Special issue: a contemporary landscape of the clinical and biological research in neurofibromatosis type 1

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. © The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. Special issue: a contemporary landscape of the clinical and biological research in neurofibromatosis type 1

Neurofibromatosis type 1 (NF1), first described by Frederich von Recklinghausen in 1882, is one of the most common autosomaldominant genetic tumor predisposition syndromes. 1 Individuals with NF1 are born with a germline mutation in the NF1 gene, which encodes a GTPase activating protein that negatively regulates the RAS signaling cascade. The clinical manifestations of NF1 can vary significantly among affected individuals and thus timely diagnosis can be difficult. NF1 is characterized by the development of numerous benign and malignant tumors that affect multiple organ systems almost anywhere within the body. Common tumors associated with NF1 include neurofibromas, malignant peripheral nerve sheath tumors (MPNSTs), optic pathway gliomas (OPGs), gastrointestinal stromal tumors (GISTs), pheochromocytomas, and leukemias. On account of these malignancies, the life expectancy is shortened in individuals with NF1 to an average of 54 years. 2 NF1 is an underrecognized and understudied disorder and, as a result, there has been little improvement in the quality of life and overall survival.
The complexity of NF1 and the wide spectrum of clinical complications emphasizes the importance of multidisciplinary teams to provide a holistic approach to patient management. An ideal model of care is for NF1 patients to be managed by a group of multiple specialists with expertise and interest in NF1, including surgeons, oncologists, neurologists, dermatologists, geneticists, genetics counselors, ophthalmologists, psychologists, and others. However, multidisciplinary clinics are rare, particularly for adults with NF1. At present, management paradigms are focused on early detection of treatable complications through routine surveillance and symptomatic treatment. Due to the gaps in our understanding of NF1, the management of patients can vary from institution to institution. There is a tremendous unmet need to establish evidence-based guidelines to build consensus on best practices and ensure dissemination of these approaches in as uniform manner as possible through all centers and physicians treating NF1.
Over the past 3 decades, substantial advances have been made by the neurofibromatosis research community in improving our understanding of this genetic condition. This special issue on neurofibromatosis constitutes a blend of clinical and basic science updates that highlight the research that helped advance the field. The primary aims of this special issue are to increase awareness of the cutting-edge research that is being conducted in the field, examine how this research can be leveraged to improve patient care, and identify gaps in knowledge and care. Here we will highlight a few of the biggest topics in the management of NF1.

Neuro-Oncology Advances
neurofibromas have a risk of malignant transformation. These differences suggested that cutaneous and plexiform neurofibromas had distinct cells of origin. However, through a series of studies over the past 3 decades, researchers have been able to link the cell of origin of these neurofibroma subtypes to a common stage in Schwann cell development. The leading candidate is the Hoxb7-and Prss56-expressing boundary cap cells/Schwann cell precursor that originates from migrating neural crest stem cells. Plexiform neurofibromas arise from those cells residing in the dorsal root ganglion and spinal nerve roots, while cutaneous neurofibromas arise from dermal glia that migrated from the dorsal nerve roots. Identifying the cell of origin enables accurate modeling of disease initiation and progression, which can help uncover key targetable vulnerabilities within these tumor cells.
After the loss of NF1 in the cell of origin, the immune microenvironment is essential for neurofibroma tumorigen-  There is a pressing need for the development of targeted therapies to treat MPNSTs. Miller et al. provide an in-depth review of the molecular landscape of MPNSTs and lay the foundation to identify potential therapeutic vulnerabilities. It appears that the malignant transformation of neurofibromas into MPNSTs involves sequential loss of tumor suppressors: NF1, CDKN2A/B, and polycomb repressive complex 2 core components. Preclinical studies have demonstrated that MPNST cell lines are sensitive to BRD4based therapies. 6 The authors highlight the importance of studies that reveal genes and regulatory pathways that are altered in malignant transformation.

