Abstract IA33: Development of effective therapies for neurofibromatosis type 1 and other pediatric RAS-driven tumors

Abstract

Abstract The RAS pathway is critical for cell survival and development. More than 20% of all adult cancers and many of the most aggressive pediatric cancers are driven by sporadic mutations of the RAS family of genes. In spite of substantial efforts by academia and the pharmaceutical industry, no effective therapies targeting RAS-mutated cancers have been identified to date. RASopathies are genetic disorders characterized by germline mutations in RAS pathway genes. These syndromes, such as neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome, and Costello syndrome (CS), have a widely variable incidence (1:1000 NS -1:300,000 CS), are usually first diagnosed in children, and exhibit a wide variety of manifestations including an increased risk of development of pediatric cancers such as sarcomas, leukemias, and CNS tumors (up to 42-fold increased risk compared to the general population). No approved medical therapies exist for RASopathies. Through the conduct of a longitudinal natural history study, preclinical studies in collaboration with extramural investigators, and early-phase trials, the NCI Pediatric Oncology Branch recently identified the MEK inhibitor selumetinib as the first active therapy for debilitating peripheral nerve sheath tumors called plexiform neurofibromas (PN) in NF1. The POB has identified and clinically characterized atypical neurofibromas (ANF) in NF1 as precursors to aggressive sarcomas called malignant peripheral nerve sheath tumors (MPNST). This has allowed for the development of targeted therapies and prevention strategies for these tumors. This example raises the possibility of developing effective therapies for manifestations of other RASopathies. Recent comprehensive molecular, epigenetic, and genomic studies have demonstrated the mechanisms of RAS pathway activation in several pediatric malignancies including rhabdomyosarcoma, relapsed neuroblastoma, gliomas, and leukemias. These studies will enable the development of clinical trials targeting these tumors more effectively. Citation Format: Brigitte Widemann. Development of effective therapies for neurofibromatosis type 1 and other pediatric RAS-driven tumors [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA33.