Index of Funded Projects

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 cNF adds an additional complexity to the clinical decision process of determining best treatment. Data on this is lacking in the literature and there is a lack of commonly agreed core outcomes set and measure instruments for NF1, a main limitation for comparing results between different treatment modalities and different centres. To address this gap, we propose a strategy to evaluate and refine a suite of outcome measures to capture the treatment outcomes of current therapies offered by our hospital. Narritive >

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 cNF adds an additional complexity to the clinical decision process of determining best treatment. Data on this is lacking in the literature and there is a lack of commonly agreed core outcomes set and measure instruments for NF1, a main limitation for comparing results between different treatment modalities and different centres. To address this gap, we propose a strategy to evaluate and refine a suite of outcome measures to capture the treatment outcomes of current therapies offered by our hospital.

We hypothesize that NF1 patients with aNF/ANNUBP represent a subset of individuals who have not developed cancer yet but who are at high risk of developing a malignancy, possibly in the short term. We further hypothesize that a subset of DNLs are imaging correlates of aNF/ANNUBP that can be characterized with advanced imaging techniques such as DWI and F18-FDG PET/CT. Imaging identification of ANNUBPs and characterization of DNLs will enable early diagnosis and management of lesions destined to become malignant, thereby potentially dramatically improving outcomes for People with NF1 at highest risk for development of MPNST. Narritive >

This study will 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 will have a treatment and a control site. Narritive >

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

This proposal seeks to investigate modifier genes that are present in adults with NF1 with high versus low burden of cutaneous neurofibromas (cNF). Our overall goal is to evaluate the genetic basis of the variability in burden of cNF in people with NF1 in order to facilitate new therapeutic development for cNF and advancing the understanding about the variability of NF1. Narritive >

For this initiative, we have designed experiments that focus on validating the 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 identifying 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. Narritive >

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. Prior attempts at defining phenotypic features predictive of tumor response to MEK inhibition have been limited due to sample size. In addition, it is currently unknown if germline NF1 variant is predictive of tumor response to MEK inhibition. This study aims to evaluate clinically impactful associations between phenotype, genotype, and PN response to therapy. Narritive >

The objective of this study is to 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. Narritive >

Project goals include identifying a mAb with increased sensitivity and specificity against neurofibromin as determined by western blot, and demonstrate expanded utility with function in ELISAs, sandwich ELISAs and immunohistochemistry (IHC) applications.  Narritive >

The goal is to 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).

The goal is to 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.

Objective: To study how often people with neurofibromatosis type 1 take medicine that has been prescribed to them for treating plexiform neurofibromas. Eligibility: People ages 18–59 already enrolled in an NF1 clinical trial. Design: Participants will need access to the internet to do the study activities. Participants will complete baseline questionnaires assessing demographic data, recent life events, how much pain interferes with daily life, ability to focus and pay attention to tasks, and emotional distress or depression. Through 18 months, participants will mark down every time they take a dose of the medicine in their clinical trial on a provided daily diary. The pill bottles they get in their trial will have a chip in the cap that will record when it is opened. Their returned pills will also be counted at clinical trial visits. Participants will also answer a series of questions about adherence in qualitive interviews with a study team member and fill out a measure assessing barriers to adherence upon study completion. Expected accrual is 12-15 participants. Narritive >

The objective of this pilot study is to establish the reliability and accuracy of measurement of cutaneous neurofibromas (cNF) made using high frequency ultrasound (HFUS) and optical frequency domain imaging (OFDI).  The primary aim is to determine the intra-rater and inter-rater reliability of HFUS measurements of cNF volume at baseline.  Secondary aims are to:  1. Determine the intra-rater and inter-rater reliability of HFUS measurements of cNF volume growth over one year;  2. Determine the intra-rater and inter-rater reliability of OFDI measurements of cNF volume at baseline and over one year; 3. Determine the accuracy of HFUS and OFDI measurements by comparing them to caliper measurement and digital photographs.  Narritive >

The goal of this project is to evaluate the therapeutic efficacy of various AAV serotypes, a TGF- β inhibitor, a VEGF inhibitor and a VEGFR inhibitor against existing plexiform neurofibromas utilizing a novel genetically engineered mouse model of plexiform neurofibroma.  The studies being conducted are highly significant from both scientific and clinical standpoints because they will mechanistically dissect novel therapeutic targets for personalized treatment of NF1-deficient tumors such as plexiform neurofibromas. Narritive >

