New Research Tools Available in the Search for Therapies for NF1

Read the full article in Scientific Data (June 12, 2018).

Press release by Cathy Gara | published by NTAP

Plexiform neurofibromas affect up to 50 percent of people with neurofibromatosis type I (NF1), a rare disease of the nervous system for which there are no approved drug therapies.  NF1 has an incidence of 1/2600 – 1/3000 and arises from mutations in the NF1 gene whose protein, neurofibromin, is normally involved in suppressing cell division. Without enough working neurofibromin, plexiform neurofibromas can form on nerves throughout the body. These tumors often appear and grow rapidly throughout childhood. Although they are non-cancerous, their size and location can cause weakness, sensory abnormalities, deformity, and pain, and in some cases, turn malignant.

Plexiform neurofibromas involve several kinds of cells, but they are believed to arise from Schwann cells, a type of neural support cell, that are missing both copies of the NF1 gene. As with all slow-growing, benign tumors, NF1 tumor cells are hard to grow in the laboratory, limiting the ability of scientists to test potential treatments in reproducible, well-characterized model systems. In 2016, researchers at the University of Florida figured out how to continuously culture normal and NF1 patient-derived Schwann cells.

Now, a multi-institutional group of scientists from The Johns Hopkins University, the National Center for Advancing Translational Sciences (NCATS), the University of Florida, and Sage Bionetworks has created a new discovery tool. They characterized, technically optimized and made publicly available a genetically diverse set of patient-derived Schwann cells with a range of NF1 mutations allowing the efficient testing of thousands of drug-cell combinations. The cells of various NF1 backgrounds were then exposed to 1,912 cancer drugs that are in late stages of clinical development and with known protein targets to assess their ability to prevent the cells from dividing at various doses. Testing drugs in cells with various patterns of NF1 mutations allows for precision in selecting drugs that are active against the specific cells that cause the tumors, but not bystander cells.

These advances are described in the manuscript “Pharmacological and genomic profiling of neurofibromatosis type 1 plexiform neurofibroma-derived Schwann cells,” published in Scientific Dataon June 12.  The results of this work set the stage for future experiments to: (1) test effective, already-approved drugs for plexiform neurofibromas and other “benign” tumors, (2) discover new pathway interactions that drive tumor growth, and (3) show how cells with different genetic signatures react to various drug combinations.

This work was a major initiative of the Neurofibromatosis Therapy Acceleration Program (NTAP) (www.n-tap.org) a research program based at the Johns Hopkins University School of Medicine. Dr. Jaishri Blakeley, the Director of NTAP said, “the goal of this project was to create a reliable and fully characterized set of cell culture systems available to all researchers to encourage therapeutic discovery for neurofibromas and thereby fill a big gap in the research landscape.” All of the data generated has been made openly available and can be accessed through http://www.synapse.org/pnfCellCulture and other sources outlined in the paper.  In addition, the cell culture systems generated are available via the biological materials resource and standards organization, ATCC (https://www.atcc.org).

About the Neurofibromatosis Therapy Acceleration Program (NTAP)

NTAP is a philanthropy driven research organization based at the Johns Hopkins University School of Medicine focused on accelerating the development of therapeutics for NF1 tumors by fostering collaboration, promoting the open and timely sharing of results, and streamlining research models.  The Johns Hopkins University and the University of Florida are academic institutions based in Baltimore, Maryland, and Gainesville, Florida, respectively.

About Sage Bionetworks

Sage Bionetworks is a nonprofit biomedical research organization, founded in 2009, with a vision to promote innovations in personalized medicine by enabling a community-based approach to scientific inquiries and discoveries. Sage Bionetworks strives to activate patients and to incentivize scientists, funders and researchers to work in fundamentally new ways in order to shape research, accelerate access to knowledge and transform human health. It is located on the campus of the Fred Hutchinson Cancer Research Center in Seattle, and is supported through a portfolio of philanthropic donations, competitive research grants, and commercial partnerships. More information is available at www.sagebase.org.

About NCATS

NCATS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services. NCATS conducts and supports research on the science and operation of translation — the process by which interventions to improve health are developed and implemented — to allow more treatments to get to more patients more quickly. For more information about how NCATS is improving health through smarter science, visit https://ncats.nih.gov. The NIH — the United States’ medical research agency — includes 27 institutes and centers and is the primary federal agency for conducting and supporting basic, clinical and translational medical research. It investigates the causes, treatments and cures for both common and rare diseases. For more information about the NIH and its programs, visit http://www.nih.gov.