Cutaneous neurofibromas (cNFs) are considered a benign peripheral nerve sheath tumor formed by the Schwann cells, fibroblasts, and perineural cells proliferation. Here at Protheragen, we know how complex cNF can be and how it needs to be actively worked on to move the field forward, which is the purpose of our preclinical services. These services are meant to aid all levels of the therapeutic and diagnostic development cycle, which spans from discovery to preclinical research.
Overview of Cutaneous Neurofibroma (cNF)
Cutaneous neurofibromas (cNFs) are classified as benign tumors related to the peripheral nerve sheath, and they are particularly associated with neurofibromatosis type 1 (NF1). cNFs are composed of Schwann cells, fibroblasts, and perineurial cells and are located in the dermal layer of the skin. cNF tumors are not merely of a cosmetic interest but rather a serious concern because they may lead to pain, pruritus, and considerable disfigurement, thus diminishing the quality of life (QOL) of the affected individuals. Although cNFs are classified as benign tumors, they tend to increase in number and size over time, which underscores the need for appropriate therapeutics.
Fig.1 Precursor cells within the Schwann cell lineage, along with intrinsic and extrinsic factors, contribute to neurofibroma formation. (Jiang C.,
et al., 2023)
Diagnostics Development for Cutaneous Neurofibroma (cNF)
Imaging Techniques
High-frequency ultrasound (HFUS) and optical coherence tomography (OCT) are advanced imaging modalities that have revolutionized the detection and monitoring of cNFs. HFUS is particularly effective for identifying small, nascent tumors beneath the skin surface, providing high-resolution images that facilitate early intervention. OCT, on the other hand, offers detailed cross-sectional images of the skin, enabling the visualization of tumor architecture and surrounding tissue. These imaging techniques are essential for tracking tumor progression and evaluating the efficacy of therapeutic interventions.
Histopathological Examination
Conventional cNFs are characterized by a mixture of spindle cells, Schwann cells, fibroblasts, and mast cells within a collagenous or myxoid stroma. Variants such as epithelioid, granular cell, balloon cell, and dendritic cell cNFs have been identified, each presenting unique histological features. For instance, epithelioid cNFs exhibit nests of epithelial-like cells with abundant eosinophilic cytoplasm, while granular cell cNFs contain PAS-positive, diastase-resistant granules. These histopathological variants can pose diagnostic challenges, necessitating the use of immunohistochemical markers such as S-100, CD34, and SOX10 to confirm the diagnosis.
Biomarker Identification
Biomarker research is a burgeoning field in cNF diagnostics. Prognostic and predictive biomarkers are being explored to identify individuals at higher risk of developing cNFs and to predict response to therapy. For example, phosphorylated ERK levels have been incorporated as endpoints in clinical trials of MEK inhibitors, reflecting the activation status of the RAS-MAPK pathway. Additionally, studies have identified distinct methylation signatures across cNFs of different sizes, suggesting potential epigenetic biomarkers for tumor growth behavior. These biomarkers hold promise for personalized therapeutic strategies and improved outcomes.
Therapeutics Development for Cutaneous Neurofibroma (cNF)
- Systemic Therapies
Systemic therapies targeting the RAS-MAPK pathway have shown promise in preclinical models and clinical trials. MEK inhibitors, such as selumetinib, have demonstrated significant activity in reducing tumor size in plexiform neurofibromas (pNFs) and are under investigation for cNFs. Selumetinib has been approved for the therapeutic of inoperable pNFs, highlighting its potential for cNF therapy. However, systemic therapeutics are often associated with significant side effects, emphasizing the need for alternative dosing schedules and better-tolerated agents.
- Topical and Intralesional Therapies
Topical therapies and intralesional injections offer a localized approach to cNF therapeutics, potentially reducing systemic side effects. For example, NFX-179 gel, a topical MEK inhibitor, has shown favorable safety and efficacy profiles in phase 2a trials, with significant reductions in phosphorylated ERK levels and tumor size. Other topical agents, such as imiquimod and diclofenac, have been explored with varying degrees of success. Intralesional therapies, including ranibizumab (an anti-VEGF antibody), have also been investigated, although responses have been highly variable.
Table 1. Summary of therapies that have been evaluated or are currently under investigation for cNF. (Ly I., et al., 2023)
| Intervention |
n |
Target |
Endpoint |
Results |
| Electrodessication for multiple cNFs (Levine et al., 2008) |
97 |
Small- to medium-sized tumors |
Patient satisfaction (cosmesis) |
High patient satisfaction, minimal scarring |
| Electrodessication in treating cNFs (Lutterodt et al., 2016) |
6 |
Small- to medium-sized tumors |
Patient satisfaction (cosmetic and functional) |
High patient satisfaction, minimal scarring |
| Ranibizumab (NCT00657202) |
11 |
VEGF angiogenesis |
PD |
Highly variable responses |
| Rapamycin (Koenig et al., 2012) |
28 |
mTOR |
Safety |
Safe but no clear change in tumor volume |
| Imiquimod (NCT00865644) |
20 |
TLR7/8 |
Tumor shrinkage |
Few patients with a minor decrease in tumor volume; responses are highly variable |
| NFX-179 gel (Sarin et al., 2021) |
35 |
RAS pathway |
Safety and tolerability; tumor shrinkage |
Tumor volume change with 0.15% and 0.5% gel, but high SD |
| Diclofenac sodium (Oliveira et al., 2021) |
7 |
COX-1, COX-2 |
Efficacy |
N/A |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen provides a full spectrum of services for the development of both diagnostics and therapeutics for cNF. This includes target identification and validation, assay development, biomarker discovery, and the creation of robust in vitro and in vivo models. We assist clients in designing and executing studies that evaluate the efficacy and safety of potential drug candidates.
Disease Models
- Primary Schwann Cell Cultures
- Immortalized Schwann Cell Lines
- Organoid Models
- NF1 Genetically Engineered Rodent Models (NF1-GERMs)
Protheragen offers highly customized services to meet specific client needs. Whether it's a bespoke animal model, a specialized analytical assay, or a full-service drug development program, our team of experts collaborates closely with clients to design a tailored approach. If you are interested in our services, please feel free to contact us.
References
- Jiang, Chunhui, et al. "Cutaneous neurofibroma heterogeneity: factors that influence tumor burden in neurofibromatosis type 1." Journal of Investigative Dermatology 143.8 (2023): 1369-1377.
- Nagrani, Neha S., and Jag Bhawan. "Histopathological variants of cutaneous neurofibroma: a compendious review." Dermatopathology 10.1 (2022): 1-19.
- Ly, Ina, et al. "Target product profile for cutaneous neurofibromas: clinical trials to prevent, arrest, or regress cutaneous neurofibromas." Journal of Investigative Dermatology 143.8 (2023): 1388-1396.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