Dr. Le proposes to establish the utility of this non-germline plexiform neurofibroma (pNF) model as a rapid preclinical therapeutic drug screening tool to identify effective therapies for pNF.  To achieve this goal, Le and his team will first explore the possibility of long term storage of DNSCs to maintain their tumorigenic potential for reliable and rapid plexiform neurofibromagenesis. Next, they will develop it into a robust plexiform neurofibroma model for preclinical drug screening by testing therapeutic effects of different pharmacological interventions. Narritive >

Dr. Walker aims to identify putative proteomic and/or phosphoproteomic signatures associated with loss of NF1. Recent advances in mass-spectrometry (MS)-based proteomics permit the determination of the extent, localization, and site-specific stoichiometry of protein phosphorylation. We propose 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). Walker’s team will perform analyses on a panel of SC lines derived from PNs. Transcriptome profiling of cell lines will complement these data sets, together providing a detailed view of the cellular signaling networks and the molecular targets controlled by neurofibromin in a cell-type relevant to the disease. Finally, Walker’s team  will use small molecule inhibitors to both known and any novel signaling pathways we identify to examine the adaptive kinome in treated cell lines. Combining the use of a novel panel of cell lines with the sensitivity of high-end MS, they expect to identify signaling pathways and targets previously implicated as being important in NF1-associated tumors, as well as new and unexpected targets downstream of NF1. Narritive >

This project’s primary goal is to 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. Narritive >

This project aims at investigating the possibility that hyperactive Ras/ERK signalling could contribute 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 be thoroughly investigated in _in vivo_ tumor models. Narritive >

The primary goals of this project are (1) to set up in vitro conditions to efficiently differentiate iPS cells into cells of the Neural Crest-Schwann cell lineage, (2) to characterize the methylome and transcriptome of these cells with distinct NF1 genotypes and test their potential engraftment/tumor formation capacity, and (3) to 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. Narritive >

The main goal of this project was to 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. Narritive >

The primary objective of this project is to 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. Narritive >

Dr. Ratner and her team hypothesize that Stat3 inhibition using a Stat3 Antisense RNA will prevent tumor formation.  Already, 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 neurofibroma formation.  The impact of this project could allow for the rapid translation of early intervention to human patients. Narritive >

This project aimed to identify molecular pathways that mediate rapid neurofibroma growth and/or response to therapy, using gene expression analysis of mouse neurofibromas followed by validation. Narritive >

The overall goals of this research are to : 1) Establish the durability of the effect of the combination of BRD4i + MEKi and also identify potential biomarkers, and 2) to determine whether EZH2 inhibition is an effective therapeutic approach.  The studies are highly significant because they will establish the durability of the BRD4/MEK combination enabling its advancement to the clinic, and help establish another target (EZH2) as a viable therapeutic approach.

This project aimed to 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 preclinical and clinical trials. Narritive >

This project aimed to: (1) assess GCPII as a clinical pathologic marker to distinguish benign neurofibromas from malignant MPNSTs; (2) complete GCPII inhibitor pharmacokinetics and pharmacodynamics in Nf1flox/flox; Dhh-Cre mice; (3) evaluate effect of daily administration of a GCPII inhibitor on tumor progression in Nf1flox/flox; Dhh-Cre mice; and (4) assess effect of GCPII genetic knock out on neurofibroma tumor development in Nf1flox/flox; Dhh-Cre mice. Narritive >

The goal is to screen/validate 2 drug compound combinations; Rapamycin & Ganetespib and Selumetinib & Panobinostat, in our primary Nf1-/- Schwann cells isolated from embryos derived from our Nf1+/- mice.

The goals of project are to improve the quality of life of NF1 patients through the identification of a biomarker to locate and evaluate cNF and through the development of a laser therapy solution.  Narritive >

Our overall goal is to determine how these 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. 

The goals of this are to demonstrate the concept of “adaptive resistance” and describe the adaptation of the signaling network to inhibition of RAS effector pathways in NF1-associated cancer.

This proposal is formally testing the hypothesis that both rare and common germline variants in Ras pathway genes may contribute to OPG risk. To achieve this, a population-based case-control study, nested within the California Birth Cohort, has been developed.  Narritive >

The proposal is to study the effect of ERK dependence on cellular pathways important for DNA damage repair.  Narritive >

The overall goal of this proposal is to determine 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). 

