Index of Funded Projects

Identify gene expression programs that are deregulated in specific subsets of cNF that appear at different stages of growth or present with specific symptoms. We will also uncover the intra- and inter-tumoral single-cell heterogeneity that leads to the biological differences among these tumors. Our functional experiments will decipher the underlying mechanism of how these pathways regulate tumorigenesis and whether they can be specifically targeted in future studies to improve the QoL of individuals with NF1.

Demonstrate safety and efficacy of HIFU treatment of cutaneous neurofibromas located close to the surface of the skin in patients with the genetic condition Neurofibromatosis Type 1. The study will use a new investigational equipment that has been specially developed for dermatological therapy. Study Description >

Several international clinics provide treatments for cutaneous manifestations of neurofibromatosis type 1 (NF1), mainly for cutaneous neurofibromas (cNF). Unfortunately, no standardized practice has been established largely due to a lack of a prospective and systematic evaluation of the available treatment options and their outcomes. The variety of skin types and forms of cNF increases complexity for the clinical decision process of determining best treatment. This study evaluates and refines a suite of outcome measures to capture the treatment outcomes of current therapies offered in routine medical practice in two medical centers focused on cNFs. Australia Study > France Study >

Evaluate the tolerability and effectiveness of four FDA-approved treatments in Neurofibromatosis Type 1 Cutaneous Neurofibromas. These treatments are: a 980nm laser, a 755nm laser, radio-frequency injection, and a Kybella injection. Each patient has a treatment and a control site. Tolerability and efficacy outcomes are assessed immediately and at 12 months after treatment. Study Description >

Investigate modifier genes that are present in adults with NF1 with high versus low burden of cutaneous neurofibromas (cNFs). The overall goal is to evaluate the genetic basis of the variability in burden of cNFs in people with NF1 in order to facilitate new therapeutic development for cNFs and advancing the understanding about the heterogeneity of NF1 manifestations. Study Description >

Assess the reliability of using whole-body (WB) 3D photography to detect cNFs and describe their natural history relative to change in number and size, patient reported outcomes and germline NF1 variant across a range of children and adults with Neurofibromatosis Type 1 (NF1) over five years. Study Description >

Determine the intra-rater and inter-rater reliability of high frequency ultrasound (HFUS) and optical frequency domain imaging (OFDI) versus calipers and digital photography for the measurement of NF1 associated cutaneous neurofibromas (cNFs). Study Description >

Dose finding study based on tolerability and biologic markers of efficacy with the oral MEK inhibitor mirdametinib to treat cutaneous neurofibromas in adults with NF1.

Assessment of Alexandrite laser vs two injectable surfactants, deoxycholate and polidocanol in the treatments of cutaneous neurofibroma (cNF). The study will include ex-vivo dose optimization and optimization of treatment associated pain in adults. Ultimately, the most effective and well tolerated therapy for cNF treatment will be advanced to a clinical trial for adolescents with NF1 associated cNFs. Study Description >

Identify the checkpoints which hold pre-cNF fields from progressing into cNF, to understand how they fail, and how they can be pushed toward maintaining normal Homeostasis. The investigators will use Drosophila genetic tools to identify the NF1 functional kinome, explore local cell-cell interactions as an approach to controlling dNF1-/- cells, and identify candidate NF1 lead therapeutics by screening for compounds that reduce or reverse the impact of dNF1-/- activity. Study Description >

Explore the potential of RASL11A to serve as a new therapeutic target for inducing cutaneous neurofibroma (cNF) regression. The investigators will test the hypothesis that RasL11A is a downstream target of Nf1 by investigating RASL11A’s expression levels in human cNF tumors, its impact on proliferation and survival of human cNF cells, and its sensitivity to Nf1 expression.

