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Page 8 of 15 Brown. Rare Dis Orphan Drugs J. 2025;4:21 https://dx.doi.org/10.20517/rdodj.2025.14

self-limited growth most common with human CN, and interestingly, the findings were mostly associated
with gonadally intact male pigs, suggesting some role for androgens in CN tumorigenesis within this model.

In vitro models of CNs include primary cell culture and co-culture of Schwann-like tumor cells and
tumor-associated fibroblasts from human donors, genetically engineered mouse models, and minipigs.
Skin-derived precursor cells can be isolated and grown in culture, and semi-immortalized cells from
donated human CNs were generated by introducing human TERT and mouse CDK4 genes via gene
transduction. Induced pluripotent stem cells have been derived from human and rodent tissues, and have
[54]
been used to generate orthotopic xenografts in mice . Because two-dimensional culture conditions cannot
replicate the complex 3-dimensional cellular and ECM organization of CNs, neurofibroma-sphere/organoid
[56]
models and complex multicellular skin grafts have been utilized to better understand the tumor
[55]
microenvironment and ultimately for preclinical drug testing.
Innovative research has demonstrated that the cell of origin could reside in various sources, including
[57]
multipotent bulge hair follicle cells , a specialized population of skin-derived precursor cells of neural crest
origin , boundary cap cells of the dorsal root ganglia , dysplastic vascular pericytes , or deviant
[59]
[7]
[58]
endoneurial or cutaneous nerve axon-associated Schwann cells - potentially through misactivation of the
injury-repair pathway [60-63] . Confounding this research is the inherently plastic nature of many neural
crest-derived tissues, which can be driven, either by physiological processes or experimentally, to give rise to
most of the cell types found in CNs.

CN tumorigenesis and ultimate dormancy are likely multifactorial, contingent upon microenvironmental
contributions from haploinsufficient tumor-associated nerve, immune, and dermal cells through the release
of growth factors, chemokines, and cytokines. Pleiotropic effects from germline variants in different genes
may also contribute.

THERE ARE NO APPROVED PHARMACOTHERAPIES FOR CNS
Currently, there are no FDA-approved medical treatments for CNs. While surgical resection of the
exophytic component combined with evacuation of the hypodermal portion and careful suturing can
achieve permanent tumor control and an aesthetically acceptable appearance , this technique can only go
[64]
so far. It does not address the ongoing development of new tumors nor the often substantial burden of
[65]
existing tumors. Other destructive approaches include focused ultrasound , CO laser, radiofrequency
2
ablation , photodynamic therapy [67,68] , Er:YAG or Nd:YAG laser , and electrodessication . The efficacy
[69]
[66]
[70]
of these approaches varies depending on tumor size and number, tolerance for scarring/ pigmentation
changes, and post-procedural pain. A number of topical and systemic medications have been tested, with
the most promising results to date seen with MEK inhibitors [70-72] . Most notably, NFX-179, a topical
ointment applied daily for 28 days to five medium-sized CNs (5-10 mm) in 42 subjects, resulted in a ≥ 50%
reduction in tumor volume in 20% of tumors and patients. In addition, there was a 47% reduction in
phosphorylated ERK levels measured via automated Western blot, with practically no adverse events.
However, CN-related quality of life outcomes were not assessed in this Phase 2a trial. Overall, patient
satisfaction regarding efficacy, pain, scarring, durability, and side effect profiles across all treatments
evaluated to date leaves room for improvement.

A search of ClinicalTrials.gov at the time of writing identified eighteen clinical trials using the search term
[14]
“cutaneous neurofibroma” in the indication field [Table 1]. Of these, the majority were sponsored by
academic medical centers, while the remaining four were industry-sponsored (covering three drugs). Ten
trials investigated novel indications/pharmacotherapies, including three drugs targeting MEK inhibition;