Cutaneous Neurofibromas (cNFs) Symposiums And Research Initiatives
$11.5M in grants for cNF research in 2020
Over $20M in funding for cNF research since inception
Symposiums & Research Initiatives overview
The cNF Symposium and Research Initiative supports identifying and developing effective therapies, and ultimately cures, for NF1-associated cNFs. The symposium strategy provides a major mechanism to accelerate the process of reflection, recruitment and research enablement.
NTAP launched the first cNF scientific initiative in 2016, when it held the 2016 Cutaneous Neurofibromas Summit [details below]. This was followed by symposiums in 2018 and 2022, respectively.
Symposiums & Research Initiatives methodology
We bring the best thinkers from around the world to our NTAP Symposiums and in order to use their time effectivly – and get to the best answers possible – we follow the following process:
- Identify core questions in a field
- Recruit thought leaders from inside and outside of the field
- Form diverse teams to research and address specific questions
- Teams teach each other at in-person think tank
- Core questions and research priorities are identified and serve as the basis
of request for solicited proposals and evaluating open proposal applications.
Symposium & Research Initiatives 2018-2022 outcomes
- Six manuscripts to be published in Journal of Investigative Dermatology, July 2023
- Growth in cutaneous neurofibroma research landscape
- 2018: 15 applications, 9 funded applications, 9 publications
- 2022: 17 applications, 9 funded applications, 3 each in clinical, discovery and translational science projects
The 2022 Symposium and Research Initiative: Overview
- 25 participants with diverse experiences and expertise pertinent to cNF
- 3 days of analysis, collaboration and brainstorming
- Disciplined review and identification of gaps and opportunities to advance cNF research
- 5 priority areas of research identified
The 2022 Symposium and Research Initiative: 5 priority cNF research areas identified
A key outcome of the the 2022 Symposium and Research Initiative was the identification of five priority areas for advancing cNF research. NTAP then funded research in these five areas through the Biology and Therapeutic Development for Cutaneous Neurofibromas Initiative.
Although the application window for the solicited proposals is now closed, proposals that advance work in any of these priority areas are welcomed on a rolling basis through the open proposals program.
- 1. Investigate the processes underlying the stages of cNF initiation, progression, maintenance and senescence in general via the following specific topic areas:
- a. Integrate multi-omic approaches such as single cell (RNA, DNA, etc.); epigenetics (e.g. ATAC seq); phosphoproteomics; metabolomics; temporal-spatial assessment strategies and cell-cell signaling analyses in human and preclinical cNF samples.
- b. Validate existing preclinical models and explore novel models (including co-cultures, assembloids, organoids) that predict human cNF behavior, accounting for age, sex, ethnicity and race.
- Including clinicopathologic studies across humans and preclinical systems (in vitro and in vivo models).
- c. Assess tumor microenvironment including neuronal components that contribute to cNF pathogenesis at all stages of cNF development (initiation, progression, maintenance and senescence).
- d. Investigate the NF1 gene (or other genes that effect NF1 function), neurofibromin structure and function, and cNF biology, including non-RAS pathway functions as specifically related to cNF initiation, progression, maintenance or senescence.
- e. Investigate the contributions of paracrine or autocrine factors, cytokines, chemokines, collagens, hormones and other proteins to cNF initiation, progression, maintenance or senescence.
- 2. Identify and validate therapeutic candidates across the various stages and expressions of cNF in preclinical or clinical systems, including strategies focused on prevention of cNF and identifying candidate therapy-matched biomarkers.
- 3. Identify or validate non-invasive approaches in humans and preclinical systems for detection and assessment of change (growth or response) of cNF.
- 4. Define or validate key variables (i.e. patient or tumor specific characteristics) and endpoints for cNF clinical trials, including but not limited to:
- a. Develop reliable and sensitive metrics for assessment of cNF appearance
- b. Identify and validate biomarkers of treatment response or toxicity, including but not limited to circulating and tumor-specific markers and patient-specific prognostic markers of cNF course.
- 5. Develop the infrastructure for patient-driven engagement programs to enable registries and rapid enrollment into clinical trials for cNF.
The 2022 Symposium and Research Initiative: Funding outcome
NTAP established the The Biology and Therapeutic Development for Cutaneous Neurofibromas Initiative as a follow on initiative to the priority areas identified at the 2022 symposium.
Nine projects were funded in 2022 generating some of the most critical data needed for cNF therapeutic advancement. Details about the 2022 cNF Symposium outcomes can be found below:
BTD for CUTANEOUS NEUROFIBROMAS INITIATIVE PROJECTS
“Novel Treatments for Cutaneous Neurofibroma”
- Rox Anderson, M.D. (Massachusetts General Hospital, Boston, MA)
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.
“A Whole Animal Approach For Developing A Novel cNF Therapeutic Lead”
Ross Cagan, Ph.D. (Medical Research Council, Glasgow, Scotland)
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.
“Is RasL11A a mechanism for cutaneous neurofibromas regression?”
Katherine Gurdziel, Ph.D. (Wayne State University, Detroit, MI, USA)
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.
