemistry Genetics and Molecular Biology Mice Pigmented Clinical Research hapten melanoma Animals Heterografts Humans topical Nevus Melanoma Neoplasm Transplantation Biotechnology Cancer Developmental Biology |
| Zdroj: | Cell, vol 185, iss 12 |
| ISSN: | 1097-4172 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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