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Recent advances in Neurofibromatosis type 1 research: Towards tailored therapeutics and treatment strategies
Journal of Genetic Medicine 2024;21:51-60
Published online December 31, 2024;  https://doi.org/10.5734/JGM.2024.21.2.51
© 2024 Korean Society of Medical Genetics and Genomics.

Su Jung Park*

Research Institute for Korean Medicine, Pusan National University, Yangsan, Korea
Su Jung Park, Ph.D. https://orcid.org/0000-0002-6122-0790
Research Institute for Korean Medicine, Pusan National University, 49 Busandaehak-ro, Yangsan 50612, Korea.
Tel: +82-51-510-8428, Fax: +82-51-510-8420, E-mail: sujupark@pusan.ac.kr
Received November 19, 2024; Revised December 23, 2024; Accepted December 24, 2024.
cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem disorder caused by germline mutations in the NF1 gene, classified as a RASopathy. The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein that modulates the Ras-MAPK signaling cascade. MEK1 inhibitors targeting the Ras-MAPK pathway were initially developed for cancer treatment and have since expanded their applications to RASopathies due to shared molecular mechanisms. Following the FDA approval of MEK1 inhibitor selumetinib for NF1-associated plexiform neurofibromas, drug development has focused on combination therapies, multi-pathway targeting, AI-driven drug discovery, preclinical models, and orphan drug designation to address a broad spectrum of NF1-associated tumors and conditions. Over the past 30 years, significant progress has been made in understanding NF1. This review aims to summarize recent research advancements that enhance the development of NF1 therapeutics, addressing existing gaps in current knowledge and treatment strategies. Ultimately, this could promote personalized medicine, tailoring treatments to the unique genetic and tumor microenvironmental characteristics of each NF1 patient.
Keywords : Neurofibromatosis 1, GTPase-activating proteins, Ras pathway, Loss of heterozygosity, Tumor microenvironment
INTRODUCTION

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant tumor predisposition syndromes, affecting approximately 1 in 3,000 individuals worldwide [1-4]. Individuals with NF1 are born with one mutated, nonfunctional copy of the NF1 gene and exhibit a broad spectrum of clinical manifestations that begin in infancy and progressively worsen [1,5].

Patients typically exhibit café-au-lait macules (CALMs), skinfold freckling, Lisch nodules, and tumors including peripheral nerve tumors such as cutaneous neurofibromas, plexiform neurofibromas (PNs), and malignant peripheral nerve sheath tumors (MPNSTs), as well as brain tumors like optic nerve gliomas and brainstem gliomas [1,6-8]. Additional symptoms include skeletal abnormalities, vascular issues, learning disabilities, attention deficits, an increased risk of autism, and social and behavioral problems [7,9]. Cognitive and behavioral disorders impact up to 80% of children diagnosed with NF1 and are among the most significant clinical manifestations for patients and their families [9,10]. Hematopoietic neoplasms, such as juvenile myelomonocytic leukemia, and pheochromocytomas are also common in NF1 patients [11].

NF1 gene encodes neurofibromin [12,13], which functions as a GTPase-activating protein (GAP) for p21 RAS, facilitating the hydrolysis of active GTP-bound RAS to its inactive GDP-bound form [14,15], thereby acting as a key regulator in cellular growth and differentiation processes. Additionally, neurofibromin is a multifunctional protein capable of regulating multiple signaling pathways, including Ras/MAPK, Raf/MEK/ERK, PI3K/AKT/mTOR, Rho/ROCK/LIMK2/cofilin, PKA-Ena/VASP, and cAMP/PKA [16-19]. Consequently, neurofibromin influences various cellular processes such as proliferation, migration, differentiation, cytoskeletal dynamics, apoptosis, and stress responses [14,17,20-23].

In this review, we comprehensively summarize recent research knowledge that significantly enhances the development of NF1 therapeutics.

