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Page 10 of 15 Brown. Rare Dis Orphan Drugs J. 2025;4:21 https://dx.doi.org/10.20517/rdodj.2025.14

[74]
period if it could reduce the number of CNs by 30% and prevent the formation of new tumors .

Emerging data from clinical trials of systemic MEK inhibitors suggest that this drug class may play a role in
[75]
slowing or halting the development of new CNs and/or reducing the size of existing CNs . Special
consideration must be allotted to drug development for this benign tumor, as currently approved MEK
inhibitors (mirdametinib and selumetinib) are designed to treat large, functionally impactful plexiform
neurofibromas, and have a side effect profile that is unlikely to be acceptable for managing cutaneous
manifestations. The primary detriment to quality of life associated with CNs derives from tumor
disfigurement, while over 90% of patients on currently approved MEK inhibitors additionally experience a
conspicuous acneiform rash. This visible adverse effect could exacerbate societal stigmatization and likely
hinder the use of MEK inhibitors for treating CNs, despite potential benefits in tumor reduction. A 2025
study was the first to unequivocally demonstrate that systemic MEK inhibition can reduce CN tumor
burden, achieving a maximum response of a 29% decrease in CN volume. However, similar to other trials,
[76]
adverse events such as dry skin and rash were common . It is possible that a reduced dose of MEK
inhibitors, administered prophylactically or longitudinally, could mitigate these adverse events while
slowing tumor growth; however, this approach has not yet been explored.

Data released in 2025 provided the most compelling evidence to date for the treatment of CNs using the
[72]
topical selumetinib formulation NFX-179 . At the highest dose tested, CNs exhibited approximately a 50%
reduction in phosphorylated ERK levels, a recognized biomarker of MEK inhibition. Decreases in tumor
volume were observed in all groups, including the control group, but the highest drug dose led to an
additional ~10% average reduction in tumor volume compared with the control. Most notably, around 20%
of CNs treated with the highest dose of the topical formulation exhibited a ≥ 50% reduction in volume.
Future generations of MEK inhibitors, as well as novel molecularly targeted therapies and topical, biologic,
or injectable treatments, may further expand the arsenal of approaches to address this psychologically and
socioeconomically impactful aspect of NF1. Beyond MEK inhibition, several groups are also investigating
the unique transcriptional and cellular fingerprints of CNs to identify multi-target therapeutic strategies [77,78] .

DISCUSSION
People with NF1 are hugely impacted by the visual appearance and physical symptoms of CNs, but current
treatment options are largely limited to destructive techniques. Surgical specialties (general surgery, plastic
surgery, dermatology, or neurosurgery) do not generally have the bandwidth to dedicate extensive operating
room time to removing the substantial tumor burden that affects many NF1 patients. Electrodessication,
although effective against small CNs measuring 5 mm or less, cannot treat larger lesions. Moreover, it is
rarely offered, given the need for general anesthesia, specialized training and equipment, and its relatively
low reimbursement rate compared with other procedures. Laser therapies can be very effective, but are
limited by post-procedural pain. All destructive techniques carry the risk of scarring and pigmentation
changes that may ultimately offset the cosmetic benefits. Neurologists and primary care doctors can help
address the need for CN management by training in tumor resection, which can be performed in a clinical
setting without the need for a sterile operating room. A well-vetted training course with certification by a
respected institution such as the Children’s Tumor Foundation could provide the education for doctors and
advanced practice providers, and a recertification course providing continuing medical education credits
could ensure a durable skillset.

The human relevance of preclinical CN models has been improving over the past decade, but still requires
further refinement. Porcine skin closely resembles human skin in cellular morphology, architecture, and the
thickness of the four dermal layers. However, minipigs have additional cell layers in the stratum spinosum