The goal is to study to 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. 

The goal of this project is to produce the most reliable, valid, and feasible measures of pain intensity and pain interference, as end-points in clinical trials or intervention studies. Narritive >

The goal of this project is to establish that interventions to NF1-associated pNFs improve/benefit a patient’s QoL, in addition to clinical status. The study was designed to develop a patient-based measure that determines the impact of plexiforms on need fulfilment in affected individuals. Narritive >

The goal is  to 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.  Narritive >

To address the need for a pNF-specific PRO measure for use in clinical trials, this project sought to 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 dysfucntion measures), 3) Evaluating psychometric properties of the pools, 4) affirming clinical differences. Narritive >

For this Project, Sage will i) maintain the content on the NF Data Portal, ii) maintain the NF Data Portal codebase and computational infrastructure, iii) provide standardized processing of genomic and transcriptomic NTAP data, and iv) conduct NTAP-reviewed NF1-related research projects using publicly available datasets.

The goal of this contract is i) to manage NTAP dunded project derived data, ii) to develop website and community engagement, and iii) to conduct NF1-related research project.

The general goal is creating a path for in vivo NF1 gene replacement to prevent cutaneous neurofibromas. 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. Narritive >

MEK inhibitor treatment does not eliminate tumors. It is not known whether this is due to incomplete effectiveness of the inhibitor in blocking hyperactive RAS, or due to the concurrent use of other kinase pathways to support tumor growth. As a proof-of-concept that gene therapy can be effective in eliminating cNF tumors, and therefore be a better treatment strategy, we will carry out gene therapy using the RAS-GAP domain of NF1. These studies will help determine whether gene therapy might be a superior treatment option for cNF. Narritive >

Dr. Chelsea Kotch received her BA from Boston University and her MD from Tufts University School of Medicine. She subsequently completed internship and residency in pediatrics at Johns Hopkins Hospital. After residency training, she completed fellowships in Pediatric Hematology-Oncology and Pediatric Neuro-Oncology at Children’s Hospital of Philadelphia. In addition, she received a Master of Science in Clinical Epidemiology and Biostatistics at the University of Pennsylvania. During her fellowship training, she developed an interest in the application of advanced epidemiologic research approaches to improve outcomes for children with neurofibromatosis-associated tumors. Dr. Kotch joined the Center for Childhood Cancer Research at Children’s Hospital of Philadelphia as an attending physician and faculty in 2021 and has further established her research focus in epidemiology and risk stratification for patients with neurofibromatosis-associated tumors. As a Francis Collins Scholar, Dr. Kotch’s research will include evaluating the comparative effectiveness of existing treatment approaches for plexiform neurofibroma utilizing advanced epidemiologic analyses and novel clinical trial emulation methods. Dr. Kotch is originally from Maine but now lives in the Philadelphia area with her husband, daughter, and golden retriever. In her free time, she enjoys camping, hiking, and reading fiction.

Dr. R. Taylor Sundby received his undergraduate education at Haverford College before completing his medical training at the Vanderbilt University School of Medicine. At Vanderbilt, Dr. Sundby worked in the laboratory of Dr. Jennifer Pietenpol studying the effect of obesity on genetic heterogeneity in triple negative breast cancer. In 2014, Dr. Sundby started his pediatrics residency at the University of California San Francisco where he was a member of the Clinical and Translational Science Pathway, working with pediatric geneticist Dr. Joseph Shieh to investigate how vastly different malignant phenotypes and accumulated mutations arise across cancers stemming from common driver mutations. Dr. Sundby then joined the combined Pediatric Hematology and Oncology Fellowship training program at the National Cancer Institute (NCI), Pediatric Oncology Branch (POB) and Johns Hopkins University in 2017 under the mentorship of Dr. Jack Shern. His research in Dr. Shern’s lab led to the CCR milestone publication “Cell-free DNA ultra-low-pass whole genome sequencing to distinguish malignant peripheral nerve sheath tumor (MPNST) from its benign precursor lesion: A cross-sectional study.” Dr. Sundby became an Assistant Research Physician in 2022. Current efforts focus on the development of circulating biomarkers for non-invasive surveillance and the study of tumor evolution. Narritive >

