Targeting RAS in Pediatric Cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

This project will be a major focus of the lab moving forward. We have initiated several subprojects with respect to this project; the aims and accomplishments in these subprojects are listed below: A project to identify synergistic drug combinations in RAS mutated neuroblastoma was funded by NCATS, which identified a novel combination of a MEK inhibitor and a cereblon modulator. Work has begun to validate the synergy and establish a mechanism (collaboration with Carol Thiele and Craig Thomas) A project to evaluate a combination of romidepsin and the dual BRD4/PI3K inhibitor, SF2523, in RAS-driven pediatric cancers was funded by CAPR and work has begun on this project. The first aim of the project, evaluating PK after different modes of administration of romidepsin, has been completed (collaboration with Rob Robey). The second aim of this project, evaluation of the efficacy of the combination in RMS, revealed disappointing efficacy of the combination in vivo. Evaluating the efficacy of the combination of a MEK inhibitor and pan-RAF inhibitor in RMS (collaboration with Angelina Vaseva). This work led to a collaborative manuscript that is in resubmission and a concept that was approved by ComboMATCH for clinical translation. Evaluating the efficacy of the combination of a MEK inhibitor and a BCL-XL inhibitor in RMS (collaboration with Ben Braun). Evaluating the combination of a MEK inhibitor and a SHP2 inhibitor in pediatric cancer (collaboration with Meredith Irwin and Christine Pratilas). I will serve as vice-chair of the APEC1621M arm of the CTEP-COG Pediatric MATCH trial, which will evaluate the efficacy of tipifarnib in HRAS-mutant pediatric cancers. This protocol has so far enrolled 3 participants. In addition, I am collaborating with Christine Pratilas to evaluate tipifarnib in HRAS mutated RMS preclinically. I am collaborating with Rob Kortum to evaluate combinations of tipifarnib in RMS and NB. Disappointing efficacy of a combination of tipifarnib and trametinib has been observed in RMS. We have begun to evaluate the efficacy of KRAS G12C inhibitors in neuroblastoma (ARS-1620, AMG 510, AZD1569, MRTX849). Interestingly, in collaboration with Dr. Kent Rossman, we have been able to show efficacy of these inhibitors in cells with HRAS and NRAS G12C. MCRADA in place to evaluate KRAS antisense oligonucleotide in pediatric cancers (AZD4785, now Ionis). We have a new MCRADA with Revolution Medicines to evaluate SHP2 inhibitors in RMS and RASopathies. Finally, we will also evaluate a novel switch I/II pocket binder BI 2852. We have also recently started a collaboration with Dr. Michael Sargen in DCEG to study the natural history of pediatric melanoma, particularly that arising in large congenital nevi (NRAS driven).