FDA-APPROVED SELUMETINIB AND INVESTIGATIONAL MIRDAMETINIB: A NEW ERA IN NF1-PN TREATMENT

Since the discovery of the NF1 gene in 1990 [12], there has been a focus on understanding the molecular mechanisms of neurofibromin, the protein encoded by this gene. This research particularly concentrated on the role of the Ras/Raf/MEK/ERK signaling pathway [16-19].

Loss of NF1 function results in constitutive Ras/Raf/MEK/ERK signaling activation, a primary driver of tumorigenesis in NF1 patients [14,20-23]. In 2011, a pivotal phase I clinical trial demonstrated that selumetinib, a selective MEK1/2 inhibitor, could reduce PNs in NF1 patients [24]. This was a significant breakthrough because PNs are often inoperable and can cause severe pain, disfigurement, and other complications. Subsequent phase II trials confirmed these findings, showing tumor reduction in 68% of patients and improved quality of life. Selumetinib, became the first Food and Drug Administration (FDA)-approved treatment for PNs in pediatric patients in 2020 [25-27]. In 2024, mirdametinib received orphan drug, fast track, and rare pediatric disease designations from both the FDA and European Medicines Agency [28-30].

Despite these advancements, several challenges remain in developing therapeutics for NF1. Current MEK inhibitors show limited efficacy against more aggressive tumors, such as MPNSTs and high-grade gliomas. Additionally, PNs is a heterogeneous disease, with patients displaying variable responses to MEK inhibitors, highlighting the need for personalized treatment approaches. The long-term safety profiles and potential resistance to MEK inhibitors require further investigation to ensure sustained efficacy and patient safety. Exploring combination therapies that target multiple pathways simultaneously could enhance treatment outcomes. Furthermore, identifying new therapeutic targets beyond the MEK pathway is crucial for developing more effective treatments for NF1.

Currently, other MEK inhibitors (trametinib, binimetinib, etc.) and the tyrosine kinase inhibitors (cabozantinib, etc.) that target a broad range of pathways, are being investigated in clinical trials for children and adults with PNs (Fig. 1) [26,28,31-33].

GENOTYPE-PHENOTYPE CORRELATIONS IN NF1

To date, identifying specific NF1 variants has not generally predicted disease progression or outcomes, even within familial contexts. However, with the advent of whole genome sequencing (WGS) along with emerging insights from cancer microenvironment studies, there is potential for establishing robust genotype-phenotype correlations.

Up to now, four clinically confirmed genotype-phenotype correlations have been reported out of more than 3,197 identified constitutional NF1 pathogenic variants, relevant to 10-15% of the NF1 population [34].

1. NF1 microdeletion

Approximately 4.7-11% of NF1 patients have microdeletions involving 14 protein-coding genes, including NF1, and 4 microRNA genes [34-36]. These microdeletions are classified into four types based on their size.

Type-1 deletions: the most common, span 1.4 Mb and are usually caused by maternal meiosis-related non-allelic homologous recombination (NAHR) between NF1-REPa and NF1-REPc. These deletions include 14 protein-coding genes and 4 microRNA genes [37,38].

Type-2 deletions: cover 1.2 Mb and include 13 protein-coding genes including LRRC37B. These arise from mitotic NAHR, leading to somatic mosaicism and a milder phenotype.

Type-3 deletions: span 1.0 Mb and involve 9 protein-coding genes, mediated by NAHR between NF1-REPb and NF1-REPc.

Type-4 deletions: lack recurrent breakpoints, exhibit variable gene loss, and can be either constitutional or postzygotic.

The extent of the deletion and the accompanying loss of adjacent genes can significantly influence the severity of NF1 deletion syndrome compared to NF1 arising from intragenic mutations. Furthermore, the mechanism of deletion, particularly in type-2 deletions, can result in mosaicism, which inherently contributes to phenotypic variability [34].

Patients with type-1 deletions display a more severe phenotype, with increased cutaneous, subcutaneous, plexiform, and spinal neurofibromas, and a significantly higher burden of internal neurofibromas [35,39]. They have a fourfold increased risk of MPNSTs, particularly when SUZ12 or EED genes are co-deleted. Additionally, these patients exhibit dysmorphic facial features, overgrowth characteristics, and increased cardiovascular anomalies. Cognitive impairments are also prevalent in this group. Type-1 microdeletion-associated somatic mosaicism is rare and usually presents a milder phenotype [34]. The overall clinical severity in patients with NF1 microdeletions is influenced by deletion size and the presence of somatic mosaicism [35].