Explore the potential of targeting TGFβ pathways as a treatment of cutaneous neurofibromas by determining: (1) The cellular and molecular mechanisms which underline TGFβ role in neurofibroma formation (e.g., defining the nerve microenvironments that promote/suppress neurofibroma formation, and the impact of TGFβ on the biology of Nf1-/- Schwann cells); (2) The role of TGFβ signaling in mouse models of cutaneous neurofibroma formation; and (3) The relevancy of the above to the human disease. Study Description >

Detect and monitor normally invisible tumors in people with NF1 using a high-tech camera called spatial frequency domain imaging (SFDI); (2) Image the detected tumors with optical coherence tomography (OCT) to record their three-dimensional structure and obtain biopsies for histologic analysis of SFDI/OCT detection accuracy; (3) Measure photothermal response of nascent cNF with photoacoustic spectroscopy (PAS); and (4) Utilizing the photothermal spectra to develop laser dosimetry for treatment of nascent cNF. Study Description >

Define variables and endpoints for cutaneous neurofibroma (cNF) clinical trials by: (1) Looking for correlations between cNF physical features (e.g., size, location, subtype and color), symptoms (e.g., itch and pain), and quality of life in NF1 patients; (2) Developing automated measurements from cNF photographs to reduce variability degree; and (3) Determine the natural history of cNFs to help guide endpoints for prevention studies. In addition, the investigators will develop infrastructure for patient-driven engagement programs to enable registries and rapid enrollment into clinical trials for cNF. Study Description >

Investigate whether a combination of a MEK inhibitor and a cAMP-pathway activator can reduce and/or eliminate cNF tumors in in vivo Nf1 pre-clinical models. Study Description >

Identify predictive biomarkers of drug response by: (1) Establishing a molecular baseline profile for patient NF1 associated cutaneous neurofibroma (cNF) organoid models; (2) Screening cNF organoid models for drugs that reduce tumor growth; and (3) Utilizing machine learning and network algorithms to identify specific transcripts, proteins, and phosphosites that are associated with drug sensitivities. Study Description >

Investigate the role of sensory innervation in the development of cutaneous neurofibroma (cNF) tumors by: (1) Characterizing defective innervation of cNFs; (2) Exploring the role of sensory neurons in tumor development; (3) Investigating the impact of Nf1 mutant Schwann cells and direct-contacting neurons on each other; and (4) Examining whether Calcitonin Gene Related Peptide promotes the development of cNFs. Study Description >

Investigate the impact and potential mechanism of peripheral neurons on NF1-deficient Schwann cell growth, with respect to : 1) Generating and characterizing sensory neurons from selected iPSCs, 2) Assessing if sensory neurons with or without NF1 deletion have differential effects on SC which are NF1 expressing and non-expressing, and 3) Assessing if there are differential effects of neurofibromin on SC of various NF1 backgrounds over time. Study Description >

Explore the role of heterotypic interactions between SC and fibroblasts on cNF pathogenesis. Evaluate heterotypic interactions between SC and fibroblasts in cNFs to specifically identify the gene expression profiles produced, and dissect from the expression profiles which part is expressed by SC and which part by fibroblasts. Study Description >

Investigate the effect that neurofibromin protein expression levels at specific stages of Schwann cell development have on disease pathogenesis. The team will investigate the role of NF1 at different stages of neural crest/Schwann cell development by utilizing “isogenically paired” NF1+/+, NF1+/- and NF1-/- pluripotent stem cells, and SMASh (small molecule-assisted shutoff) tag methodology, which allows the tunable and reversible control protein production/degradation (such as NF1 protein). Study Description >

Investigate the roles and effects of T-cells and mast cells as microenvironment components in promoting tumorigenesis with respect to: 1) characterization and quantification of T cells residing in cNFs, 2) evaluation of the clonality of T cells, 3) characterization and quantification of cNF mast cells by measuring relative abundancies of mast cell types, 4) studies on expression of NGF and receptors for progesterone and estrogen in cNF mast cells, and 5) evaluation of T-cell-Schwann cell interactions and mast cell-Schwann cell interactions by mass spectrometry. Study Description >

Utilize a genetically engineered mouse model of cNF based on Hoxb7-Cre; Nf1flox/flox to: 1) Identify the cNF cell of origin (from human iPSC) with focus on establishing the presence and location of HoxB7 in human cells and its characterization as a cell of origin marker, and 2) Conduct mouse xenograft studies involving murine derived SKPs with respect to the transplant of in vitro skin reconstructs into hormone-primed nude mice in vivo. Study Description >

