Search Results (66)

Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). By cross-comparison of RNA sequencing and RUNX1-CHIP sequencing data on mouse PNFs, we found that transcripts encoding the NF1-interacting p97/valosin-containing protein (VCP) gene are overexpressed in PNFs. Co-immunoprecipitation confirmed that VCP bounded to neurofibromin. Western blot and immunostaining confirmed VCP overexpression in both mouse and human PNFs. Treatment of primary mouse PNF Schwann cells with CB-5083, a p97/VCP inhibitor, led to accumulation of poly-ubiquitinated proteins and generation of irresolvable proteotoxic stress. Pharmacological or genetic inhibition of VCP reduced mouse PNF cell-derived sphere number, and genetic inhibition of Vcp in Schwann cell precursors decreased tumor-like lesion numbers in a cell transplantation model. In vivo treatment with CB-5083 in Nf1^fl/fl;DhhCre PNF mice significantly inhibited cell proliferation, increased cell apoptosis and reduced PNF volume. The combination with a MEK inhibitor did not increase efficacy compared to the single agent, supporting the hypothesis that VCP functions in parallel to, and may be modulated by, RAS–MAPK signaling under stress or oncogenic conditions. The significant effects of VCP inhibition in this pre-clinical study suggest a potential novel therapy for patients with PNFs. Full article

Background: Vestibular schwannomas (VSs) are benign tumors that can cause significant morbidity, particularly in neurofibromatosis 2 (NF2) patients, in whom conventional treatments have important limitations. Merlin is a tumor suppressor protein encoded by the Neurofibromin 2 (NF2) gene, and the loss of its function leads to the activation of multiple signaling pathways, providing a rationale for targeted pharmacological therapies. Agents such as bevacizumab and other receptor tyrosine kinase inhibitors (TKIs) have shown variable efficacy but remain limited by toxicity and inconsistent responses. This review aims to evaluate the efficacy and safety of targeted therapies for VSs. Methods: This study was conducted according to PRISMA 2020 guidelines, using a PICO-based search of PubMed, EMBASE, and Scopus to identify studies on pharmacological therapies for VSs published between 2000 and 2025. Eligible human studies included clinical trials and observational studies reporting efficacy, safety, neuroimaging and audiological outcomes. Results: In total, 23 studies were analyzed, predominantly involving NF2-associated VSs. Treatment with bevacizumab was the most frequently investigated medical therapy and yielded the most consistent tumor control along with occasional hearing improvement, albeit with frequent but mostly manageable adverse events. Other targeted agents, including everolimus and TKIs, demonstrated limited or variable efficacy with acceptable toxicity profiles. Conclusions: VSs, particularly in NF2 patients, can cause significant morbidity and are often poorly managed by surgery or radiotherapy. Consequently, targeted medical therapies, especially anti-angiogenic agents, have emerged as valuable alternatives. Bevacizumab shows the most consistent benefits in tumor control, hearing stabilization, and quality of life, despite heterogeneous responses and notable toxicity. Evidence suggests that treatment discontinuation may lead to rapid tumor rebound, highlighting the need for long-term or maintenance strategies and careful monitoring. Future studies are needed to evaluate medical therapy integration with conventional treatments. Full article

