Abstract 1177: Targeting NEDD8 to uncover an exceptional responder molecular subtype in glioblastoma

Abstract

Abstract Neddylation is a post-translational mechanism that marks proteins for degradation through activity of NEDD8 Activating Enzyme (NAE). NAE blocks cullin-RING ligases from initiating proteosomal degradation of select substrates including cell cycle regulators and apoptosis modulators. MLN4924, or Pevonedistat, targets NAE and inhibits Neddylation and induces apoptosis in sensitive cells. We have discovered, in a cohort of glioblastoma PDX models, an exceptional responder to MLN4924 (GBM102). Most pertinently the effects we observe are in a PDX cultured as 3D neurospheres that more closely resemble the true tumor architecture, heterogeneity, and “stem-like” phenotype characteristic of tumor growth. We have leveraged RNAseq expression data from Cancer Cell Line Encyclopedia (CCLE) and Pevonedistat response data from The Cancer Therapeutics Response Portal (CTRP) to apply a network-based analysis to identify pathways enriched with differential dependencies between cell lines sensitive and non-sensitive to MLN4924. The analysis also identifies potential mediating genes that appear to play critical roles in such differential dependency networks. Identified differential networks and mediators provide insight for cellular mechanisms underlying drug response. Additionally, we also investigated the efficacy of MLN4924 against orthotopic glioma PDX models (GBM102 and GBM116) in vivo to validate our findings in vitro. Thus genomic characterization of patient samples may lead to the identification of a molecular signature which is associated with a subset of GBMs vulnerable to MLN4924. As the treatment options for GBM are extremely limited, this may highlight a novel alternative opportunity to treat a select fraction of patients with this aggressive disease. Citation Format: Lauren K. Hartman, Darren Finlay, Peiwen Pan, Seungchan Kim, Gil Speyer, Jeff Kiefer, Harshil Dhruv, Kristiina Vuori, Michael Berens. Targeting NEDD8 to uncover an exceptional responder molecular subtype in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1177. doi:10.1158/1538-7445.AM2017-1177