“New targets for the treatment of cutaneous neurofibromas”
Alison Lloyd, Ph.D. (University College of London, London, United Kingdom)
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.
“Optical Detection of Nascent cNF and Development of a Laser Treatment Strategy”
Thomas Milner, Ph.D. (The Regents of the University of California (Irvine), Irvine, CA, USA)
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.
“Investigating the clinical impact of cutaneous neurofibromas in a large clinical and photographic database”
Kavita Sarin, M.D., Ph.D. (The Board of Trustees of the Leland Stanford Junior University, Redwood City, CA, USA)
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.
“Combining the inhibition of the Ras/MAPK pathway and the activation of the cAMP/PKA pathway as a therapeutic strategy for cutaneous neurofibroma”
Eduard Serra-Arenas, Ph.D. (Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Spain); Piotr Topilko (Mondor Institute for Biomedical Research, Créteil, France)
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.
“Leveraging patient-derived cutaneous neurofibroma organoid models to identify biomarkers of drug response”
Alice Soragni, Ph.D. (The Regents of the University of California, Los Angeles, USA); Sara Gosline, Ph.D. (Columbia University, New York, NY, USA)
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.
“Exploring the role of cutaneous innervation in the initiation and development of cNFs in neurofibromatosis type 1”
Piotr Topilko, Ph.D. (Mondor Institute for Biomedical Research, Créteil, France)
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.
However, *investigators and inventors from all scientific and clinical backgrounds, around the world, who have research proposals relevant to the five priority areas identified above are invited to submit a proposal under the Open Proposals Program, which accepts applications on a rolling basis. *
The formal applications window for new proposals under the Biology and Therapeutic Development for Cutaneous Neurofibromas Initiative closed on August 5, 2022 for Letter of Intent and on September 2, 2022 for full application.
You may review the full RFA for the 2022 Biology and Therapeutic Development for Cutaneous Neurofibroma announcement for details and application guidelines and submit your research ideas for funding under the Open Proposals program instead.
Learn more about how to submit a proposal under the Open Proposal program.
2016 cNF Symposium & Research Initiative
In 2016 NTAP assembled a team of experts from various disciplines and backgrounds to deeply investigate questions pertinent to cNF. The teams met monthly to review published and unpublished materials, and created summaries about the material known and unknown that may influence therapeutic development for cNF. Teams prioritized questions and organized supporting data, which was presented to the entire body of experts by each team at a research summit. From these efforts, the first cNF RFA was announced in 2017 and five manuscripts setting the international cNF research agenda were published. Ten projects were funded in 2018 generating some of the most critical data needed for cNF therapeutic advancement. Details about the 2016 cNF Summit outcomes can be found below.
The first ever cNF scientific initiative
- Launched in 2016
- 17 thought leaders reviewed existing data and identified the most urgent needs for cNF research and clinical therapeutic development
- cNF priority areas identified and research ideas proposed
- 5 manuscripts produced
- 10 ten new scientific projects created to advanced NF1 cNF understanding
NTAP cutaneous neurofibroma summit scientific partners
The persons listed below (alphabetically) were presenters at the summit, and are vested scientific partners with NTAP in advancing our efforts in targeting cutaneous neurofibroma. A core value of NTAP is collaboration, and this group will work with us to seek partners to help us in our shared cause – to accelerate the development of medicines for patients with cutaneous neurofibroma.
- Richard ‘Rox’ Anderson, MD (Harvard, Massachusetts General Hospital)
- Jaishri Blakeley, MD (NTAP, Johns Hopkins)
- Isaac Brownell, MD, PhD (National Cancer Institute)
- Denise Casey, MD (Food and Drug Administration)
- Kurt Jarnagin, PhD (Anacor/Pfizer)
- Hon-Sum Ko, MD (Food and Drug Administration)
- Bruce Korf, MD, PhD (U. Alabama)
- Robert Lavker, PhD (Northwestern)
- Lu Le MD, PhD (U. Texas, Southwestern)
- James Lee, MD (Roivant Pharmaceuticals)
- Eric Legius, MD, PhD (U. Leuven)
- Scott Plotkin, MD, PhD (Harvard, Massachusetts General Hospital)
- Vincent ‘Vic’ Riccardi, MD, MBA (The NF Institute)
- Sharad K. Verma, PhD (NTAP, Johns Hopkins)
- Hubert Weinberg, MD (Private Practice, and Mt. Sinai)
- Brigitte Widemann, MD (National Cancer Institute)
- Pierre Wolkenstein, MD, PhD (Paris Est University)
Cutaneous Neurofibroma Initiative Projects (initiated 2018)
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. 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 >
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 >
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. 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 >
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 >
The Institute for Health Science Research Germans Trias i Pujol (IGTP) 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.