Dr Fertitta completed her M.D. and dermatologic residency training at Université Paris Cité School of Medicine, Paris, France. She is currently working as a dermatologist, in the Department of Dermatology at Henri-Mondor Hospital – University Paris Est Créteil (UPEC), housing the French Referral Center for Neurofibromatosis (CERENEF) and directed by Prof. Pierre Wolkenstein. She has experience in both pediatric and adult dermatology, with a special interest in neurofibromatosis type 1 (NF1). Her clinical practice and research project are focused on cutaneous neurofibromas (cNF). Within CERENEF, where around 2000 NF1 patients are followed, she has her own NF1-dedicated clinic and performs laser and surgical sessions to treat cNF. She is involved in NF1 clinical research, including the definition a core outcome set for cNF within the international REiNS consortium. She is also member of Prof. Piotr Topilko lab team and is actively involved in translational research and the design of pre-clinical studies. The team recently developed a genetically engineered NF1 mouse model which faithfully recapitulates numerous aspects of the human disease. Using this model and other state-of-the art technologies, Dr Fertitta is working on the identification of candidate drug capable of treating cNF and/or preventing their development.  Narritive >

Dr. Harish Vasudevan attended the California Institute of Technology for his undergraduate education before completing his MD/PhD training at the Icahn School of Medicine at Mount Sinai, where his thesis work focused on understanding receptor tyrosine kinase signaling during development. He is now a Holman Pathway Research Fellow in the Department of Radiation Oncology at the University of California San Francisco (UCSF) where his postdoctoral work has elucidated genomic mechanisms underlying tumor heterogeneity and oncogenic signaling in neurofibromatosis type I (NF1). As a Francis Collins Scholar, Dr. Vasudevan will focus 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 will play an active role in the multidisciplinary care of tumors arising in patients with NF1 and translate discoveries made at the laboratory to the clinic. Narritive >

Dr. Suganth Suppiah completed his medical training at Western University and is currently completing his neurosurgical residency and Ph.D. at the University of Toronto. In 2022, he will be a fellow in peripheral nerve surgery at the University of Calgary. During his graduate training, he has 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. Narritive >

Dr. Nicole Brossier obtained her MD and PhD from the University of Alabama School of Medicine, then completed her Pediatric residency and Pediatric Hematology/Oncology fellowship at Washington University in St. Louis (WUSL) as part of the Pediatric Physician Scientist Training Program. She is a pediatric neuro-oncologist who specializes in the 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 will study whether germline NF1 gene variants and maternal diet are risk factors for NF1-glioma formation. Narritive >

Dr. Green is a physician-scientist and a child psychiatrist. She gained her training as a child psychiatrist at Tel Aviv University in Israel. She has completed a postdoctoral research fellow in neuroscience at the Center for Interdisciplinary Brain Sciences Research at Stanford University. Currently, she is an Assistant Professor at the Department of Psychiatry and Behavioral Sciences at Stanford. 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. Dr. Green holds a career developmental award from NICHD studying Ras/MAPK mutations’ effects on the developing brain. These studies are directed at uncovering neural correlates associated with deficits in attention, memory, and social skills in Noonan syndrome. As an FCS scholar, Dr. Green will expand her focus to study 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. Narritive >

Dr. Steven Rhodes completed his M.D., Ph.D. and pediatric residency training at the Indiana University School of Medicine/Riley Hospital for Children. He is currently completing his fellowship training in Hematology-Oncology as part of the Pediatric Scientist Development Program (PSDP) supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the American Society of Pediatric Department Chairs (AMSPDC). He is performing his post-doctoral research in the laboratory of Dr. Wade Clapp. During his training, he has developed new mouse models that accurately mimic the progression of cutaneous and atypical neurofibroma precursor tumors to a deadly sarcoma called malignant peripheral nerve sheath tumor (MPNST); the leading cause of death in people with NF1. 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. As a pediatric oncologist, he plans to devote his clinical practice to caring for children with NF1-associated neurofibromas, MPNST, and other related tumors. Narritive >

