Advancing RAS and RASopathy Therapies

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

The specific aims of the ART Program are 1) To develop a RASopathy natural history study and clinic at the NIH Clinical Center with the goal to study RASopathy manifestations and develop outcome measures for interventional trials 2) To harness a "genotype-first" approach to maximize characterization of previously described RASopathies and potentially identify new ones and 3) To develop and use relevant pre-clinical disease models to evaluate the efficacy of RAS/MAPK targeted agents with goal for rational translation to the clinic. The progress on our aims is described below. Specific Aim 1 Accomplishments: In February 2019, we assembled a multidisciplinary group of RASopathy experts, including care providers, basic scientists, and representatives from the patient advocacy group RASopathiesNet, for an "ART Initiation" meeting. The goal of the meeting was to define the RASopathies and RASopathy-associated genes for the purposes of ART, identify the available tools for translational research in the RASopathies and describe the proposed RASopathy natural history study (Gross AM et al, Am J Med Genet A, 2020). At the conclusion of the meeting, we drafted what became the Clinical, Genetic, and Epidemiologic Study of Children and Adults with RASopathies (NCT04888936), which opened for enrollment in July 2021. The objectives of this prospective longitudinal cohort study are to determine the incidence of malignancy in patients with RASopathies and determine the underlying differences in those who develop tumors as compared to those who do not, in order to inform cancer screening recommendations. In addition, this study will provide a better understanding of non-tumor RASopathy manifestations and allow for development of outcome measures for interventional trials. As of December 2024, a total of 109 participants have enrolled in the Field cohort, including 81 carriers and 28 unaffected family members. In addition, 16 participants have completed evaluations at the NIH Clinical Center. Interim results from this Natural History study have been presented including at the 8th International RASopathies Symposium (July 2023). With the initiation of the RASopathy natural history study came a recognition that parents of children with RASopathies are at increased risk for stress. Members of the POB Health Psychology and Neurobehavioral Research Group launched a pilot study for these parents investigating the feasibility and acceptability of a remote Acceptance and Commitment Therapy (ACT) intervention. This remote 8-week pilot intervention was found to be feasible and acceptable, and preliminary results suggest that the intervention may provide clinically meaningful effects (Little P et al, Clinical Practice in Pediatric Psychology, 2024). The study now continues as a phase III randomized controlled trial. Specific Aim 2 Accomplishments: To date, germline RASopathy variants have been obtained from adult participants in UK Biobank (n= 469,802), Geisinger MyCode (n=167,050) and Mount Sinai BioMe (n=30,470). This study is the first genomic ascertainment of non-NF1 RASopathy prevalence, penetrance, cancer phenotype and survival in three population-scale biobanks. In both Geisinger and UKBB there was no significant increase in cancer incidence in Noonan and CFC syndromes. In the UKBB cohort but not the Geisinger cohort, Legius syndrome had significantly increased cancer incidence compared to controls, which has not previously been reported (Kim J et al, medRxiv, 2024). In addition to this prospective work, our team has completed several systematic reviews with pooled case analysis that evaluate the risk of cancer development in patients with RASopathies as a whole (Ney G et al, Am J Med Genet C, 2022), Costello syndrome (Astiazaran-Symonds E et al, Br J Cancer, 2023), Mosaic RASopathies (Windrich J et al, Clinical Cancer Research, 2024), and CFC (submitted). The data from these papers contributed to recommendations on cancer screening surveillance in patients with RASopathies which included several ART team members as co-authors (Perrino MR et al, Clinical Cancer Research, 2024). Specific Aim 3 Accomplishments: The pre-clinical aspect of ART began in 2021. In collaboration with the Center for Advanced Preclinical Research (CAPR), the Yohe group established a colony of the HrasG12S/+ mouse model of Costello syndrome and are currently testing potential therapeutics in this model. This work has been presented in abstract form at several international meetings such as the 8th International RASopathies Symposium (July 2023) and the 5th RAS Initiative Symposium (October 2024). In addition, we have established a multi-disciplinary approach for the functional characterization of novel germline RAS/MAPK variants identified by by both the public health genomics and longitudinal cohort studies. We assess impact of RASopathy-associated variants on the enzymatic activities of RAS/MAPK proteins using biochemical assays with purified proteins. Mammalian cell systems are used to study the effect of RASopathy variants on proliferation, differentiation, and cell signaling. The impact of RAS variant expression on zebrafish development including early convergence and extension (CE) at the gastrulation stage is determined in collaboration with Dr. Christine Kettenhoffen in the LCDS Zebrafish core facility, providing information regarding the impact of the RASopathy variants in the context of an intact model organism. To date, we have evaluated 12 novel HRAS variants of uncertain significance (VUS).