Utilize a newly developed genetically engineered mouse model of cNF based on Prss56Cre, NF1fl/-, R26tdTom to: 1) evaluate stromal changes in the progression from micro cNFs to cNFs, 2) identify the derivatives of neural-crest-derived basal cap cells that give rise to cNFs, and 3) test the efficacy of a MEK inhibitor (Selumetinib) in inhibiting or preventing formation of cNFs in the mouse model. Study Description >

Deconstruct human cNFs using single cell transcriptomics (via scRNA-Seq) to define cell populations involved in the tumor, and then develop pathomimetic avatars (based on those sub-populations) from which 3D co-culture models of the tumors will be developed for preclinical screening. Study Description >

Develop and validate the self-report Disfigurement Rating Scale to assess change in tumor-related disfigurement in pNF and cNF clinical trials. The secondary objective is to develop and validate a measure of appearance concerns for pNF and cNF trials.

Validate newly-identified Schwann cell growth factors, demonstrating that they are both sufficient and necessary for hiPSC-sensory neuron-driven paracrine regulation of NF1-deficient SC growth, and identify molecular targets to block sensory neuron production of these growth factors and/or their ability to induce NF1-deficient SC growth relevant to human neurofibroma pathobiology. Study Description >

The goals are 1) Test four HSP90 inhibitors in five PN cell lines and related Schwann cell lines; 2) Evaluate four HSP90 inhibitors in sorted mouse stem-like tumor-initiating cells with three mutation configurations and the corresponding wild type control cells; 3) Study mechanisms of HSP90 inhibitors in stem-like cells in PN cells and mouse PN-initiating cells; 4) Evaluate the combinations between Selumetinib and HSP90 inhibitors in human PN cell lines and mouse cells; 5) Evaluate the in vivo response of combination of Selumetinib and HSP90 inhibitor. Study Description >

Imaging identification of lesions that may be pre-malignant in people with NF1 and clinical features that are associated with an increased risk of developing MPNST. Characterization of DNLs with functional MRI and FDG-PET to enable early diagnosis and management of lesions destined to become malignant, Study Description >

The goals of this project are i) assess the feasibility of collecting, transferring and storing tissue samples collected as part of two DoD NFCTC clinical trials, ii) establish governance policies for the maintenance, expansion, testing and sharing of these samples, and iii) ensure all regulatory requirements for human tissue and data are maintained throughout all processes. Study Description >

Mitogen activated kinase kinase inhibitors (MEK) have shown promising efficacy in the treatment of patients with plexiform neurofibroma (PN), however a subset of patients have minimal response to therapy. This study evaluates clinically impactful associations between phenotype, genotype, and PN response to therapy. Study Description >

Investigate the efficacy of the MEK1/2 inhibitor CIP‐137401 (Allomek) in reducing existing tumor burden, as a single agent in a NF1‐associated pNF mouse model (Nf1flox/flox;Postn‐Cre mice). Study Description >

Evaluate the therapeutic efficacy of an Erk1/2 inhibitor, a CDK4/6 inhibitor, and a PI3K inhibitor, against existing plexiform neurofibromas utilizing our novel plexiform neurofibroma GEM model. Study Description >

Investigate how often people with neurofibromatosis type 1 take oral medicine that has been prescribed to them for treating plexiform neurofibromas and the factors that influence medication adherence. Study Description >

Evaluate the therapeutic efficacy of various AAV serotypes, a TGF- β inhibitor, a VEGF inhibitor and a VEGFR inhibitor against established plexiform neurofibromas utilizing a novel genetically engineered Nf1 mouse model.   Study Description >

Identify putative proteomic and/or phosphoproteomic signatures associated with loss of NF1 using two complementary MS-based approaches to define (i) the proteome and phosphoproteome and (ii) the activated kinome signature of NF1-deficient Schwann cells (SCs) in conjunction with transcriptome profiling of cell lines providing a detailed view of the cellular signaling networks and the molecular targets controlled by neurofibromin in a cell-type relevant to the disease. Study Description >