Ina Ly, M.D., grew up in Cologne, Germany, and attended King’s College London for medical school before coming to the U.S. for a postdoctoral research fellowship in neuro-oncology at Massachusetts General Hospital (MGH), Boston, in 2010. After completing her residency in neurology at the University of Washington, Seattle, she returned to MGH and the Dana Farber Cancer Institute in 2015 for her clinical fellowship. 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 goal is to apply her knowledge of advanced MRI to identify imaging features that predict tumor growth and malignant transformation in PNSTs. She is grateful to NTAP and the NF1 community for supporting her research in order to advance our understanding of NF1 and have a positive impact for patients. Narritive >

Shruti Garg, M.B.B.S., Ph.D., is a child and adolescent psychiatrist from Mumbai, India. After finishing medical school there, she moved to the U.K. to complete her training at Oxford University and the University of Manchester. She now splits her time researching and seeing patients at the Royal Manchester Children’s Hospital. After learning about NF1 during her residency in 2008, she noticed a lack of understanding about its deep psychological, social and cognitive effects. “Much of the real-life impact of NF1 on children and families comes from learning and behavioral difficulties that aren’t well studied,” she says. “For example, many kids with NF have autism, too.” With this award, Garg plans on studying working memory in children with NF1. (Working memory helps us pay attention, follow instructions, reason through things and make decisions.) She will use 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. She is honored to be the first non-U.S. resident and the first cognitive researcher to be inducted as a FCS. Narritive >

Dr Angela Hirbe is a graduate of the Washington University M.D. Ph.D. program and completed her residency in Internal Medicine and fellowship in Oncology as part of the Physician Scientist Training Program. Dr. Hirbe has had a longstanding interest in Neurofibromatosis research and her post-doctoral work was performed in the laboratory of Dr. David Gutmann where she used 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. This work has transitioned into her own lab when she joined the faculty at Washington University. Dr. Hirbe is currently an Assistant Professor in the Division of Medical Oncology in the Department of Medicine at Washington University in St. Louis. 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. Narritive >

Dr. Ping Chi is an Assistant Member in the Human Oncology and Pathogenesis Program (HOPP), and an Assistant Attending Physician in the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York City. Dr. Chi completed clinical training in internal medicine at the Brigham and Woman’s Hospital and Medical Oncology at Memorial Sloan-Kettering Cancer Center, and a concurrent postdoctoral training in 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. Narritive >

Ashley Cannon, PhD, MS, CGC is an Assistant Professor at the University of Alabama at Birmingham in the Department of Genetics. Dr. Cannon was named to the Francis S. Collins Scholars Program in 2016. She 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. She currently provides genetic counseling for the Neurofibromatosis Clinic and Undiagnosed Diseases Program. Her current research comprises the longitudinal quantification, treatment, and psychosocial impact of cutaneous neurofibromas in individuals with NF1. She is a native of Jacksonville, Florida and loves science fiction novels and movies. Narritive >

Dr. Verena Staedtke received her MD/PhD from the Charite, Medical School of the Humboldt and Free University in Berlin (Germany). Currently an Assistant Professor and Director of pediatric Neurofibromatosis at Johns Hopkins, she completed her pediatric neurology residency and UCNS neuro-oncology fellowship at Johns Hopkins. Dr. Staedtke’s 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 is interested in immunotherapies and chemoprevention in NF1. In her free-time, Dr. Staedtke is an avid swimmer, painter and plays the piano, flute and ping-pong. Narritive >

Miriam Bornhorst, M.D., received training in Pediatrics and Hematology/Oncology through the University of Michigan followed by a Neurooncology fellowship at Children’s National Health System. She currently works as an assistant professor in Oncology and Cancer Genetics at Children’s National Health System in Washington, DC. Under the mentorship of Dr. Yuan Zhu, her primary research focus is the use of preventative therapy for optic pathway gliomas. She was awarded the Neurofibromatosis Therapeutic Acceleration Program’s Francis S. Collin’s Scholarship in 2016 and plans to use this opportunity to enhance her clinical and research knowledge in NF1. Through her work, her overall goal is early detection and management of tumors in patients with cancer predisposition syndromes. Outside of work, she spends most of her time with family, particularly enjoying outdoor activities (hiking, camping, fishing, canoeing)  Narritive >

