RESUMEN
RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.
Asunto(s)
Síndrome de Costello , Síndrome de Noonan , Síndrome de Costello/genética , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Síndrome de Noonan/genética , Transducción de Señal , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
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.
Asunto(s)
Síndrome de Costello/terapia , Displasia Ectodérmica/terapia , Insuficiencia de Crecimiento/terapia , Cardiopatías Congénitas/terapia , Terapia Molecular Dirigida , Mutación , Neurofibromatosis 1/terapia , Síndrome de Noonan/terapia , Proteínas ras/antagonistas & inhibidores , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Síndrome de Costello/genética , Síndrome de Costello/patología , Displasia Ectodérmica/genética , Displasia Ectodérmica/patología , Facies , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/patología , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Humanos , Colaboración Intersectorial , National Cancer Institute (U.S.) , Neurofibromatosis 1/genética , Neurofibromatosis 1/patología , Síndrome de Noonan/genética , Síndrome de Noonan/patología , Informe de Investigación , Transducción de Señal , Estados Unidos , Proteínas ras/genéticaRESUMEN
The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion.
Asunto(s)
Enfermedades Genéticas Congénitas/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Proteínas ras/genética , Enfermedades Genéticas Congénitas/patología , Mutación de Línea Germinal/genética , Humanos , Transducción de Señal/genéticaRESUMEN
This report summarizes and highlights the fifth International RASopathies Symposium: When Development and Cancer Intersect, held in Orlando, Florida in July 2017. The RASopathies comprise a recognizable pattern of malformation syndromes that are caused by germ line mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. Because of their common underlying pathogenetic etiology, there is significant overlap in their phenotypic features, which includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, gastrointestinal and ocular abnormalities, neurological and neurocognitive issues, and a predisposition to cancer. The RAS pathway is a well-known oncogenic pathway that is commonly found to be activated in somatic malignancies. As in somatic cancers, the RASopathies can be caused by various pathogenetic mechanisms that ultimately impact or alter the normal function and regulation of the MAPK pathway. As such, the RASopathies represent an excellent model of study to explore the intersection of the effects of dysregulation and its consequence in both development and oncogenesis.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas ras/genética , Animales , Regulación de la Expresión Génica , Estudios de Asociación Genética/métodos , Desarrollo Humano , Humanos , Modelos Biológicos , Terapia Molecular Dirigida , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Organogénesis/genética , Transducción de Señal , Síndrome , Proteínas ras/metabolismoRESUMEN
The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation-arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field. © 2016 Wiley Periodicals, Inc.