Investigating the possibility that hyperactive Ras/ERK signaling contributes to pro-neoplastic metabolic rearrangements in mitochondria of neurofibroma cells by regulating TRAP1 chaperone activity, thus crucially contributing to the processes of growth and malignant transformation of PNs. Colombo and Rasola will dissect the mode of action of TRAP1, connecting it with the metabolic status of PNs and MPNSTs, which will investigated in in vivo tumor models. Study Description >

Determine if BRD4 inhibitors can prevent or delay the onset of tumors in a mouse model for MPNST development in NF1 microdeletion patients (NPS mice) and if the treatment with BRD4 inhibitors prevents the recruitment of immune cells to tumor initiation sites. Study Description >

Evaluate whether patients receiving an Acceptance and Commitment Training (ACT) intervention demonstrate improved outcomes on a measure of pain interference (Pain Interference Index) when compared to a wait-list comparison group in adolescents and young adults with NF1 and PNs who experience chronic pain that interferes with daily functioning. Study Description >

Assess if Stat3 inhibition using a Stat3 Antisense RNA will prevent plexiform neurofibroma (pNF) tumor formation. The  inhibitor, AZD 9150 / ISIS 481464 has shown efficacy in multiple myeloma and is in Phase1/1b trials in other cancers. This project will identify methods to prevent pNF formation. Study Description >

Identify molecular pathways that mediate rapid neurofibroma growth and/or response to therapy, using gene expression analysis of mouse neurofibromas followed by validation. Study Description >

This research collaborative via a Children’s Tumor Foundation and NTAP partnership supported multiple pre-clinical therapeutic studies in plexiform neurofibroma (pNF) genetically engineered mouse models enabling pre-clinical assessment of agents such as BRD4i + MEKi; EZH2 inhibitors for pNFs.

Identify molecular signatures of Schwann cells and non-Schwann cells (macrophages, fibroblasts, mast cells and endothelial cells) to define the neurofibroma interactome and potential therapeutic targets for plexiform neurofibroma preclinical and clinical trials. Study Description >

Evaluate if the Schwann cell enzyme Glutamate Carboxypeptidase II (GCPII) is a potential diagnostic marker to distinguish between malignant and benign peripheral nerve sheath tumors in patients with NF1 and the potential therapeutic effect of inhibiting GCPII enzymatic activity on the growth of plexiform neurofibromas in animal models. Study Description >

Develop and test the feasibility, reliability and validity of the child self-report and parent proxy-report versions of the Pediatric Quality of Life InventoryTM (PedsQL-TM) NF1 module for pediatric patients ages 5-25 with NF1 from the perspectives of patients and parents. Study Description >

Enrollment and treatment of children ≥2 years old on the open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with NF1 associated plexiform neurofibromas and to assess clinical benefit.

Preclinical Drug Screening using the MIPE library for single and combination therapies. As a result of a collaboration between University of Florida, NTAP, and NCATS, a panel of cell culture systems that represented pNF complexity was used to screen new compounds (as single and combination agents) and identify novel therapeutic targets to be advances to in vivo studies. Study Description >

Evaluate the safety and efficacy of drug combinations identified in cellular screens in Nf1+/- genetically engineered mouse models. Initial combinations assessed included rapamycin – ganetespib and selumetinib – panobinostat. Study Description >

Develop and validate the self-report Disfigurement Rating Scale to assess change in tumor-related disfigurement for people with NF1 associated pNF and cNF clinical trials. The secondary objective is to develop and validate a measure of appearance concerns for pNF and cNF trials.

Identification of an imaging biomarker to locate and treat early stage cNFs enabling prevention studies with the ultimate goal of improving the quality of life of people with NF1 and cNFs. Study Description >

Assess how NF1 genotypes affect the function of neurofibromin and its interactions with other proteins. We will test the hypothesis that neurofibromin differentially interacts with binding partners in a cell type-specific manner and that mutations differentially disrupt those interactions. Study Description >

Explore the concept of “adaptive resistance” and describe the adaptation of the signaling network to inhibition of RAS effector pathways in NF1-associated cancer. Study Description >

Test the hypothesis that both rare and common germline variants in Ras pathway genes contribute to OPG risk. To achieve this, a population-based case-control study, nested within the California Birth Cohort, has been developed. Study Description >