Peter de Blank, MD, MA, MSCE was a Francis S. Collins Scholar in NF Clinical and Translational Research from 2014-2016 and continues to receive funding for ongoing projects from NTAP. He is also a current St. Baldrick’s Scholar. He graduated from the University of California, San Francisco School of Medicine in 2005, and completed a Masters of Arts in English and American Literature at Stanford University, and a Master’s of Science in Clinical Epidemiology and Biostatistics at the University of Pennsylvania. He completed residency in Pediatrics, and fellowships in Pediatric Hematology & Oncology and Pediatric Neuro-Oncology at the Children’s Hospital of Philadelphia. Dr. de Blank was a member of the faculty at Rainbow Babies & Children’s Hospital from 2012-2016 where he served as Scientific Director of the NF Clinic from 2014-2016. He joined the faculty at Cincinnati Children’s Hospital Medical Center in 2017 where is an Associate Professor in the division of Neuro-Oncology and 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. Dr. de Blank has two wonderful girls (Casey 8 years and Reed 6 years) and a wife he doesn’t deserve (Robin). When he has free time, he remembers that he liked to play Ultimate Frisbee. Narritive >

Dr. Matthew Steensma received his B.A. from Hope College in Holland, Mich., and his M.D. from Wayne State University School of Medicine in Detroit, Mich. He subsequently completed internship and residency training in the Grand Rapids Orthopaedic Surgery Residency Program. After completing residency, he trained in the laboratories of Drs. George Vande Woude and Rick Hay at VARI under an Orthopaedic Research and Education Foundation training award. Subsequently, Dr. Steensma was admitted into the prestigious fellowship program in Musculoskeletal Surgical Oncology in the Department of Surgery at Memorial Sloan Kettering Cancer Center in New York where he obtained sub-specialty training in the surgical management of musculoskeletal tumors. His fellowship in New York also provided Dr. Steensma with the opportunity to work in the laboratory of Dr. Steve Goldring, Chief Scientific Officer of the Hospital for Special Surgery (HSS) in New York. Dr. Goldring is one of the world’s leading orthopaedic researchers and has a particularly strong reputation for training leading clinician-scientists. During his training with Dr. Goldring, Dr. Steensma further developed his interests in understanding the molecular and cellular mechanisms underlying the development of bone and soft-tissue sarcomas. Dr. Steensma joined Van Andel Research Institute in 2010 as an Associate Scientific Investigator in the Center for Skeletal Disease Research. Narritive >

Dr. Anderson and co-workers will conduct a head-to-head comparison of the effectiveness of alexandrite laser vs two injectable surfactants, deoxycholate and polidocanol in the treatments of cutaneous neurofibroma (cNF). First, the doses of the two surfactants will be determined in ex-vivo cNFs, followed by optimization in adults. Thereafter, pain control without anesthetic drugs during the surfactant and laser treatments will be pursued with methods of skin cooling. Finally, adolescents will be treated with the modality(-ies) which will be demonstrate the highest safety and effectiveness in adults. Narritive >

Dr. Cagan and co-workers seek to 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. Narritive >

Dr. Gurdziel and co-workers will 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.

Dr. Lloyd and co-workers will 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. Narritive >

Dr. Milner and co-workers aim at finding an effective laser treatment for targeting and removing early-stage cNF without changing how the skin looks. Toward this goal they will: (1) Detect and monitor normally invisible tumors in NF1 patients by 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. Narritive >

Dr. Sarin and co-workers will seek to define variables and endpoints for cutaneous neurofibroma (cNF) clinical trials by: (1) Looking for potential correlation 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. Narritive >

Dr. Serra, Dr. Topilko and co-workers will investigate whether a combination of a MEK inhibitor and a cAMP-pathway activator can reduce and/or eliminate cNF tumors in in vivo pre-clinical models.

Dr. Soragni, Dr. Gosline and co-workers will seek to identify predictive biomarkers of drug response by: (1) Establishing a molecular baseline profile for patient organoid models; (2) Screening cutaneous neurofibroma 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. Narritive >

Dr. Topilko and co-workers will 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 secreted by sensory neurons promote the development of cNFs. Narritive >

Dr. Soragni and co-workers will seek to 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. Narritive >

Dr. Gutmann and co-workers will 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) Showing that sensory neurons with or without NF1 deletion have differential effects on SC which are NF1 expressing and non-expressing, and 3) Evaluating neurofibromin expression over multiple time points to determine if there are differential effects of neurofibromin on SC of various NF1 backgrounds over time. Narritive >

