Children's Tumor Foundation

Synodos for NF2 is a collaborative research initiative aimed at accelerating the development of treatments for NF2-related schwannomatosis, a complex and rare genetic disorder. Leveraging resources like the National Center for Advancing Translational Sciences drug screening platform with the MIPE oncology collection, the team identified Brigatinib, an unexpected hit, as a potential therapeutic agent. Through subsequent proteomics analysis, Focal Adhesion Kinase was identified as the primary target of Brigatinib, revealing a novel mechanism of action for the drug in NF2-related schwannomatosis. This discovery led to the development of the Innovative Trial for Understanding the Impact of Targeted Therapies in NF2-Related Schwannomatosis platform-basket trial, which rapidly translated these findings into a clinical trial framework. Preliminary results from this trial have shown promising efficacy, marking a significant step forward in NF2-related schwannomatosis treatment. The collaborative efforts of Synodos and the innovative platform trial approach are paving the way for more efficient drug discovery and development in NF2-related schwannomatosis, offering new hope for patients with this challenging disorder.

Abstract BackgroundNeurofibromatosis 1 (NF1) is a rare, neurogenetic disorder predisposing individuals to central and peripheral nervous system tumors, as well as a wide range of other physical, neurocognitive, and psychosocial issues. Regular health monitoring throughout the lifespan is needed to identify these heterogenous disease complications, but the degree to which this is implemented in routine clinical practice is unknown. This, this study aimed to investigate U.S. patients’ access to specialized NF1 clinics and receipt of evidence-informed health surveillance.MethodsAn online cross-sectional survey was distributed in May 2021 to adults with NF1 and parents of children with NF1 enrolled in the NF Registry (n=6908). Rate of NF1 clinic attendance and self-reported receipt of health surveillance amongst all NF Registry participants was estimated using inverse propensity scores. Differences in these outcomes based on participant demographics were assessed using weighted logistic regression and robust linear regression, respectively.Results322 individuals responded (160 adults, 162 parents; 4.7% overall response rate). We estimate that 51.7% of children and 35.6% of adults attend NF1 clinics. Younger children were more likely to attend an NF1 clinic, as were adults living in urban areas, with a college degree or higher, or with a household income ≥$130,000 (all ps<0.05). Completion rates for each individual health surveillance evaluation ranged from 41%-79% for children and 33%-61% for adults. Higher rates of recommended evaluations were reported by both adults and children who attend a specialized NF1 clinic, non-Hispanic White adults, and adults with commercial or Medicare insurance (all ps<0.05).DiscussionAdults with NF1 experience significant sociodemographic disparities in care, and patients of all ages attending NF1 specialty clinics receive more recommended health surveillance. Given the limited access to specialty NF clinics, quality improvement efforts are needed to increase access for underserved adults and improve provision of recommended health surveillance outside specialty clinics.

PurposeBy incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). MethodsWe used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. ResultsWe reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. ConclusionThe revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS. [Display omitted]

Neurofibromatosis type 1 (NF1) is a rare genetic disorder, characterized by the development of benign and malignant nerve tumors. Although all individuals with NF1 harbor genetic alterations in the same gene, the clinical manifestations of NF1 are extremely heterogeneous even among individuals who carry identical genetic defects. In order to deepen the understanding of phenotypic manifestations in NF1, we comprehensively characterized the prevalence of 18 phenotypic traits in 2051 adults with NF1 from the Children’s Tumor Foundation’s NF1 registry. We further investigated the coassociation of traits and found positive correlations between spinal neurofibromas and pain, spinal neurofibromas and scoliosis, spinal neurofibromas and optic gliomas, and optic gliomas and sphenoid wing dysplasia. Furthermore, with increasing numbers of cutaneous neurofibromas, the odds ratio of malignant peripheral nerve sheath tumor increased. Phenotypic clustering revealed 6 phenotypic patient cluster subtypes: mild, freckling predominant, neurofibroma predominant, skeletal predominant, late-onset neural severe, and early-onset neural severe, highlighting potential phenotypic subtypes within NF1. Together, our results support potential shared molecular pathogenesis for certain clinical manifestations and illustrate the utility of disease registries for understanding rare diseases.

