Clinical Trials Targeting Neurofibromatoses-associated Tumors: A Systematic Review

Background There is a paucity of literature that comprehensively analyzes previous and current clinical trials targeting neurofibromatoses-related tumors. This article aims to provide readers of drug development efforts targeting these tumors by analyzing translational and clinical findings. Methods This systematic review was written according to the PRISMA guidelines. Inclusion criteria were clinical trials involving patients with neurofibromatosis type 1, type 2, or schwannomatosis that were treated with therapies targeting neurofibromatoses-associated tumors and that were registered on clinicaltrials.gov. In addition, a search was performed in PubMed, Web of Science, Google Scholar, and Embase European for articles fully describing these clinical trials. Results A total of 265 clinical trials were registered and screened for eligibility. Ninety-two were included in this systematic review involving approximately 4,636 participants. The number of therapies analyzed was more than 50. Drugs under investigation mainly act on the MAPK/ERK and PI3K/AKT/mTOR pathways, tumor microenvironment, or aberrantly over-expressed cell surface receptors. Selumetinib was the most effective medication for treating a neurofibromatosis type 1-associated tumor with approximately 68-71% partial response for inoperable or progressive plexiform neurofibromas in children 2 years of age and older and bevacizumab for a neurofibromatosis type 2-related tumor with approximately 36-41% partial response for vestibular schwannomas in patients 12 years of age and older. Conclusions This systematic review presents the results of previous clinical investigations and those under development for neurofibromatoses-associated tumors. Clinicians may use this information to strategize patients to appropriate clinical trials.

Current Aspects on the Pathophysiology of Bone Metabolic Defects during Progression of Scoliosis in Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1), which is the most common phacomatoses, is an autosomal dominant disorder characterized by clinical presentations in various tissues and organs, such as the skin, eyes and nervous and skeletal systems. The musculoskeletal implications of NF1 include a variety of deformities, including scoliosis, kyphoscoliosis, spondylolistheses, congenital bony bowing, pseudarthrosis and bone dysplasia. Scoliosis is the most common skeletal problem, affecting 10–30% of NF1 patients. Although the pathophysiology of spinal deformities has not been elucidated yet, defects in bone metabolism have been implicated in the progression of scoliotic curves. Measurements of Bone Mineral Density (BMD) in the lumbar spine by using dual energy absorptiometry (DXA) and quantitative computer tomography (QCT) have demonstrated a marked reduction in Z-score and osteoporosis. Additionally, serum bone metabolic markers, such as vitamin D, calcium, phosphorus, osteocalcin and alkaline phosphatase, have been found to be abnormal. Intraoperative and histological vertebral analysis confirmed that alterations of the trabecular microarchitecture are associated with inadequate bone turnover, indicating generalized bone metabolic defects. At the molecular level, loss of function of neurofibromin dysregulates Ras and Transforming Growth factor-β1 (TGF-β1) signaling and leads to altered osteoclastic proliferation, osteoblastic activity and collagen production. Correlation between clinical characteristics and molecular pathways may provide targets for novel therapeutic approaches in NF1.

Social behavior in RASopathies and idiopathic autism

Background RASopathies are genetic syndromes that result from pathogenic variants in the RAS-MAPK cellular signaling pathway. These syndromes, which include neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, and Costello syndrome, are associated with a complex array of medical and behavioral health complications. Despite a heightened risk for social challenges and autism spectrum disorder (ASD), few studies have compared different aspects of social behavior across these conditions. It is also unknown whether the underlying neuropsychological characteristics that contribute to social competence and socially empathetic (“prosocial”) behaviors differ in children with RASopathies as compared to children with nonsyndromic (i.e., idiopathic) ASD. Methods In this cross-sectional, survey-based investigation, caregivers of preschool and school-aged children with RASopathies (n = 202) or with idiopathic ASD (n = 109) provided demographic, medical, and developmental information about their child, including psychiatric comorbidities. For children who were able to communicate verbally, caregivers also completed standardized rating scales to assess social competence and empathetic behavior as well as symptoms of hyperactivity/inattention and emotional problems. Results As compared to children with idiopathic ASD, children with RASopathies were rated as demonstrating more resilience in the domain of empathy relative to their overall social competence. Similarities and differences emerged in the psychological factors that predicted social behavior in these two groups. Stronger communication skills and fewer hyperactive-impulsive behaviors were associated with increased empathy and social competence for both groups. Greater emotional challenges were associated with lower social competence for children with RASopathies and stronger empathy for children with idiopathic ASD. Among children with RASopathy and a co-occurring ASD diagnosis, socially empathetic behaviors were observed more often as compared to children with idiopathic ASD. Conclusions Findings suggest that the development of social behavior among children with RASopathies involves a distinct pattern of strengths and weaknesses as compared to a behaviorally defined disorder (idiopathic ASD). Identification of areas of resilience as well as behavioral and social challenges will support more targeted intervention.