Studies have demonstrated a positive correlation between NF1 deletion length and the incidence of learning disabilities. Patients with NF1 deletions exhibit a higher prevalence of learning disabilities, particularly those with type-1 deletions. In one study, all type-1 deletion patients (n=16) with neurodevelopmental data displayed learning disabilities, whereas none of the type-2 deletion patients (n=2) showed such impairments [9]. Another study by Vogt et al. [40] observed no neurodevelopmental delay in two patients with type-2 deletions. Additionally, Pasmant et al. [41] reported an 86% incidence of learning disabilities in type-1 deletion patients (n=44), surpassing the 80% incidence observed in all NF1 deletion patients (n=58).

2. Neurofibromin p.Met992del

The genotype-phenotype correlation of the p.Met992del variant was first described in 2007 in relation to an in-frame deletion at codon 992, and it has been further characterized through multiple study cohorts [42]. Patients with the p.Met992del mutation typically exhibit a milder phenotype, primarily consisting of café-au-lait spots and axillary freckling, without the characteristic cutaneous and PNs of NF1. Other clinical features include learning disabilities (17-38.8%), thoracic abnormalities (16%), short stature (11%), scoliosis (10%), pulmonary stenosis (9%), macrocephaly (9%), and symptomatic spinal neurofibromas (2%). Although 4.8% of individuals were found to have non-optic pathway tumors, these were mostly low-grade and asymptomatic, with no detectable cutaneous or PNs. The overall prevalence of lipomas was 5.5%. The molecular mechanisms underlying this mutation remain unknown. This mild phenotypic spectrum overlaps with the clinical features observed in Legius syndrome, caused by pathogenic variants in SPRED1. However, Legius syndrome patients differ from NF1 patients in that they do not exhibit Lisch nodules [43].

3. Neurofibromin p.Arg1809

Patients with NF1 carrying the p.Arg1809Cys mutation, resulting from a missense change NF1 c.5425C>T, which affects an arginine residue within the pleckstrin homology (PH) domain of neurofibromin, presented with café-au-lait spots and freckles, macrocephaly, thoracic abnormalities, growth retardation, and learning disabilities [44]. Similar to those with the p.Met992del mutation, these patients did not exhibit overt cutaneous, spinal, or PNs, optic pathway gliomas, other malignancies, or skeletal abnormalities. Approximately 25% of individuals displayed Noonan-like features, with pulmonary stenosis and short stature being significantly more prevalent in this group compared to the classical NF1 cohort [45].

4. Missense mutations in neurofibromin codons 844-848

Patients with missense mutations affecting one of the codons 844-848 within the cysteine-serine rich (CSR) domain exhibit a severe phenotype [46]. These patients show a high prevalence of plexiform or spinal neurofibromas, symptomatic and asymptomatic optic pathway gliomas, malignant neoplasms, and skeletal abnormalities. This severe phenotype is observed in 75% of adult NF1-affected individuals with these variants, clearly indicating that missense mutations outside the GAP-related domain (GRD) can result in severe clinical presentation. Notably, 25% of patients with NF1 carrying these variants do not present with the typical severe phenotype.

MOSAIC NEUROFIBROMATOSIS AND LOSS OF HETEROZYGOSITY

In alignment with genotype-phenotype correlations, the identification of mosaicism and loss of heterozygosity (LOH) events through deep sequencing can more effectively associate specific genetic alterations with clinical outcomes. This capability enhances the prediction of disease progression and the customization of individualized treatment strategies.