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 >
Cutaneous Neurofibroma Supplement Paper summaries
The Clinical Definition of cNF
Since characteristics of cNF and other neurofibromas can overlap, there has been uncertainty about how to define and classify cNF. Various classification schemes have been proposed, but the lack of consensus has hindered consistent communication among clinicians and scientists, slowing progress on the development of new therapeutics. In the second paper of the supplement, titled ‘Cutaneous Neurofibromas: Current Clinical and Pathologic Issues,’ these challenges are discussed. The paper presents the existing classification schemes for the various forms of neurofibromas and the learnings from two multidisciplinary meetings. The experts in these meetings reviewed the core features of cNF (including clinical and histological features, and data about effects of cNF on quality of life) and they propose necessary elements for a modern classification scheme for cNF. Taking into consideration the learnings from previous efforts, an initiative is now underway to create a commonly accepted classification scheme validated in a prospective study with blinded review by dermatopathologists, neuropathologists and NF1 clinicians that accurately describes each tumor type by its clinical classification, clinical appearance, pathological, and molecular and histological features. By having such a classification scheme in place, researchers, clinicians, drug makers, and regulators will be able to communicate more consistently, thereby facilitating research and discovery aimed at developing tumor-specific management strategies.
The Biology of cNF
Summit participants agreed that the current limited knowledge of the underlying mechanistic, structural, and genetic factors responsible for the formation of cNF represents a major hurdle to understanding the progress of the disease and ultimately to being able to develop effective treatments. To identify knowledge gaps and define future research priorities, the authors undertook a comprehensive examination of published (and unpublished) results from which five key areas of research priority were identified. As described in the third paper of the supplement, titled ‘The Biology of Cutaneous Neurofibromas,’ these are: (1) identifying the human cells of origin for cNF and understanding how these cells influence and drive cNF initiation and progress, (2) understanding how both nerve and tumor microenvironment contribute to cNF development, (3) identifying and elucidating the specific genetic and molecular factors that underlie cNF initiation and progression, including factors that contribute to tumor size and number, (4) generating preclinical model systems to elucidate disease biology and enable preclinical therapeutic testing and (5) understanding how age and sex hormones influence tumor growth. These research topics provided the basis for a first request for applications (RFA) sponsored by NTAP in 2017, from which nine projects were launched. These coordinated projects are a critical early step towards answering key questions that will facilitate the development of therapeutics for these tumors.
Current clinical management of cNF involves surveillance or some form of procedure-based treatment, but lacks a therapeutic (drug-based) approach. To overcome barriers to new treatment development and focus resources on options most likely to succeed, a working group of experts reviewed existing methods, outcomes, patient characteristics, and drug trials for cNF. Insights into current procedural approaches, endpoints applied to assess biologic effect and clinical benefit, and specific factors to consider when developing a drug-based therapy are described in the fourth paper of the supplement, titled ‘Considerations for Development of Therapies for Cutaneous Neurofibromas.’ A key finding is that, while multiple procedures are available for the removal of cNF and each provides treatment options for patients, there were several limitations to the trials that evaluated these approaches. These included a lack of detailed enrollment criteria, distinction among the diﬀerent types of cNF evaluated, comparisons of treated versus untreated areas, duration of follow-up, and standardized endpoints. Additional, unaddressed challenges include scarring, pain, risk of infection, and the cost and availability of the interventions. As such, no single approach has been identified as optimal, owing to a lack of prospective data about short- and long-term adverse events or the eﬃcacy of treatments. Beyond procedure-based techniques, there have been a few interventional drug trials for cNF, but outcomes were highly variable. As cNF is a disease of a nonfatal nature with relatively limited patient numbers, it was concluded that for any product to have a higher likelihood of acceptance, it will have to demonstrate an eﬀect that is clinically meaningful, have a safety proﬁle conducive to long-term dosing, and have a low manufacturing cost. In consideration of these factors, four speciﬁc elements were identified as being critical to incorporate into a cNF drug development path : (1) safety, (2) anatomic distribution of cNF, (3) numbers of tumors to be treated, and (4) route of administration. As the number, size, and distribution of tumors is so variable among patients, diﬀerent groups of patients will require diﬀerent drug development paths and thus provide opportunities for multiple therapeutic approaches.
Clinical Trial Design
The fifth and final paper of the supplement, titled ‘_Clinical Trial Design for Cutaneous Neurofibromas describes recommendations to consider for cNF clinical trials. The priority areas presented include: (1) assessment of existing methods for the measurement and quantification of cNF, (2) advances in technological methods and outcome tools utilized in other skin diseases that may be applicable to cNF studies, and (3) consideration of clinical factors that may influence or confound clinical trial outcomes, including sex and age. To guide clinical trial design, a sound understanding of the natural history of cNF is required. The authors report that two ongoing studies of this kind have led to some important insights, but go on to identify six areas that should be addressed in future prospective studies: (1) the rate of appearance and development of cNF in children and young adults, (2) the growth rates of new versus mature tumors, (3) the influence of hormones and other growth factors on tumors, (4) the rate of spontaneous tumor shrinkage, (5) the identification of biomarkers, and (6) an evaluation of tools used to count and measure tumors. The group agreed that all cNF clinical trials should monitor tumor size, tumor number and patient-reported outcomes to assess efficacy but it emphasized that consensus must first be reached on best methods for monitoring each type of outcome. To this end, the authors detail the tools available, including several developed for other skin diseases. In addition to studying the utility of each technology as applied to cNF, they recommend the creation of a global assessment scale to consistently capture therapeutic effects on patients’ quality of life.