Advancing RAS/RASopathy therapies: An NCI-sponsored intramural and extramural collaboration for the study of...

Area of Science:

• Genetics and molecular biology
• Oncology
• Pediatric medicine

Background:

• RASopathies are a group of genetic disorders caused by variants in RAS pathway genes.
• These conditions, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), present diverse clinical features.
• Manifestations include congenital heart disease, failure to thrive, and elevated cancer risk.

Purpose of the Study:

• To explore the development of effective therapies and prevention strategies for non-NF1 RASopathies.
• To address tumors with somatic RAS mutations.
• To advance understanding and treatment of RAS pathway-related disorders.

Main Methods:

• Review of discussions from a February 2019 NCI initiative meeting (Advancing RAS/RASopathy Therapies - ART).
• Incorporation of international collaboration from basic and clinical researchers and patient advocates.
• Leveraging previous work on RAS pathway-targeted therapies, including clinical trials.

Main Results:

• Identification of the MEK inhibitor selumetinib as the first active therapy for NF1-related plexiform neurofibromas (PNs).
• Selumetinib received FDA breakthrough therapy designation for PN treatment.
• Demonstrated potential for RAS-targeted therapies to benefit other RASopathy manifestations.

Conclusions:

• Targeted therapies hold significant promise for managing the diverse clinical manifestations of RASopathies.
• The Advancing RAS/RASopathy Therapies (ART) initiative aims to accelerate the development of novel treatments.
• Further research and collaboration are crucial for improving outcomes in patients with RASopathies and RAS-mutated tumors.