Efficacy and Safety of Selumetinib in Pediatric Patients With Neurofibromatosis Type 1: A Systematic Review and Meta-analysis

Background and Objectives:Although the recent approval of selumetinib is expected to transform the management of children with Neurofibromatosis type 1 (NF1), particularly those with symptomatic and inoperable PN, no systematic review has summarized their efficacy and safety based on the latest studies. This study was conducted to systematically evaluate the efficacy and safety of selumetinib in children with NF1Methods:Original articles reporting the efficacy and safety of selumetinib in patients with NF1 were identified in PubMed and EMBASE up to January 28, 2021. The pooled objective response rates (ORRs) and disease control rates (DCRs) were calculated using the DerSimonian–Laird method based on random-effects modeling. The pooled proportion of adverse events (AEs) was also calculated. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation system.Results:Five studies involving 126 patients were included in our analysis. The studies had a very low to moderate quality of the evidence. The pooled ORR was 73.8% (95% CI: 57.3–85.5%), and the DCR was 92.5% (95% CI: 66.5–98.7%). The two most common AEs were diarrhea, which had a pooled rate of 63.8% (95% CI, 52.9–73.4%) and an increase in creatine kinase levels, which had a pooled rate of 63.3% (95% CI, 35.6–84.3%).Discussion:Our results indicate that selumetinib is an effective and safe treatment for pediatric patients with symptomatic, inoperable plexiform neurofibromas. Further larger-scale randomized controlled studies are needed to confirm the long-term outcome of patients treated with this drug.

Do non-pathogenic variants of DNA mismatch repair genes modify neurofibroma load in neurofibromatosis type 1?

Non-pathogenic mismatch repair (MMR) gene variants can be associated with decreased MMR capacity in several settings. Due to an increased mutation rate, reduced MMR capacity leads to accumulation of somatic sequence changes in tumour suppressor genes such as in the neurofibromatosis type 1 (NF1) gene. Patients with autosomal dominant NF1 typically develop neurofibromas ranging from single to thousands. Concerning the number of neurofibromas NF1 patients face a situation that is still not predictable. A few studies suggested that germline non-pathogenic MMR gene variants modify the number of neurofibromas in NF1 and by this mechanism may promote the extent of neurofibroma manifestation. This review represents first evidence that specific non-pathogenic single nucleotide variants of MMR genes act as a modifier of neurofibroma manifestation in NF1, highlighting MSH2 re4987188 as the best analysed non-pathogenic variant so far. In summary, besides MSH2 promotor methylation, specific non-pathogenic germline MSH2 variants are associated with the extent of neurofibroma manifestation. Those variants can serve as a biomarker to facilitate better mentoring of NF1 patients at risk.

