Topical therapy for regression and melanoma prevention of congenital giant nevi

Area of Science:

• Dermatology
• Oncology
• Genetics

Background:

• Giant congenital melanocytic nevi (GCMN) are NRAS-driven skin proliferations.
• These nevi can cover extensive body surface areas and carry a risk of melanoma transformation.
• Current treatment often involves extensive surgery in childhood, leading to lifelong challenges.

Purpose of the Study:

• To develop and utilize preclinical models for testing topical pharmacologic agents to treat GCMN.
• To identify therapeutic strategies that avoid surgical intervention for GCMN.
• To explore treatments targeting both proliferative and senescent phases of GCMN.

Main Methods:

• Development of genetically engineered mouse models and xenografted human lesions.
• Testing of locally applied pharmacologic agents, including MEK, PI3K, and c-KIT inhibitors, and squaric acid dibutylester (SADBE).
• Evaluation of treatments for their ability to induce regression and prevent melanoma transformation in GCMN models.

Main Results:

• Preclinical models recapitulated the histologic and molecular features of human GCMN, including melanoma risk.
• Cutaneous delivery of MEK, PI3K, and c-KIT inhibitors, as well as SADBE, resulted in major regressions.
• SADBE triggered innate immunity, ablated nevocytes, prevented melanoma, and regressed human GCMN xenografts.

Conclusions:

• Topical interventions targeting mechanistic vulnerabilities of GCMN are feasible.
• SADBE demonstrates significant efficacy in regressing GCMN and preventing melanoma.
• These findings suggest potential for topical treatments to alter therapeutic options for children with GCMN.