Advancing RAS/RASopathy therapies: An NCI‐sponsored intramural and extramural collaboration for the study of RASopathies |
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| Authors: | Andrea M. Gross Megan Frone Karen W. Gripp Bruce D. Gelb Lisa Schoyer Lisa Schill Beth Stronach Leslie G. Biesecker Dominic Esposito Edjay Ralph Hernandez Eric Legius Mignon L. Loh Staci Martin Deborah K. Morrison Katherine A. Rauen Pamela L. Wolters Dina Zand Frank McCormick Sharon A. Savage Douglas R. Stewart Brigitte C. Widemann Marielle E. Yohe |
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| Affiliation: | 1. Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland;2. Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland;3. Department of Genetics, Division of Pediatrics, Al duPont Hospital for Children, Wilmington, Delaware;4. Department of Pediatrics, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York;5. Department of Genetics and Genomic Sciences, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York;6. RASopathies Network, Altadena, California;7. Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland;8. NCI RAS Initiative, Frederick National Laboratory for Cancer Research, Frederick, Maryland;9. Laboratory for Neurofibromatosis Research, Department of Human Genetics, KU Leuven University Hospital, Leuven, Belgium;10. Department of Pediatrics, Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California;11. Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, Maryland;12. Department of Pediatrics, Division of Genomic Medicine, University of California Davis, Sacramento, California;13. Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland;14. https://orcid.org/0000-0001-5356-9426;15. Marielle E. Yohe, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD. |
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| Abstract: | RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1‐related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non‐NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates. |
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| Keywords: | cardiofaciocutaneous syndrome Costello syndrome Noonan syndrome Ras/MAP kinase pathway RASopathies |
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