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1.
Am J Med Genet A ; 182(4): 866-876, 2020 04.
Article in English | MEDLINE | ID: mdl-31913576

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.


Subject(s)
Costello Syndrome/therapy , Ectodermal Dysplasia/therapy , Failure to Thrive/therapy , Heart Defects, Congenital/therapy , Molecular Targeted Therapy , Mutation , Neurofibromatosis 1/therapy , Noonan Syndrome/therapy , ras Proteins/antagonists & inhibitors , Biomarkers, Tumor/antagonists & inhibitors , Biomarkers, Tumor/genetics , Costello Syndrome/genetics , Costello Syndrome/pathology , Ectodermal Dysplasia/genetics , Ectodermal Dysplasia/pathology , Facies , Failure to Thrive/genetics , Failure to Thrive/pathology , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology , Humans , Intersectoral Collaboration , National Cancer Institute (U.S.) , Neurofibromatosis 1/genetics , Neurofibromatosis 1/pathology , Noonan Syndrome/genetics , Noonan Syndrome/pathology , Research Report , Signal Transduction , United States , ras Proteins/genetics
2.
Dis Model Mech ; 15(2)2022 02 01.
Article in English | MEDLINE | ID: mdl-35178568

ABSTRACT

The RASopathies are a group of disorders caused by a germline mutation in one of the genes encoding a component of the RAS/MAPK pathway. These disorders, including neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome and Legius syndrome, among others, have overlapping clinical features due to RAS/MAPK dysfunction. Although several of the RASopathies are very rare, collectively, these disorders are relatively common. In this Review, we discuss the pathogenesis of the RASopathy-associated genetic variants and the knowledge gained about RAS/MAPK signaling that resulted from studying RASopathies. We also describe the cell and animal models of the RASopathies and explore emerging RASopathy genes. Preclinical and clinical experiences with targeted agents as therapeutics for RASopathies are also discussed. Finally, we review how the recently developed drugs targeting RAS/MAPK-driven malignancies, such as inhibitors of RAS activation, direct RAS inhibitors and RAS/MAPK pathway inhibitors, might be leveraged for patients with RASopathies.


Subject(s)
Costello Syndrome , Neurofibromatosis 1 , Noonan Syndrome , Animals , Costello Syndrome/genetics , Failure to Thrive/genetics , Humans , Neurofibromatosis 1/genetics , Noonan Syndrome/genetics , ras Proteins/genetics
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