Background/Objectives: Neurofibromatosis Type 1 (NF1) is a genetic syndrome caused by pathogenic NF1 variants encoding neurofibromin, a Ras GTPase activating protein. Individuals with NF1 develop peripheral nerve sheath tumors called neurofibromas. Approximately 50% of NF1 patients develop plexiform neurofibromas (pNFs) which have up to 13% lifetime risk of transformation into malignant peripheral nerve sheath tumors (MPNSTs). Current therapeutic strategies emphasize surgical resection with wide margins, radiation, and traditional chemotherapy for unresectable MPNSTs. However, NF1 patients diagnosed with MPNSTs have 5-year survival rates as low as 16%. The two recently FDA-approved drugs for pNFs, the MEK inhibitors selumetinib and mirdametinib, are not used to prevent or treat MPNSTs. Methods: The MEK inhibitor trametinib and the dual HDAC/PI3K inhibitor fimepinostat were assessed for growth inhibitory effects in nine unique patient-derived MPNST cell lines, as both drugs have preclinical efficacy in other Schwann cell-derived tumors. Results: Trametinib, which is approved for malignant melanomas, promoted cell death in 7/9 MPNST cell lines with a geometric mean GI50 = 17 nM. When directly compared to selumetinib and mirdametinib in a subset of four MPNST cell lines, trametinib had the lowest mean GI50 (trametinib = 38 nM, mirdametinib = 1.6 µM, selumetinib = 4.9 µM). Trametinib was also superior to selumetinib and mirdametinib in blocking ERK1/2 phosphorylation for 24 h. Fimepinostat promoted cell death in all cell lines with a geometric mean GI50 = 17 pM. Conclusions: These studies demonstrate in vitro efficacy for two candidate MPNST therapeutics which could reduce tumor burden and metastasis in NF1 patients. Full article

The neurofibromin 1 (NF1) splice-site mutation c.61-2A>G (rs1131691100) is a rare, pathogenic, autosomal dominant variant that disrupts NF1 tumor-suppressor function, causing neurofibromatosis type 1 (NF1). Its pathogenic mechanism is poorly understood, and the potential for personalized therapeutic genome editing remains unknown due to the absence of a standard framework for investigating splicing disorders. Here, we performed a comprehensive multi-omics analysis of a de novo c.61-2A>G case from South Korea, integrating short- and long-read whole genome sequencing, whole transcriptome sequencing, and methylation profiling. We confirm that c.61-2A>G abolishes the canonical splice acceptor site, activating a cryptic splice acceptor 16 nucleotides downstream in exon 2. This splicing shift generates a 16-nucleotide deletion, causing a frameshift and premature stop codon that truncates the protein’s N-terminal region. Long-read sequencing further reveals that the mutation creates a novel CpG dinucleotide, which is methylated in the majority of reads. Finally, we assessed therapeutic correction strategies, revealing that CRISPR-Cas9 prime editing is the only viable approach for in vivo correction. This study provides the first comprehensive multi-omics characterization of the NF1 c.61-2A>G mutation and establishes a minimal framework for precision therapeutic development in silico in monogenic splicing disorders. Full article

Background/Objectives: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder driven by mutations in the NF1 gene, whose pathogenesis centers on the loss of neurofibromin function and subsequent hyperactivation of the RAS/MAPK pathway. Notably, to the best of our knowledge and following a systematic literature search conducted by our research team, no cases of NF1 complicated by severe cardiac structural abnormalities that ultimately lead to cerebral infarction have been reported to date. Thus, it is of paramount importance to avoid missed diagnosis by performing comprehensive cardiac-related examinations in patients with NF1. Case Presentation: A 20-year-old male patient diagnosed with NF1 presented with right-sided limb weakness and was initially identified with cerebral infarction. To clarify the underlying etiology, a comprehensive clinical evaluation was performed, including cardiac imaging assessments (to characterize cardiac structural changes) and whole-exome sequencing (to identify the presence of procoagulant gene mutations). Comprehensive evaluation revealed a spectrum of cardiac structural abnormalities in the patient: aortic valve prolapse with severe regurgitation, non-infective vegetations on the aortic valve leaflets, mild-to-moderate mitral regurgitation, left ventricular hypertrophy and dilation, and left atrial dilation. Whole-exome sequencing detected exclusively a pathogenic variant in the NF1 gene, with no other pathogenic/likely pathogenic variants or thrombophilia-associated polymorphisms being found. Laboratory investigations ruled out infectious etiologies, supporting the notion that NF1-mediated cardiac structural and developmental anomalies are the primary driver of cardiac vegetation formation, given the absence of other identified contributing factors; embolization of one such vegetation ultimately led to both splenic and cerebral infarction. Conclusions: This case emphasizes the necessity of implementing early and proactive cardiac evaluations in patients with NF1. Additionally, for NF1 individuals—particularly those presenting with suggestive vascular or cardiac symptoms—a comprehensive multifactorial assessment of thrombotic risk is critical. Collectively, maintaining clinical vigilance for cardiac abnormalities in NF1 patients and avoiding diagnostic oversight is essential to reduce life-threatening risks. Full article

