# Preclinical models and therapeutic strategies for treatment of giant congenital melanocytic nevi

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $353,411

## Abstract

Project Summary
Giant congenital melanocytic nevi are virtually always NRAS-driven clonal proliferations of melanocytes that
develop in utero independently of UV and may cover up to 80% of the body. The most dangerous
consequence of giant nevi is the risk of progression to melanoma. This prompts complete surgical excision of
the lesions, producing profound and permanent morbidity. Drug treatments capable of regressing these lesions
and minimizing lifetime risk of melanoma could be extremely beneficial to these children. We have generated
several murine giant nevus models using either constitutive Cre or topical tamoxifen-inducible Cre expression
(both melanocyte restricted) to activate oncogenic NRASQ61R expression from its endogenous promoter. In
addition to clear histologic and biomarker features resembling human giant nevi, these models exhibit a
proliferative phase followed by a senescent phase, and transform to invasive melanoma at similar frequencies
as in humans. Aim 1 will characterize these features, identifying transition time to senescence, since therapies
may produce distinct efficacies in early/proliferative vs. later/senescent lesions. We will also examine altered
hair growth in our model (also similar to human giant nevi), as well as apparently increased aggressiveness of
these lesions in the Mc1re/e red-haired genetic background, as recently suggested for humans. We have begun
to apply surgery-sparing, primarily locally administered drug therapies to these models (Aim 2), including:
1) small molecule antagonists of NRAS downstream signaling (MEK, ERK, PI3 kinase, and AKT inhibitors);
2) melanocyte lineage-specific toxic agents (antagonists targeting cKIT, MITF, and tyrosinase); and 3) immune
approaches triggering localized inflammation and epitope spreading with vitiligo-like results (imiquimod,
chemical haptens [contact sensitizers], a lipophilic STING (Stimulator of Interferon Genes) agonist, and BCG,
alone and in combinations with anti-PD1). Our preliminary results demonstrate significant clearance of nevus
populations using multiple single and combination approaches, albeit requiring further optimization. We
hypothesize that effective, safe therapies for giant congenital melanocytic nevi can be derived from application
of the above approaches exploiting key benefits of localized drug delivery. Treatments will focus on eradicating
both actively proliferating cells (as in neonatal lesions) and senescent cells (as in older children), both modeled
here. We have validated a set of rigorous biomarkers of signaling activities as well as key cell populations, for
use in sensitive monitoring of lesions and treatments. Prevention of melanoma formation can also be tested
using our models. To further validate promising approaches in actual living human giant nevi, we now routinely
and stably engraft surgically resected giant nevus tissue from children onto immunodeficient mice (Aim 3).
These lesions will be subjected to the best single or...

## Key facts

- **NIH application ID:** 10245261
- **Project number:** 5R01AR072304-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** DAVID E FISHER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $353,411
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245261

## Citation

> US National Institutes of Health, RePORTER application 10245261, Preclinical models and therapeutic strategies for treatment of giant congenital melanocytic nevi (5R01AR072304-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10245261. Licensed CC0.

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