1. Mosaic neurofibromas or segmental NF1

Mosaic neurofibromas or segmental NF1 occur when the NF1 mutation happens after fertilization, leading to a mixture of normal and mutated cells in the body [47]. This results in neurofibromas that are localized to specific areas rather than being widespread. The severity and distribution of symptoms can vary significantly depending on the extent and location of the affected cells. Diagnosing mosaic NF1 has been more challenging than classic NF1 because of the localized nature of the symptoms, but recent advances in genetic testing (e.g., targeted deep sequencing of DNA) and imaging techniques (e.g., MRI) have improved accuracy. Common features include freckling, café-au-lait spots, neurofibromas, Lisch nodules, and bone abnormalities [48-50].

2. Loss of heterozygosity

LOH, which occurs due to somatic loss, refers to the loss of the normal (wild type) allele in cells that already possess one mutated NF1 allele.

The first report of NF1 LOH was published in 2007 by researchers investigating the genetic mechanisms in patients with pheochromocytoma and NF1 [51]. They found that 67% of patients with NF1-related tumors had somatic loss of the unmutated allele at the NF1 gene locus, which was not the case in non-NF1-associated tumors.

In melanocytes, LOH in NF1 increases melanogenic gene expression and activates the MAP kinase pathway, resulting in pigmentary abnormalities such as CALMs and freckling. This loss of neurofibromin disrupts the Kit-Mitf signaling axis, essential for melanocyte development and differentiation [52]. In Schwann cells, LOH leads to the formation of PNs and cutaneous neurofibroma [53-56]. LOH in astrocytes contributes to the development of optic pathway gliomas, low-grade tumors that can impair vision [53]. In hematopoietic cells, LOH can result in hematologic malignancies such as juvenile myeloid leukemia [56].

Recent studies focus on identifying genetic variations in LOH through WGS as well as understanding the mechanisms of LOH.

While not discussed in detail here, pathophysiological studies have shown that benign tumors such as PNs and low-grade gliomas (LGGs) in NF1 patients can transform into MPNSTs and high-grade gliomas, respectively. Atypical neurofibromatous neoplasms (ANNUBPs) represent an intermediate stage between neurofibromas and MPNSTs. ANNUBPs are associated with the loss of the CDKN2AB gene [57-59], and their diagnosis and classification remain areas of ongoing research (Fig. 2).

NF1+/- TUMOR MICROENVIRONMENT

The involvement of the tumor microenvironment (TME) in NF1 pathogenesis is increasingly recognized. Recent advances in single-cell RNA sequencing have delineated the intricate cellular composition and signaling dynamics within mature neurofibromas, elucidating the complexity of the TME [60,61].

Research has demonstrated that schwann cells-immunes (mast cells, T cells) in PNs [62-67], microglia and T cells in LGGs [68-71], and hematopoietic cells in MPNSTs [72,73], play a significant role in promoting the development of NF1-associated tumors. These interactions between immune cells and the TME present potential targets for therapeutic intervention.

In the beginning, Nf1flox/flox; Krox20Cre+ mouse models have demonstrated that the development of neurofibromas requires the loss of both Nf1 alleles in Schwann cells destined to become neoplastic [54].

Research has shown that Nf1 haploinsufficiency in bone marrow is sufficient to drive PN tumorigenesis in Nf1flox/flox; Krox20Cre+ mice, mechanistically linking the pathological increase in Nf1+/- mast cell proliferation to hyperactivation of Ras and Erk [63].

In a mouse model of neurofibromas, the CXCL10/CXCR3 axis involving dendritic cells and T cells plays a critical role in the early development (approximately 2 months) of neurofibromas. Macrophages contribute to neurofibroma formation through STAT3 and CSF-1/CSF1R signaling. These findings suggest that inhibitory molecules targeting STAT3, CSF-1/CSF1R, and pegylated interferon alpha 2b may have the potential to suppress tumor growth [67].

Approximately 15-20% of children with NF1 develop LGGs along the optic pathway, leading to visual impairment in 30-50% of these cases [68,69]. In the microenvironment of NF1 glioma tumors, increased c-Jun N-terminal kinase (JNK) activity in Nf1+/− microglia promotes tumor growth. Inhibiting JNK with SP600125 reduces tumor proliferation, indicating that targeting NF1+/− microglia could be a promising strategy for developing therapies [70]. Additionally, reduced expression of the chemokine receptor CX3CR1on microglia delays glioma development. Increased T cells and microglia in the NF1-related LGG microenvironment suggest that T cell-microglia interactions are essential for tumor engraftment and growth, mediated by chemokines such as Ccl2 and Ccl12 [66,71].