Mutations in the NF1 gene cause Neurofibromatosis Type 1 (NF1), one of the most common genetic disorders. This gene encodes neurofibromin, a member of the GTPase-activating protein (GAP) family that functions as a negative regulator of RAS signaling. Loss of NF1 function leads to persistent RAS activation and promotes tumor growth. The clinical manifestations of NF1 mainly include pigmentary changes, benign and malignant peripheral nerve sheath tumors, as well as gliomas affecting the central nervous system. Currently, MEK inhibition is the only approved therapy and is primarily effective in controlling plexiform neurofibromas (pNFs). However, more comprehensive treatments are needed to address the full spectrum of NF1 manifestations and malignant transformation. Novel therapeutic strategies, including AAV-based gene therapy aimed at restoring NF1 function, oncolytic herpes simplex virus (oHSV) therapy targeting RAS-dysregulated tumor cells, and chimeric antigen receptor T cell (CAR-T) therapy targeting NF1-associated tumors, are under active investigation. In this review, we explore the genetic mechanisms underlying NF1 and highlight recent advances in therapeutic development with a special focus on AAV-based gene therapies alongside other approaches with recent clinical and translational advancements. Full article

Malignant peripheral nerve sheath tumors (MPNSTs) are one of the most difficult sarcomas to treat. Due to the rarity of MPNSTs, many of the therapeutic approaches used are from treatment guidelines for soft tissue sarcoma. Besides surgery, little success has been achieved using these therapies. Traditional chemotherapy and radiation therapy regimens designed to treat sarcoma have unclear efficacy when used to treat MPNSTs. Targeted therapeutics that succeeded in other sarcomas failed to produce positive results in MPNSTs. Moreover, investigational agents that have shown efficacy in preclinical models have produced disappointing outcomes in clinical trials. While therapeutic options for patients with MPNST have remained relatively stagnant, dramatic improvements in therapeutic outcomes of other rare sarcomas have been made. This difference in success is likely caused by the complex heterogeneity of MPNSTs that hinders drug development, although many MPNSTs are associated with neurofibromatosis type 1 (NF1), a genetic disorder resulting from mutations in the NF1 gene that encodes the negative RAS regulator neurofibromin. The development of new agents for MPNST treatment has shifted away from solely targeting RAS pathway gene products to stimulating the immune system and manipulating other MPNST driver mutations such as CDKN2A/B, SUZ12, EED, and TP53. This review presents recent advances in the treatment of sarcomas and the future of drug development targeting MPNSTs. Full article

Neurofibromatosis type 1 (NF1) is a complex, multisystem, genetic disorder caused by germline NF1 variants that predispose affected individuals to tumors of the nervous system. With the identification of the NF1 gene in the late 1980s and the elucidation of the role of the encoded protein, neurofibromin, in regulating RAS signaling, considerable research effort has been invested to identify therapeutic treatments for NF1 tumors. Over the past two decades, high-throughput drug screening approaches have been a significant component of these endeavors. However, considerable variability exists among studies in terms of disease models, symptom targets, screening libraries, methods, and outcomes. In this review, we present an overall summary of efforts toward discovering new therapeutic strategies for NF1-related tumors using high-throughput screening and how such findings can be employed for prospective research in the NF1 field. Full article