Evaluate the effect of ERK dependence on cellular pathways important for DNA damage repair in gliomas with NF1 loss. Study Description >

Assess the therapeutic benefit of blocking IL-6 signaling in MPNSTs using a combination of pharmacological, genetic, and mouse model approaches. This project will implement in vivo CRISPR/Cas9 tools to determine the impact of autocrine IL-6 blockade on MPNST growth (Aim 1) and the effects of paracrine IL-6 loss on MPNST growth and infiltration of immunosuppressive cells (Aim 2). Study Description >

Immunologically phenotype MPNSTs during C. novyi-NT treatment to identify upregulated immune checkpoint targets and develop a rationale for the combinatorial use of checkpoint blockade with C. novyi-NT. Study Description >

Dr. Chelsea Kotch is a pediatric neuro-oncologist at the Center for Childhood Cancer Research at Children’s Hospital of Philadelphia with a research focus in epidemiology and risk stratification for patients with neurofibromatosis-associated tumors. As a Francis Collins Scholar, Dr. Kotch’s is evaluating the comparative effectiveness of existing treatment approaches for plexiform neurofibromas utilizing advanced epidemiologic analyses and novel clinical trial emulation methods.

Dr. R. Taylor Sundby is a pediatric oncologist in the National Cancer Institute (NCI), Pediatric Oncology Branch (POB). His research focus in developing and applying cell-free DNA techniques to identify and manage pre-malignant and malignant manifestations of tumor predisposition conditions such as NF1. Current efforts focus on the development of circulating biomarkers for non-invasive surveillance and the study of tumor evolution from plexiform neurofibroma to MPNST to enable early intervention and cancer prevention for people with NF1. Study Description >

Dr. Laura Fertitta is an oncologic dermatologist at Henri-Mondor Hospital – University Paris Est Créteil (UPEC), housing the French Referral Center for Neurofibromatosis (CERENEF) of which she is deputy director to director Prof. Pierre Wolkenstein. Her clinical practice and research project are focused on cutaneous neurofibromas (cNF). The team at UPEC recently developed a genetically engineered NF1 mouse model which faithfully recapitulates numerous aspects of the human condition. Using this model and other state-of-the art technologies, Dr Fertitta is working on the identification of candidate drugs capable of treating cNF and/or preventing their development and appropriate endpoints for choosing agents to translate from preclinical to clinical studies. Study Description >

Dr. Harish Vasudevan is a radiation oncologist at the University of California San Francisco (UCSF) where his postdoctoral work elucidated genomic mechanisms underlying tumor heterogeneity and oncogenic signaling in NF1. As a Francis Collins Scholar, Dr. Vasudevan focuses on understanding the transformation of neurofibroma to malignant peripheral nerve sheath tumor (MPNST) with an emphasis on identifying and testing novel treatments for patients with NF1. In addition, through his clinical practice as a radiation oncologist, Dr. Vasudevan plays an active role in the multidisciplinary care of tumors arising in patients with NF1 and translates discoveries made at the laboratory to the clinic. Study Description >

Dr. Suganth Suppiah is a neurosurgeon with special expertise in peripheral nerve surgery at the University of Toronto. During his graduate training, he characterized the molecular landscape of peripheral nerve sheath tumors associated with NF1, including neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs) using state-of-the-art technologies. Integrating these valuable datasets, Dr. Suppiah is working to identify the molecular pathways that drive malignant transformation in the context of NF1 and identify therapeutics to treat these tumors. Through his research and his clinical exposure to the Elisabeth Raab Neurofibromatosis Clinic in Toronto, he developed a commitment to NF1. As a peripheral nerve surgeon, he plans to specialize in surgical management of these tumors and improve the quality-of-life of NF1 patients. Study Description >

Dr. Nicole Brossier is a pediatric neuro-oncologist at Washington University in St. Louis (WUSL). She specializes in the clinical care of children with NF1-related brain tumors. During her postdoctoral work in the lab of Dr. David Gutmann, she built a platform to assess how different factors impact brain tumor penetrance in children with NF1. Her laboratory now focuses on how different factors (including environmental, developmental and genetic) impact neural stem cells to modulate pediatric brain tumor development. As an FCS scholar, Dr. Brossier studies whether germline NF1 gene variants and maternal diet are risk factors for NF1-glioma formation. Study Description >

