A forum to identify priorities and advance the field of neurofibromatosis type-1 (NF1) research

Introduction to NTAP symposia
NTAP convenes leading researchers and innovators from across multiple fields and scientific backgrounds in regular symposia to establish priorities for the future NF1-related research. These symposia provide a deliberate process for assessing the state of the science, reflecting on areas of priority to advance meaningful therapeutics for pNF and cNF and creating a framework for a focused research. These invitation-only events bring together a depth and breadth of expertise that creates unparalleled opportunities for collaboration and innovative thinking about the science of NF1.

The 2022 Cutaneous Neurofibroma Symposium was held in San Diego, California. 25 participants were recruited and formed into teams that focused on specific topic areas. The teams met and shared knowledge in the months before the symposium. At the symposium, the teams spent three days presenting to one another, determining the core questions and research priorities and drafting the next NTAP request for applications. Manuscripts designed to benchmark the state of the science and areas of greatest need for investigation are often generated.

Fast facts
25 participants convened with diverse experiences and expertise pertinent to cutaneous neurofibromas (cNFs)
3 days of analysis, collaboration and brainstorming
5 priority areas of research identified
9 projects awarded totalling $6.3 million in grants
Launched studies in fly and mouse models to identify new druggable targets for cNF and markers of drug response as well as clinical trials for cNFs.

9 Funded Projects Resulting from the 2022 Cutaneous Neurofibroma Initiative

“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.