Background/Objectives: This study presents the first molecular characterization of NF1 gene variants in Kazakhstani patients, expanding regional understanding of neurofibromatosis type 1 (NF1). The NF1 gene encodes neurofibromin, a tumor suppressor protein that regulates the MAPK signaling pathway; its inactivation results in NF1, a multisystem disorder with pigmentary and tumor manifestations. Methods: A total of 60 pediatric and young adult patients of University Clinic Aksai were selected based on Legius criteria and studied clinically; genetic variants of NF1 gene were determined with AmpliSeq for Illumina Myeloid Panel (next generation sequencing). Results: Pathogenic or likely pathogenic (with some variants of unknown significance) were detected in 58 of 60 (96.7%) patients. Among them, 27 (46.6%) carried point variants, 21 (36.2%) had genomic deletions, 3 (5.2%) had duplications, 3 (5.2%) insertions, and 4 (6.9%) had exon–intron splicing site variants. Notably, all patients with duplication insertions and splicing variants presented with plexiform neurofibromas. Conclusions: The study defines the first variant spectrum in a Kazakhstani population, confirming genotype–phenotype correlations consistent with European cohorts (l.). These data highlight the predominance of structural and splicing alterations in patients with plexiform neurofibromas and support the integration of molecular testing into clinical management of NF1 in Kazakhstan. Full article

More than 70% of breast cancers are estrogen receptor-positive (ER⁺). Endocrine therapy that blocks estrogen signaling remains the cornerstone of treatment, yet relapses continue to affect many patients. Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate the G1-S phase transition in the cell cycle, and pharmacological inhibition of this pathway has been successfully leveraged to reduce recurrence. CDK4/6 inhibitors combined with endocrine therapy are now the standard of care, although determining the optimal patient population for treatment remains a key challenge. A newly published study provides important insight, showing that loss of the NF1/neurofibromin tumor suppressor confers greater sensitivity to CDK4/6 inhibition, as these tumors rely heavily on CDK4/6 activity for survival under endocrine therapy. Full article

Neurofibromin (NF) inhibits the RAS/RAF/ERK pathway through its interaction with SPRED1 (Sprouty-related EVH1 domain-containing protein 1). Here, we investigated the functional relationship between NF and SPRED2 in breast cancer (BC). Human BC cell lines were transfected to downregulate or overexpress NF and SPRED2 and subsequently subjected to functional assays. Protein and mRNA levels were analyzed by Western blotting and RT-qPCR, respectively. Protein–protein interactions were examined by immunoprecipitation. Database analyses and immunohistochemistry (IHC) of BC tissues were performed to validate the in vitro findings. Downregulating NF or SPRED2 expression in BC cells enhanced cell proliferation, migration and invasion accompanied by RAF/ERK activation, whereas overexpression produced opposite effects. NF formed a protein complex with SPRED2 and facilitated its translocation to the plasma membrane. By IHC, SPRED2 membrane localization was absent in NF-negative luminal A and triple-negative BC (TNBC) but present in a subset of luminal A BC. By database analyses, both NF1 and SPRED2 mRNA levels were reduced in BC tissues, and luminal A BC patients with high expression of both NF1 and SPRED2 mRNA exhibited improved relapse-free survival. These results suggest a critical role for the NF–SPRED2 axis in BC progression and highlight it as a potential therapeutic target. Full article

Background/Objectives: Therapeutic strategies for Neurofibromatosis Type I (NF1) that correct the underlying pathogenic NF1 variant hold promise for restoring neurofibromin function, reducing tumor burden, and improving patient outcomes by addressing the root cause of the disease rather than its symptoms. Beyond gene editing, transcript reprogramming via RNA trans-splicing has gained attention, particularly with the recent FDA approval of two trans-splicing-based drugs for IND phase 1/2a trials. This study tests whether trans-splicing group I intron ribozymes from Tetrahymena thermophila can be used to repair pathogenic variants of NF1 (pre-)mRNA by 3′-tail replacement. Methods: Splice sites on the NF1 mRNA were identified computationally and validated biochemically, and an efficiency-enhancing Extended Guide Sequence (EGS) of the corresponding ribozyme was identified in a combinatorial experiment. Results: The correct trans-splicing product of this ribozyme was validated in HEK293 NF1−/− cells expressing mNf1. Conclusions: This study established a splice site and activity-enhancing extended guide sequences for the repair of NF1 mRNA. Further optimization of the ribozyme, as well as improved delivery methods, may establish ribozyme-based RNA repair as a viable strategy for NF1 treatment. Full article