Dr. Tamar Green is a physician-scientist and a child psychiatrist at Stanford University. She provides clinical care to children with behavior and cognitive manifestations related to RASopathies. Her lab takes a “genetic first” approach, which is the study of children with known genetic conditions who present with attention deficits, hyperactivity, and deficits in social cognition. Her lab’s focus is on the RASopathies, a collection of syndromes associated with genetic mutations affecting the Ras/MAPK pathway. As an FCS scholar, Dr. Green is focusing on the study of brain development and organization in children with NF1. The ultimate goal to understand how brain imaging in NF1 can serve as sensitive indicators of a treatment’s effects on cognitive and behavioral functions related to ADHD, autism spectrum disorders, and learning disabilities in NF1. Study Description >

Dr. Steven Rhodes is a pediatric oncologist at Indiana University School of Medicine/Riley Hospital for Children. He is performed his post-doctoral research in the laboratory of Dr. Wade Clapp. During his training, he developed new mouse models that accurately mimic the progression of cutaneous and atypical neurofibroma precursor tumors to the deadly sarcoma malignant peripheral nerve sheath tumor (MPNST). Using these models and other state-of-the art technologies, Dr. Rhodes is working to identify potential new therapies that can not only treat MPNST, but ultimately prevent the development of these devastating tumors in individuals who are at risk. He devotes his clinical practice to caring for children with NF1-associated neurofibromas, MPNST, and other related tumors. Study Description >

Dr. Ina Ly is an adult neuro-oncologist at Massachusetts General Hospital. Her current research involves the use of advanced magnetic resonance imaging techniques, such as diffusion, perfusion and spectroscopy imaging, to study the biology of nervous system tumors. Through her clinical exposure to NF1 patients, she developed a strong interest in peripheral nerve sheath tumors (PNST), which can become malignant and contribute to significant patient morbidity and mortality. Her FCS project leverages her knowledge of advanced MRI to identify imaging features that predict tumor growth and malignant transformation in PNSTs. Study Description >

Dr. Shruti Garg is a child and adolescent psychiatrist at the University of Manchester. She divides her time researching and seeing patients with NF1 and cognitive and behavioral manifestations at the Royal Manchester Children’s Hospital. With her FCS award, Dr. Garg is studying working memory in children with NF1 using imaging to monitor levels of the brain chemical GABA, which is related to working memory. She already has preliminary data suggesting that GABA levels improve with transcranial direct stimulation to the frontal area of the brain. Study Description >

Dr Angela Hirbe is an oncologist and sarcoma specialist at Washington University St. Louis. Her post-doctoral work in the laboratory of Dr. David Gutmann focused on the use of next-generation sequencing technologies to identify b-III spectrin as a protein involved in malignant peripheral nerve sheath tumor (MPNST) pathogenesis and developed a mouse model for this deadly type of sarcoma. Clinically, Dr Hirbe treats patients with sarcoma and has a strong clinical interest is in the care of patients with NF1-MPNST. Her laboratory continues to use genomics to identify drivers in MPNST pathogenesis and further develop mouse models for preclinical studies and therapeutic drug testing. Study Description >

Dr. Ping Chi is an oncologist and sarcoma specialist at Memorial Sloan Kettering Cancer Center in New York City. Her postdoctoral work focused on epigenetics and chromatin biology in the C. David Allis’ lab at the Rockefeller University. Dr. Chi’s current laboratory research focuses on understanding the genetic and epigenetic mechanisms of transcriptional activation of novel oncogenic transcripts and oncogenic transcription factors in solid tumor malignancies. Through mechanistic studies, she aims to identify novel therapeutic strategies to target oncogenic transcription factors and aberrant transcriptional activation of oncogenes. Dr. Chi also maintains an active academic clinical practice, leads early phase clinical trials, and works with a multidisciplinary team to care for patients with sarcomas, with the goal to expedite clinical translation of laboratory research. Study Description >