Development of Targeted Therapies for MPNSTs
Terribas et al. studied the functional role of mitotic kinesins and their potential as a therapeutic vulnerability. Through in vitro studies, the authors demonstrated that kinesins are overexpressed in MPNSTs and required for cell survival. MPNST cell lines were also more sensitive to KIF11 inhibitors (ispinesib and ARRY-520). In addition, co-targeting with KIF11 and BRD4 reduced MPNST cell viability, synergistically killing a much higher proportion of MPNST cells than control fibroblasts. Since single-agent therapies have not shown clinical effect, the results of this study suggest further studies should examine the role of combination therapies targeting multiple oncogenic programs.
Despite wide local surgical resection followed by adjuvant radiotherapy, MPNSTs have a high rate of local recurrence and metastasis. The molecular mechanisms that enable tumor metastasis are not well understood. To address this question, Godec et al. investigated the mutational profile of tumors from 2 patients with spatially and temporally distinct metastasis. The authors identified point mutations and copy number losses of TRIM23 within the metastatic lesions, suggesting that this alteration may be critical for metastatic progression. Furthermore, Trim23 knockdown in MPNST cell lines demonstrated a decreased propensity for metastasis. The results of this study establish TRIM23 as a potential driver of metastasis and a candidate for targeted therapies.  Editorial Individuals with NF1 are at high risk of developing central nervous system tumors, with low-grade gliomas (OPGs and brain stem gliomas) common in early childhood and malignant glioblastomas manifesting in adulthood. Costa and Gutmann provide an in-depth review of the clinical and biological basis of gliomas in NF1. Since low-grade gliomas are not routinely biopsied, the authors emphasize the role of the NF1 murine glioma models in advancing our understanding of the pathogenesis. Use of these NF1 genetically engineered mouse glioma models was instrumental in discovering the specific progenitor cells that line the third ventricle as the cell-of-origin for OPGs. In addition, these models have permitted interrogation of promising targeted therapies in a preclinical setting prior to translation to human clinical trials. This review highlights the importance of faithful animal models for basic and preclinical translational research. The recently developed genetically engineered NF1 minipig models that better recapitulate the NF1 syndrome may be better suited for further preclinical drug testing. Lobon-Iglesias et al. investigated the possible molecular mechanisms driving OPG in a group of 16 pediatric patients with typical radiological features of NF1-associated OPG but without the NF1 diagnostic criteria. The authors identified RAS-MAPK pathway alterations in 8 of the tumors, including BRAFV600E mutations and BRAF-KIAA oncogenic fusions. In addition, one of these patients had an NF1 nonsense mutation (8% and 70% variant allele frequency in blood and tumor, respectively) suggestive of NF1 mosaicism. Further in vivo and in vitro studies of sporadic and NF1-associated OPGs will help explore the sensitivity to MAPK pathway inhibitors. Cutaneous neurofibromas, a hallmark of NF1, are benign tumors that cause considerable morbidity through physical and psychosocial burden. These tumors are often cosmetically disfiguring and physically distressing due to the hundreds to thousands of lesions present on a single individual. 7 This often leads to a significant lowering of quality of life through feelings of embarrassment and low self-esteem. 8,9 There is no one treatment option that is effective for cutaneous neurofibromas and can eradicate these lesions in a ready manner. In this issue, Chamseddin et al. review the existing literature on current treatment modalities including surgical excision, CO 2 laser ablation, photocoagulation, electrodessication, and radiofrequency ablation. Based on the efficacy and limitations of each treatment technique, the authors propose a management algorithm to aid clinicians. Despite the strong evidence that cutaneous neurofibromas cause significant mental health complications, treatment is still often classified as elective and cosmetic by most insurance companies. Further long-term studies are needed to assess the psychosocial and quality-of-life benefits of treating these cutaneous neurofibromas, in order to advocate for increased treatment accessibility. A change in approach to how these lesions are managed requires strong patient-driven advocacy in order to allow the health care team to more effectively address the needs of the patient population. One of the major challenges with studying cutaneous neurofibromas is the lack of a universally accepted nomenclature to describe the various subtypes. Current terminology varies based on subspecialties and institutions. 10 For instance, one lesion can be described by multiple terms (nodular, discrete, or localized cutaneous neurofibromas) and, similarly, multiple lesions can be described by a single term (nodular neurofibromas may be intra-or extraneural). Though seemingly a minor factor, the confusion that stems from this lack of consensus terminology reflects a clear lack of understanding of the etiology and pathophysiology of cutaneous neurofibromas. Advancement of understanding of cutaneous neurofibroma biology is hindered, as we cannot reliably compare the results of different studies. As a first step in developing a unified classification system, Ortonne et al. evaluated the interobserver agreement across pathologists in describing and reporting cutaneous neurofibromas. The study demonstrated that there was strong agreement among pathologists that not all neurofibromas involving the skin are cutaneous neurofibromas. However, there was less concordance on classifying cutaneous neurofibroma subtypes based on patterns of growth, composition, extent, and histological subtypes. Identifying the schema and histological features that pathologists use to characterize cutaneous neurofibromas will be the first step toward developing a robust classification system. Hamoy-Jimenez et al. characterize the quality of life of patients with NF1 and NF2. They utilized patientcompleted generic measures such as SF-36, EQ-5D-5L, PROMIS and disease-specific measures such as the PedsQL NF1 module and NFTI-QOL for NF2. The study demonstrated that neurofibromatosis patients suffer a significant reduction in quality of life, as expected. Most notably, the pain was the main driver of physical health and disease visibility was the main driver of mental health. The results of this study highlight potential functional and patient-reported outcome measures that may be used to assess the clinical efficacy of novel therapeutics for nonmalignant tumors.

Management of Abdominal Neoplasms in NF1
In addition, the development of noninvasive imaging biomarkers may address the challenges of developing clinical trials in NF1. de Blank et al. report their experience with diffusion tensor imaging (DTI) to assess white matter integrity. This study describes DTI measures in 93 children with and without NF1 throughout the brain and specifically the optic radiations. Individuals with NF1 demonstrate increased diffusion throughout the brain. The findings also suggest that children with NF1 may have an altered and delayed maturation of white matter in the developing brain. Better characterization of the trajectory of white matter integrity in children with NF1 may help target early intervention efforts and be used as biomarkers for assessing the efficacy of novel treatments.

Conclusions
In this special issue, we highlight the current landscape of biological and clinical research in neurofibromatosis. We provide several fundamental recommendations for the future of the field. First, although the last decade has led to significant advancements in our understanding of the biology of tumors in NF1, further developments are necessary and critical for improving treatment paradigms for patients. Identification of molecular alterations driving the malignant transformation of neurofibromas into MPNSTs will be critical to advance development of novel targeted therapeutics and should be done in parallel with the development of reliable preclinical models that allow for rapid translation. In addition to this, standardized core outcomes and definitions that evaluate the quality of life are needed to facilitate the assessment of clinical trials in NF1. Lastly, centers of excellence that are able to provide NF1 patients with multidisciplinary clinics to address the complex needs of these patients in a longitudinal fashion will be key to improving the management of this growing population of patients.