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1 gene, typically diagnosed during early childhood and characterized by significant phenotypic heterogeneity. Despite advancements in next-generation sequencing (NGS), the diagnostic process remains challenging due to the gene’s complexity, high mutational burden, and frequent identification of variants of uncertain significance (VUS). This review explores the emerging role of artificial intelligence (AI) in enhancing NF1 variant detection, classification, and interpretation. A systematic literature search was conducted across PubMed, IEEE Xplore, Google Scholar, and ResearchGate to identify recent studies applying AI technologies to NF1 genetic analysis, focusing on variant interpretation, structural modeling, tumor classification, and therapeutic prediction. The review highlights the application of AI-based tools such as VEST3, REVEL, ClinPred, and NF1-specific models like DITTO and RENOVO-NF1, which have demonstrated improved accuracy in classifying missense variants and reclassifying VUS. Structural modeling platforms like AlphaFold contribute further insights into the impact of NF1 mutations on neurofibromin structure and function. In addition, deep learning models, such as LTC neural networks, support tumor classification and therapeutic outcome prediction, particularly in NF1-associated complications like congenital pseudarthrosis of the tibia (CPT). The integration of AI methodologies offers substantial potential to improve diagnostic precision, enable early intervention, and support personalized medicine approaches. However, key challenges remain, including algorithmic bias, limited data diversity, and the need for functional validation. Ongoing refinement and clinical validation of these tools are essential to ensure their effective implementation and equitable use in NF1 diagnostics. Full article

The homozygous Leu100Pro amino acid substitution in SPRED2, a protein negatively controlling RAS function, has recently been identified to be causally linked to a recessive form of Noonan syndrome. The amino acid substitution was documented to affect protein stability and cause a decreased and/or less stable interaction with neurofibromin, a RAS-specific GTPase activating protein negatively regulating RAS function. To further investigate the structural and functional impact of Leu100Pro, we structurally characterized the consequences of this change on the interaction of SPRED2 with neurofibromin, by 1 µn-long molecular dynamics (MD) simulations. Our analyses failed in identifying local perturbations predicted to disrupt or dramatically affect SPRED2 binding to neurofibromin, though a rearrangement of their interaction was observed. On the other hand, MD simulations also identified long-range structural rearrangements of the SPRED2 EVH-1 domain, which might be relevant for an aberrant folding of the mutant driving the previously documented accelerated degradation. Overall, the performed MD simulations suggest the occurrence of multiple intramolecular and intermolecular structural perturbations driven by the Leu100Pro change that likely contribute to its LoF behavior. Full article

Mesothelioma is characterized by the inactivation of tumor suppressor genes, with frequent mutations in neurofibromin 2 (NF2), BRCA1-associated protein 1 (BAP1), and cyclin-dependent kinase inhibitor 2A (CDKN2A). These mutations lead to disruptions in the Hippo signaling pathway and histone methylation, thereby promoting tumor growth. NF2 mutations result in Merlin deficiency, leading to uncontrolled cell proliferation, whereas BAP1 mutations impair chromatin remodeling and hinder DNA damage repair. Emerging molecular targets in mesothelioma include mesothelin (MSLN), oxytocin receptor (OXTR), protein arginine methyltransferase (PRMT5), and carbohydrate sulfotransferase 4 (CHST4). MSLN-based therapies, such as antibody–drug conjugates and immunotoxins, have shown efficacy in clinical trials. OXTR, upregulated in mesothelioma, is correlated with poor prognosis and represents a novel therapeutic target. PRMT5 inhibition is being explored in tumors with MTAP deletions, commonly co-occurring with CDKN2A loss. CHST4 expression is associated with improved prognosis, potentially influencing tumor immunity. Immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in some cases; however, resistance mechanisms remain a challenge. Advances in multi-omics approaches have improved our understanding of mesothelioma pathogenesis. Future research will aim to identify novel therapeutic targets and personalized treatment strategies, particularly in the context of epigenetic therapy and combination immunotherapy. Full article