Ashley Cannon, PhD, MS, CGC is a neuroscientist and certified genetic counselor. Her previous research experience at Mayo Clinic Florida encompassed molecular genetics, neuropathology, and mouse modeling of neurodegenerative diseases. This research exposed her to the significance of genetic counseling for individuals and families affected by genetic conditions and motivated her to become trained as a genetic counselor. She received an MS in Genetic Counseling at UAB in 2015. Her research focused is the longitudinal quantification, treatment, and psychosocial impact of cutaneous neurofibromas in individuals with NF1. Study Description >

Dr. Verena Staedtke is a pediatric neuro-oncologist and expert in cellular biology and therapeutics. Dr. Staedtke’ s work spearheaded the use of the therapeutic “anti-cancer” agent Clostridium novyi-NT (C. novyi-NT), a genetically modified anaerobic bacterium, for the use in nervous system cancers, particularly glioblastomas and malignant peripheral​ nerve sheath tumors, the most common malignancy in NF1 patients. In addition, she has developed novel approaches to enable use of immunotherapies and chemoprevention in NF1. Clinically, she is director of the pediatric branch of the Comprehensive Neurofibromatosis Center at Johns Hopkins where she provides care for children with NF. Study Description >

Dr. Miriam Bornhorst is a pediatric neuro-oncologist in Oncology and Cancer Genetics at Children’s National Health System in Washington, DC where she is the director of the NF clinical center and provides care to children with NF. Her primary research focus is the use of preventative therapy for optic pathway gliomas. Her FCS work is focused on early detection and management of tumors such as NF1 associated optic pathway gliomas. Study Description >

Dr. Peter de Blank is a pediatric neuro-oncologist at Cincinnati Children’s Hospital Medical Center where he leads efforts on cancer imaging in the Cancer & Blood Diseases Institute. His research focuses on the application of advanced MR techniques in children with NF1 and brain tumors. He is interested in the characterization of novel MR sequences to investigate brain tumors, and the development of early radiographic biomarkers of functional complications of brain tumors and brain tumor therapy. Study Description >

Dr. Matthew Steensma orthopedic oncology surgeon and scientist focused on the molecular and cellular mechanisms underlying the development of bone and soft-tissue sarcomas. As a FCS, he focused on evaluating the similarities and differences in the genomic profiles of cNFs and MPNSTs from people with NF1. He further investigated the molecular signatures of cNFs based on the stage of CNF development (incipient versus established lesions) to address gaps in knowledge in cNF pathophysiology. Study Description >

Create a path for in vivo NF1 gene replacement to prevent or stall progression of cutaneous neurofibromas (cNFs). This initiative includes in vitro and in vivo proof-of-principle studies, novel AAV vector development, HSV1 vector development and in vivo efficacy and safety studies. Study Description >

Leverage two unique cNF preclinical models to determine whether application of AAV will effectively deliver NF1 via various forms of delivery, target cNF cells of origin and impact cNF development and progression preclinically. These studies will help determine whether gene therapy might be a superior treatment option for cNF. Study Description >

The NF1 biorepository repository collects, processes and manages NF1 tumor associated tissue, cells, specimens and data donated by people with NF1 who are undergoing surgical removal of tumors. Tumors are genomically characterized and annotated. Infrastructure supports the compliant sharing of multiple forms of NF1 tumor samples and data with the research community. This project improves access to critical NF1 tumor tissue as a core tool to support discovery of new therapeutics for NF1 patients. Study Description >

Identify and develop a mAb with increased sensitivity and specificity for the protein neurofibromin as determined by western blot, and demonstrate expanded utility with function in ELISAs, sandwich ELISAs and immunohistochemistry (IHC) applications. Study Description >

Establish the utility of a non-germline plexiform neurofibroma (pNF) model as a rapid preclinical therapeutic drug screening tool to identify effective therapies for pNF. To achieve this goal, investigators will first explore the possibility of long term storage of DNSCs to maintain their tumorigenic potential for reliable and rapid plexiform neurofibromagenesis and develop it into a robust plexiform neurofibroma model for preclinical drug screening. Study Description >

Determine the role of the Extracellular Matrix (ECM) in the neoplastic transformation of Schwann cells (SCs). The in vitro systems investigated will enable discovery of the ECM influence on Schwann cell progression toward malignancy in plexiform neurofibromas and its importance in/for drug screening. Study Description >

Sage Bionetworks creates and maintains the NF Data Portal on Synapse to organize and make accessible the data content generated from NTAP funded projects; provide the codebase and computational infrastructure for the data; provide standardized processing of genomic and transcriptomic data, and conduct NTAP-reviewed NF1-related computational biology research projects.