These findings highlight the importance of microglia and immune interactions in NF1 tumor development, offering potential targets for therapeutic intervention to prevent visual decline.

NF1-related MPNSTs are aggressive tumors that develop from PNs in about 5-10% of NF1 patients [72]. A recent study compared the tumor environments of two NF1-related MPNST mouse models, one with and one without Nf1 gene haploinsufficiency [72,73]. The study found that MPNSTs with Nf1 haploinsufficiency had more myeloid and mast cells, and these hematopoietic cells sped up MPNST development. Further research is needed to understand how these mutated cells contribute to NF1-related MPNST, which could lead to new treatments for this type of tumor (Fig. 3).

This enhanced understanding of the TME has been instrumental in the development of targeted therapies, including combination approaches, and has propelled the application of personalized medicine for NF1-associated malignancies. Progress in TME research has unveiled new avenues for diagnostic strategies, risk assessment, and therapeutic development, ultimately aiming to improve clinical outcomes for patients with NF1-associated tumors.

FUNCTIONAL DIFFERENCES IN GAP ACTIVITY OF NF1 ISOFORMS: THE ROLE OF EXON 23A

The nomenclature for NF1 isoforms was updated in 2017 to provide a unified annotation system for the NF1 gene. This change was necessary due to the discovery of several alternatively spliced exons (9a, 10a-2, 23a, and 48a) over the years, which led to considerable confusion and inconsistencies in clinical and scientific publications [74-76]. However, the nomenclature for these isoforms remains confusing in the literature and databases, as both isoforms are often referred to as isoform 1 or 2 (neurofibromin isoform 1 or isoform 2). In this review, we will follow the nomenclature of UniProt and refer to neurofibromatosis isoform 1 (or type 1) as a protein of 2818 amino acids (National Center for Biotechnology Information [NCBI] Genbank Accession: NP_000258.1) and neurofibromatosis isoform 2 (or type 2) as a protein of 2839 amino acids (NCBI Genbank Accession: NP_001035957.1).

The most abundant form of NF1 mRNA contains 57 exons (not including 4 alternatively spliced exons) and encodes the 2818 amino acid neurofibromin protein [74]. Several transcript variants resulting from alternative splicing of the NF1 pre-messenger RNA have been identified [74-76]. To date, five alternatively spliced exons leading to the expression of NF1 isoforms have been specifically studied: 9a, 10a-2, 23a, 43, and 48a (according to the previous nomenclature) [74-77].

It is important to note that studies have shown that alternative splicing of exon 23a impacts the GTPase activity of neurofibromin encoded by the NF1 gene. Excluding exon 23a from the NF1 gene (isoform 1) increases the GAP activity of neurofibromin, making it better at turning off Ras signaling [78-81]. When exon 23a is included (isoform 2), neurofibromin’s ability to regulate Ras is reduced, leading to more active Ras signaling and potential tumor growth (Fig. 4) [78,79].

The isoform 2 transcriptome exhibits differential expression between isoform 1 and various tissues, with isoform 2 being preferentially expressed in differentiated cells [74-76]. Embryonic stem cells expressing exclusively isoform 2 exhibit increased activity of the Ras/ERK pathway, which is crucial for NF1 cell proliferation and survival, while cAMP levels remain unchanged. This observation is consistent with previous studies in yeast, confirming a specific role for isoform 2 in regulating the Ras/ERK pathway without affecting cAMP levels [82]. Neurons expressing neurofibromin isoform 2 also demonstrate higher Ras/ERK signaling. Nguyen et al. [80] generated a mouse model that exclusively expresses isoform 2 in all tissues. These mice, referred to as NF1 23a/23a, were viable, fertile, and exhibited no physical abnormalities. However, the brains of NF1 23a/23a mice showed higher Ras/ERK pathway activity compared to wild-type mice and impairments in both short-term and long-term spatial memory [77,79,80].

