Advancing RAS and RASopathy Therapies

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

In FY 2019, a group of investigators from CCR and DCEG successfully competed for funding for a new NCI initiative for the RASopathies. With this funding, we assembled a multi-disciplinary group of international RASopathy experts at a project kick-off meeting in February 2019. As a result of this meeting, we have produced a longitudinal cohort study for patients with non-NF1 RASopathies that will be conducted through DCEG. This protocol was recently approved by the CIRB and is currently enrolling. Over 60 participants have enrolled in the field cohort and 1 patient has visited the clinical center to date. The goals of this trial are to prospectively study the incidence of cancer development in these patients but also to identify specific measurable endpoints that can be used for monitoring the success or failure of interventional trials. This includes the use of PROs, being spearheaded by the behavioral health core in the POB. Potential first interventional trials were identified, and appropriate industry contacts have been made, including a CRADA with Kura Oncology for the use of tipifarnib in Costello syndrome. In addition to the clinical protocol, we also have initiated several preclinical studies to evaluate the efficacy of RAS-targeting agents in RASopathies. We plan a study of tipifarnib in an HRASG12S model of Costello syndrome and a study of mirdametinib in a MEKY30C model of CFC. These studies will be conducted in collaboration with CAPR (Zoe Weaver-Ohler)and Dr. Lino Tessarollo. We have begun the process of creating new mouse models of Noonan syndrome in collaboration with Raj Chiari and Roackie Awasthi. Finally, in a population genomics effort headed by Dr. Douglas Stewart, we aim to identify new RASopathy variants and genes. This project has begun, and newly identified RAS variants will be functionally validated in the Yohe lab. This validation includes biochemical assessment with purified protein (collaboration with the Rossman lab), assessment of RAS-GTP and pERK and pAKT levels in cells (Yohe lab), assessment of cellular localization (Turbyville lab), assessment of interactions with downstream effectors (Turbyville lab), impact on myogenic differentiation (Yohe lab), impact on cell proliferation (Yohe lab), and impact on zebrafish embryo morphology (Christine Kettenhofen in the LCDS aquatics core). Novel RAF variants will be functionally characterized in the Morrison lab. Novel LZTR1 variants identified through the RASopathy population genomics effort and through collaborations with Dr. Michael Sargen (melanoma prone families) will also be assessed in the Yohe lab.