Create and characterize induced pluripotent stem cells (iPSCs) from human NF1 tumors to investigate the influence of the NF1 gene status on cell behavior. Explore the degree of genomic, molecular and cellular variation within regions taken from individual pNFs in order to better understand the variability within these tumors. Interrogate the expression profile of cell cultures in isolation and in co-culture conditions in order to authenticate and characterize NF1+/- and NF1-/- iPSCs to allow exploration of the functional status of the NF1 gene on biologic properties of the cells. Study Description >

Develop co-culture conditions for patient-derived tumor-associated NF1 null and heterozygous cells including Schwann cells, fibroblasts endothelial cells and macrophages. Optimize 3D co-culture conditions for pNF inclusive of the cell type found in cNF for use as confirmatory/secondary drug screens. Study Description >

Create in vitro conditions to efficiently differentiate iPS cells into cells of the Neural Crest-Schwann cell lineage and characterize the methylome and transcriptome of these cells with distinct NF1 genotypes and test their potential engraftment/tumor formation capacity. Generate new iPSC and edit control iPSC with distinct NF1 genotypes to interrogate the presence of epigenetic memory in the PNF-derived iPS cells generated. Study Description >

Generate the reliable, valid, and feasible measures to assess pain intensity and pain interference in people with NF1 and plexiform neurofibroma to be used as validated end-points in clinical therapeutic trials. Study Description >

Develop a patient-based measure that determines the impact of plexiforms on needs in adults with NF1 that can be used to establish that interventions to NF1-associated pNFs improve/benefit a patient’s QoL in addition to clinical status. Study Description >

Develop a PRO measurement system utilizing input from patients, families and clinicians, as well as well as psychometric analysis methods to ensure the developed measures are reliable and valid. Specifically this project designed a PRO system for children and young adults with pNF by (1) establishing a conceptual model describing HRQOL, 2) Developing item pools (e.g., pain, stigma, and organ dysfunction measures), 3) Evaluating psychometric properties of the pools, 4) affirming clinical differences. Study Description >

Develop and characterize a miniaturized 3D preclinical model (i.e. a ring organoid) for human cNF and then to validate the organoids by determining whether histopathology, transcriptional profile and pathway alterations of the 3D cNF organoids reflect the basic physiology of the tumor. Study Description >

Creation of semi-immortalized Schwann cells with various NF1 backgrounds (NF +/- vs. NF -/-) derived from heterogenous human cNFs and evaluate intact cNFs (from primary samples) to ascertain an RNA signature from the SC in the setting of an intact microenvironment, with comparison back to the isolated primary and semi-immortalized SC. Study Description >

Explored the development of culture systems composed of various extracellular matrix (ECM) components using MAPTRix in a 96-well format to identify the preferred substrate for NF1 null Schwann cells and evaluate a rig of microcylinders for Schwann cell attachment to mimic radial growth of cNFs around axons to assess growth characteristics of the MAPTrix ECM in 2D, 3D and the guitar rig. Study Description >

Generated (semi)-immortalized NF1 null and heterozygous Schwann cell culture models derived from human plexiform neurofibroma tissue. Fully characterized these cell lines and generated additional lines to represent the diversity of pNF and to include control Schwann cell cultures with genomic analyses conducted by Sage Bionetworks and cell lines made available via ATCC to the research community. Study Description >

Applied the techniques optimized for cell-based high-throughput screens (HTS) from pooled tumor-derived cells for GBM to the development of primary cell culture models of cNF from the mouse models of mCNF generated in their lab. Optimized the growth conditions for these cells. Study Description >