Modulation of Cortical Inhibition by Lovastatin in Neurofibromatosis Type 1: A Randomized, Triple-Blind, Placebo-Controlled Clinical Trial

Neurofibromatosis type 1 (NF1) is associated with GABAergic dysfunction which has been suggested as the underlying cause of cognitive impairments. Previous intervention trials investigated the statins’ effects using cognitive outcome measures. However, available outcome measures have led to inconclusive results and there is a need to identify other options. Here, we aimed at investigating alternative outcome measures in a feasibility trial targeting cortical inhibition mechanisms known to be altered in NF1. We explored the neurochemical and physiological changes elicited by lovastatin, with magnetic resonance spectroscopy and transcranial magnetic stimulation (TMS). Fifteen NF1 adults participated in this randomized, triple-blind, placebo-controlled crossover trial (Clinicaltrials.gov NCT03826940) composed by one baseline and two reassessment visits after lovastatin/placebo intake (60mg/day, 3-days). Motor cortex GABA+ and Glx concentrations were measured using HERMES and PRESS sequences, respectively. Cortical inhibition was investigated by paired-pulse, input-output curve and cortical silent period (CSP) TMS protocols. CSP ratios were significantly increased by lovastatin (relative: p=0.027; absolute: p=0.034) but not by placebo. CSP durations showed a negative correlation with LICI 50ms amplitude ratio. Lovastatin was able to modulate cortical inhibition in NF1, as assessed by TMS CSP ratios, highlighting the potential of this outcome measure to be considered in future large-scale studies.

Delineating the autistic phenotype in children with neurofibromatosis type 1

Background Existing research has demonstrated elevated autistic behaviours in children with neurofibromatosis type 1 (NF1), but the autistic phenotype and its relationship to other neurodevelopmental manifestations of NF1 remains unclear. To address this gap, we performed detailed characterisation of autistic behaviours in children with NF1 and investigated their association with other common NF1 child characteristics. Methods Participants were drawn from a larger cross-sectional study examining autism in children with NF1. The population analysed in this study scored above threshold on the Social Responsiveness Scale-Second Edition (T-score ≥ 60; 51% larger cohort) and completed the Autism Diagnostic Interview-Revised (ADI-R) and/or the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2). All participants underwent evaluation of their intellectual function, and behavioural data were collected via parent questionnaires. Results The study cohort comprised 68 children (3–15 years). Sixty-three per cent met the ADOS-2 ‘autism spectrum’ cut-off, and 34% exceeded the more stringent threshold for ‘autistic disorder’ on the ADI-R. Social communication symptoms were common and wide-ranging, while restricted and repetitive behaviours (RRBs) were most commonly characterised by ‘insistence on sameness’ (IS) behaviours such as circumscribed interests and difficulties with minor changes. Autistic behaviours were weakly correlated with hyperactive/impulsive attention deficit hyperactivity disorder (ADHD) symptoms but not with inattentive ADHD or other behavioural characteristics. Language and verbal IQ were weakly related to social communication behaviours but not to RRBs. Limitations Lack of genetic validation of NF1, no clinical diagnosis of autism, and a retrospective assessment of autistic behaviours in early childhood. Conclusions Findings provide strong support for elevated autistic behaviours in children with NF1. While these behaviours were relatively independent of other NF1 comorbidities, the importance of taking broader child characteristics into consideration when interpreting data from autism-specific measures in this population is highlighted. Social communication deficits appear similar to those observed in idiopathic autism and are coupled with a unique RRB profile comprising prominent IS behaviours. This autistic phenotype and its relationship to common NF1 comorbidities such as anxiety and executive dysfunction will be important to examine in future research. Current findings have important implications for the early identification of autism in NF1 and clinical management.

Neurofibromatosis in Children: Actually and Perspectives

The three types of neurofibromatosis, namely type 1, type 2, and schwannomatosis, are generally associated with various benign tumors affecting the skin and the nervous system. On rare occasions, especially in patients with neurofibromatosis type 1 (NF1), malignant neoplasms may also be present, several of them possessing a more aggressive course than in individuals without this syndrome. As such, a clear delineation between the three variants of neurofibromatosis is crucial to establish the correct diagnosis and management, as well as predict the neoplasm-related outcomes. Neurofibromin, the principal product of the NF1 gene, is a potent inhibitor of cellular proliferation, having been linked to several key signaling pathways involved in tumor growth. Therefore, it may provide a useful therapeutic target for tumor management in these patients. In this article, we want to present the association between deficiency of neurofibromin and the consequences of the lack of this protein leading to different kinds of malignant tumors. The therapy is still uncertain and most therapeutic options are in development or clinical trials.