Abstract The time from identifying a drug target to a new drug approval is often measured in decades and can take even longer for therapies to treat rare diseases. In fact, 95% of rare diseases do not have a specific therapy approved at all. Coordinated efforts to augment the drug development pipeline along with long-term and comprehensive support that enable scientific breakthroughs for rare diseases is possible, but it requires integration across multiple stakeholders. With the recently announced granted acceptance from the FDA to file status of the AstraZeneca and MSD (Merck) application for the MEK inhibitor selumetinib to treat plexiform neurofibromas in children, a major milestone towards the first-ever approved treatment for people with Neurofibromatosis Type 1 (NF1) associated tumors is closer than ever. This study analyzes the coordinated funding efforts of four federal and philanthropic organizations to advance drug development for NF1 associated tumors and discusses how these organizations collaborated and evolved practices to optimize funding and research support. This model could be replicated for other rare diseases if funders are able to take an active, coordinated approach to identify gaps, tools, and infrastructures most needed for that specific disease area. Citation Format: Salvatore La Rosa, Annette C. Bakker, Vidya Browder, Jaishri O. Blakeley, Sharad K. Verma, Ling M. Wong, Jill Morris, Naba Bora. Delivering on the Vision of Bench to Bedside: A Rare Disease Funding Community Collaboration to Develop Effective Therapies for Neurofibromatosis Type 1 Tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2057.

The main objective of this study was to determine if family history of malignant peripheral nerve sheath tumor (MPNST) increases risk of developing an MPNST in patients with neurofibromatosis-1 (NF-1). Individuals with NF-1 registered with the Children's Tumor Foundation's Neurofibromatosis Registry were emailed an anonymous 15-minute survey with regard to personal and family history of NF-1, MPNST, ages of onset, and symptomatology. Participation was voluntary and information was self-reported. The survey was sent to 4801 registrants, 878 responded. Presence of a family history of MPNST was found to be a risk factor for the development of MPNST; 19.4% of respondents confirming a family history of MPNST developed MPNST compared with 7.5% of respondents with no family history (odds ratio, 2.975; 95% confidence interval, 1.232-7.187; P=0.021). NF-1 patients with a positive family history developed MPNST at a younger age than those with no family history (8.3% vs. 0.5% P=0.003 and 13.9% vs. 2.4% P=0.003, for onset before 10 and 20, respectively). In the MPNST population with a known family history, onset prior to age 10 was significantly more prevalent (42.9% vs. 7% P=0.029). These results suggest a positive family history of MPNST represents a risk factor for the development and early onset of MPNST in individuals with NF-1.

Cutaneous neurofibromas (cNF) are a nearly ubiquitous symptom of neurofibromatosis type 1 (NF1), a disorder with a broad phenotypic spectrum caused by germline mutation of the neurofibromatosis type 1 tumour suppressor gene (NF1). Symptoms of NF1 can include learning disabilities, bone abnormalities and predisposition to tumours such as cNFs, plexiform neurofibromas, malignant peripheral nerve sheath tumours and optic nerve tumours. There are no therapies currently approved for cNFs aside from elective surgery, and the molecular aetiology of cNF remains relatively uncharacterised. Furthermore, whereas the biallelic inactivation of NF1 in neoplastic Schwann cells is critical for cNF formation, it is still unclear which additional genetic, transcriptional, epigenetic, microenvironmental or endocrine changes are important. Significant inroads have been made into cNF understanding, including NF1 genotype–phenotype correlations in NF1 microdeletion patients, the identification of recurring somatic mutations, studies of cNF-invading mast cells and macrophages, and clinical trials of putative therapeutic targets such as mTOR, MEK and c-KIT. Despite these advances, several gaps remain in our knowledge of the associated pathogenesis, which is further hampered by a lack of translationally relevant animal models. Some of these questions may be addressed in part by the adoption of genomic analysis techniques. Understanding the aetiology of cNF at the genomic level may assist in the development of new therapies for cNF, and may also contribute to a greater understanding of NF1/RAS signalling in cancers beyond those associated with NF1. Here, we summarise the present understanding of cNF biology, including the pathogenesis, mutational landscape, contribution of the tumour microenvironment and endocrine signalling, and the historical and current state of clinical trials for cNF. We also highlight open access data resources and potential avenues for future research that leverage recently developed genomics-based methods in cancer research.

Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.