Cryo-electron microscopy studies have demonstrated that NF1 isoforms 1 and 2 (exon 23a) exhibit different functional states through their 3D structures [83]. Isoform 1 typically exists in an open state, allowing it to interact with Ras and perform its GAP function effectively. Isoform 2 can exist in both closed (self-inhibited) and open states. The closed state is stabilized by zinc binding, inhibiting Ras binding, while the open state allows Ras interaction.

The distinct functional roles of NF1 isoforms underscore their involvement in various cellular processes and disease mechanisms, making these differences crucial considerations for developing novel therapeutic strategies.

CONCLUSION

Over the past century, research has significantly advanced our understanding of neurofibromas in NF1. Key discoveries include the identification of NF1 LOH in Schwann cells within neurofibromas, but not in fibroblasts. Mouse models have confirmed that the loss of NF1 in Schwann cells leads to the formation of neurofibromas, highlighting the crucial role of the TME in NF1 pathogenesis.

Recent studies suggest that NF1 LOH occurs in multipotent precursors, explaining the diverse phenotypes observed in NF1 patients. High-throughput technologies, such as next-generation sequencing (NGS) and whole-exome sequencing (WES), are revolutionizing clinical research. These technologies facilitate the development of novel therapeutics and advance precision medicine. Enhanced genotyping and phenotyping methodologies, combined with meticulous research approaches, are anticipated to elucidate the genetic complexity, underlying molecular mechanisms, and heterogeneous phenotypes observed in NF1 patients. Despite these advancements, further research is essential to develop specific therapeutic strategies tailored to the diverse mutation types observed in NF1 patients.

At this point in time, utilizing induced pluripotent stem (iPS) cells derived from patients with NF1 mutations allows researchers to study the disease in a patient-specific manner. This technology enables the development of personalized therapeutic strategies by providing a detailed understanding of NF1 pathology and testing potential treatments. iPS cells can be differentiated into relevant cell types, offering a powerful tool for advancing personalized medicine and targeted therapies for NF1.

ACKNOWLEDGEMENTS

None.

FUNDING

This research was supported by Brain Pool Program funded by the Ministry of Science and ICT through the National Research Foundation of Korea (RS-2024-00402454).

Figures
Fig. 1. Current approaches for targeting pathways in NF1-associated tumorigenesis. Inhibitors of RAF, MEK, and ERK specifically target the MAPK pathway. In contrast, mTOR inhibitors focus on the PI3K/AKT/mTOR pathway. Both receptor tyrosine kinase (RTK) inhibitors and SHP2 inhibitors influence both pathways.
Fig. 2. Biologic progression from plexiform neurofibroma (PN) to malignant peripheral nerve sheath tumor (MPNST). MPNSTs develop through a series of mutations. Initially, mutations in both copies of the NF1 gene in Schwann cells lead to the formation of a PN. Loss of the CDKN2A/B tumor suppressor gene causes this to progress to an atypical neurofibromatous neoplasm (ANNUBP). Further mutations in TP53, EGFR, SUZ12, and EED transform it into a malignant peripheral nerve sheath tumor. LOH, loss of heterozygosity.
Fig. 3. Approaches to target the microenvironment of neurofibromatosis type 1 (NF1) tumors. Immunotherapeutic approaches target the tumor microenvironment, using immune checkpoint, CSF1-R, and KIT inhibitors. Additional strategies include targeting fibroblasts and endothelial cells.
Fig. 4. Schematic representation of neurofibromin isoform 1 and 2. A diagram showing that alternative splicing of the NF1 exon 23a can give rise to two isoforms of neurofibromin. Exon 23a, previously mentioned, is now referred to as exon 31 in the current nomenclature. CSRD, cysteine-and serine-rich domain; TBD, tubulin-binding domain; GAP, GTPase-activating protein; GRD, GAP-related domain; Sec, Sec14 homologous domain; PH, pleckstrin homologous domain; CTD, C-terminal domain; NLS, nuclear localization signal.
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