TY - JOUR
T1 - Advancing RAS/RASopathy therapies
T2 - An NCI-sponsored intramural and extramural collaboration for the study of RASopathies
AU - Gross, Andrea M.
AU - Frone, Megan
AU - Gripp, Karen W.
AU - Gelb, Bruce D.
AU - Schoyer, Lisa
AU - Schill, Lisa
AU - Stronach, Beth
AU - Biesecker, Leslie G.
AU - Esposito, Dominic
AU - Hernandez, Edjay Ralph
AU - Legius, Eric
AU - Loh, Mignon L.
AU - Martin, Staci
AU - Morrison, Deborah K.
AU - Rauen, Katherine A.
AU - Wolters, Pamela L.
AU - Zand, Dina
AU - McCormick, Frank
AU - Savage, Sharon A.
AU - Stewart, Douglas R.
AU - Widemann, Brigitte C.
AU - Yohe, Marielle E.
N1 - Publisher Copyright:
Published 2020. This article is a U.S. Government work and is in the public domain in the USA.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
KW - Costello syndrome
KW - Noonan syndrome
KW - RASopathies
KW - Ras/MAP kinase pathway
KW - cardiofaciocutaneous syndrome
UR - http://www.scopus.com/inward/record.url?scp=85078606959&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.61485
DO - 10.1002/ajmg.a.61485
M3 - Article
C2 - 31913576
AN - SCOPUS:85078606959
SN - 1552-4825
VL - 182
SP - 866
EP - 876
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 4
ER -