Dr. Serra and co-workers will explore in detail the role of heterotypic interactions between SC and fibroblasts on cNF pathogenesis.  They will 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. Narritive >

Dr. Lee and co-workers will seek to understand 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). Narritive >

Drs. Peltonen and co-workers will 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. Narritive >

Dr. Le and co-workers will utilize their 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. Narritive >

Dr. Wallace and co-workers will investigate the genetic factors underlying the pathogenesis of cNFs with respect to: 1) Creation of semi-immortalized SC of various NF1 backgrounds (NF +/- vs. NF -/-) from heterogenous human cNFs, 2) Conduct of single cell authentication and exome RNA sequencing in the semi-immortalized Schwann cell lines  and analysis to compare to results previously obtained from semi-immortalized SC from cutaneous neurofibromas, and 3) Evaluating 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. Narritive >

The team led by Dr. Topilko will seek to utilize their 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. Narritive >

Dr. Mattingly and co-workers will 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. Narritive >

The goal of this study is to more fully evaluate the efficacy and safety of selumetinib in patients with NF1 and PN during phase 2 expansion.

The goal of this study is to more fully evaluate the efficacy and safety of selumetinib in patients with NF1 and PN during phase 2 expansion.

Using patient-derived cells from cutaneous neurofibromas (cNFs), Dr. Serra explored the degree of genomic, molecular and cellular variation within regions taken from individual cNFs in order to better understand the variability within these tumors. He also interrogated the expression profile of cell cultures in isolation and in co-culture conditions in order to authenticate and characterize NF1+/- and NF1-/- induced pluripotent stem cells (iPSCs) to allow exploration of the functional status of the NF1 gene on biologic properties of the cells. The primary goals of their proposal were to: [1] explore genomic, molecular and cellular variation within a single cNF; [2] investigate the effects of co-culture on cell behavior in NF1-/- Schwann cells and NF1+/- fibroblast cells; and [3] create and characterize iPSCs from human tumors to investigate the influence of the NF1 gene status on cell behavior. Narritive >

Dr. Reilly and her team 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. Simultaneously, they proposed to design a rig of microcylinders for Schwann cell attachment to mimic radial growth of cNFs around axons. They then compared the growth characteristics of the MAPTrix ECM in 2D, 3D and the guitar rig. The goals of this project were to: [1] establish the optimal conditions to encourage maintenance in culture over long passages; [2] investigate the factors in the extracellular matrix that NF1 null Schwann cells are most dependent on; and [3] investigate the physical structures that Schwann cells prefer for growth. Narritive >

Dr. Wallace and her team generated three (semi)-immortalized NF1 null Schwann cell culture models derived from human tissue. They fully characterized these cell lines and generated additional lines to represent the diversity of cNF and to include control Schwann cell cultures. The primary goals of her proposal were to [1] complete the creation and characterization of at least 5 independent cNF (semi)immortalized Schwann cell lines from human cNF; [2] fully characterize the cell lines and identify phenotypes that recapitulate the original tumor tissue; and [3] scale selected cell culture models for assays for high-throughput screening. Narritive >

Dr. Parada and his team 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. They attempted to optimize the growth conditions for these cells and expand the cells to allow for HTS. The goals of this project were to: [1] generate and validate a physiologically-relevant cell culture model of cNF, derived from genetically engineered mouse tissue; [2] optimize growth conditions for the culture model; and [3] expand the cells to allow high throughput chemical and siRNA screens, with the long term goal of conducting these screens. Narritive >

Dr. Mattingly’s laboratory applied their expertise in co-culture of breast ductal carcinoma to develop co-culture conditions for patient-derived tumor-associated cells. They executed this in collaboration with Dr. Wallace who has several NF1 null and heterozygous cells including Schwann cells, fibroblasts endothelial cells and macrophages. He also collaborated with Dr. Reilly for the development of optimal conditions for co-culture. The goals of this project were to: [1] optimize 3D co-culture conditions for cNF inclusive of the cell type found in cNF for use as confirmatory/secondary drug screens. Narritive >

Dr. Mattingly’s laboratory applied their expertise in co-culture to prove that cells grown in 3D matrices, as compared to those growing in 2D (on plastic) exhibit drug sensitivities that serve as better clinical predictors. They will performed confirmatory and secondary assays in collaboration with NCATS. Narritive >